CD19 binding molecules including CD3- and CD19- bispecific t cell engagers and related methods and uses

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CD19 and CD3 bispecific binding molecules address the need for effective B cell depletion in autoimmune diseases by specifically targeting and depleting B cells, providing safe and long-term remission with reduced toxicity.

WO2026161391A2PCT designated stage Publication Date: 2026-07-30BRISTOL MYERS SQUIBB CO

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Patent Information

Authority / Receiving Office: WO · WO
Patent Type: Applications
Current Assignee / Owner: BRISTOL MYERS SQUIBB CO
Filing Date: 2026-01-20
Publication Date: 2026-07-30

AI Technical Summary

Technical Problem

Current treatments for autoimmune diseases like systemic lupus erythematosus are inadequate, lacking effective and safe methods for broad B cell depletion and immune reset, with a need for 'off-the-shelf' treatments that offer long-term remission and reduced toxicity.

Method used

Development of CD19 and CD3 bispecific binding molecules, including antibodies and antigen-binding fragments, designed to specifically target and deplete B cells, utilizing specific CD19 and CD3 binding domains with defined CDR sequences for targeted T-cell-mediated killing.

Benefits of technology

The CD19 and CD3 bispecific binding molecules provide effective and safe B cell depletion, offering potential for long-term remission and reduced immunosuppressive drug use, with lower toxicity risk.

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Abstract

The present invention provides binding molecules comprising a CD19 binding domain and / or a CD3 binding domain. In certain embodiments, the CD19 domain specifically binds to a B cell expressing CD19, and wherein the CD3 domain specifically binds to a T cell expressing CD3. Compositions, methods, and kits comprising the binding molecules are provided for treating diseases and conditions. In certain aspects, the binding molecules, compositions, methods, and kits are useful to deplete B cells.

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Description

217372000640CD19 BINDING MOLECULES INCLUDING CD3- AND CD19- BISPECIFIC T CELL ENGAGERS AND RELATED METHODS AND USES CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. provisional application No. 63 / 747,450, filed January 21, 2025, entitled “CD19 BINDING MOLECULES INCLUDING CD3- AND CD 19- BISPECIFIC T CELL ENGAGERS AND RELATED METHODS AND USES”, the contents of which are incorporated by reference in their entirety.INCORPORATION BY REFERENCE OF SEQUENCE LISTING

[0002] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 217372000640. xml created January 17, 2026, which is 329,047 bytes in size. The information in the electronic format of the Sequence Listing is incorporated by reference in its entirety.FIELD OF DISCLOSURE

[0003] This disclosure provides monospecific binding molecules that comprise a binding domain that specifically binds to CD 19 and also bispecific binding molecules that comprise a first binding domain that specifically binds to CD 19 and a second binding domain that specifically binds to CD3. The disclosure further relates to polynucleotides that encode the binding molecules, including the antibodies or bispecific antibodies. The present disclosure further relates to pharmaceutical compositions, kits, and methods and uses of such binding molecules to reduce and / or deplete B cells in a subject and for the treatment of, for example, autoimmune diseases in which specific targeting, and in some aspects T-cell-mediated killing, of cells that express CD19 is desired.BACKGROUND

[0004] Autoantibodies and immune complexes drive inflammation and tissue damage (Lou, 2022 et al. J Autoimmun.). B cells are multifunctional lymphocytes that contribute to the pathogenesis via B cell intrinsic, antibody-mediated and T cell-dependent mechanisms. Atisha-Fregoso, et al. J Clin Invest. 2021; and Rubin et al., 2019 Nature Reviews1MF-365921286217372000640Rheumatology vol 15, 303-315. Blinatumomab, a CD19 / CD3 bispecific antibody (bsAb) designed in the BiTE (bispecific T-cell engager) format, is approved by the US Food and Drug Administration for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia. Zimmerman 2024 International Immunology vol. 27, no. 1; pp. 31-37; Robinson et al., 2018 Blood. 132(5): 521–532. B cells are also drivers of pathogenesis in numerous autoimmune diseases (e.g., systemic lupus erythematosus and Sjogren’s disease) with multiple therapeutic agents targeting B cells approved, used as standard or care (SOC), or being developed for autoimmune indications. Kansal et al., 2019 Sci Transl. Med., 11, 1-13.

[0005] Systemic lupus erythematosus (SLE) is an autoimmune disease that is considered difficult to diagnose and treat because of the episodic nature of flare-ups, the involvement of multiple organ systems and variable presentation, and severity (Rahman et al., 2008 N. Engl. J. med. 358: 929-939). Autoantibodies to DNA and protein autoantigens are observed in in SLE and contribute to pathogenesis by forming immune complex deposits in various tissues (Shlomchik et al., 2009 Curr. Opin. Immunol. 21, 626–633; Sang et al., 2014 Mol. Immunol.62, 329–338).

[0006] Approaches that inactivate or deplete B cells have been pursued as therapies for different autoimmune diseases such as lupus. These approaches include, but are not limited to, B cell depletion with a monoclonal antibody against the B cell surface marker CD20 and are currently being tested in clinical trials. See Shah et al., 2020 Nature Medicine vol. 26 pp.1569-1575; Crickx et al., 2020 Kidney Int. 97(5):885-893; Mougiakakos et al., 2021 N Engl. J. Med. 385:6; Mackenson 2022 Nat Med 28, 2124–2132.

[0007] However, more effective and safe treatments are needed, including treatments that offer “off-the-shelf’ treatment for broad B cell depletion and immune reset, delivering longterm remission and tapering of immuno-suppressive drugs, with lower toxicity risk.SUMMARY

[0008] An aspect of the inventor provides a binding molecule (i.e. antibody or antigenbinding fragment) comprising an CD 19 binding domain comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:(a) the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy 2MF-365921286217372000640chain complementarity determining region 3 (CDR-H3), wherein the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; andthe VL region comprises a light chain complementarity determining region 1 (CDR-Ll), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3), wherein the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs:, 15, 122, 126, 25, 138, 144, 149, or 157, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158; or (b) the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within any one of SEQ ID NOs: 12, 32, 34, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, or 88, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within any one of SEQ ID NOs: 17, 33, 35, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, or 89.

[0009] In some embodiments, the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; andthe CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15, 122, 126, 25, 138, 144, 149, or 157, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158.

[0010] In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 33;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 35;3MF-365921286217372000640the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 44, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 45;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 46, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 48, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 49;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 50, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 51;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 52, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 53;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 55;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 57;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 59;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises a CDR-L1, a CDR-L2, a the CDR-L3 contained within SEQ ID NO: 61;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 63;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 12, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 17; or4MF-365921286217372000640the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 88, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89.

[0011] In some of any embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 120, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 121, 122, and 123, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 124, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:125, 126, and 127, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 128, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 129, 126, and 130, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 131, 132, and 133, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 134, 25, and 135, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 136, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:137, 138, and 139, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:140, 141, and 142, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 143, 144, and 145, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 146, 119, and 147,5MF-365921286217372000640respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 148, 149, and 150, respectively; the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 151, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 152, 126, and 153, respectively; or the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:131, 154, and 155, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 156, 157, and 158, respectively.

[0012] In some of any embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 44, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 45; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 46, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 47; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 48, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%,6MF-36592128621737200064092%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 49; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 50, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 51; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 52, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61; the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63; the VH region comprises an amino acid sequence that 7MF-365921286217372000640has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 17; or the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 88, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 89.

[0013] In some of any embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 32 and 33, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 34 and 35, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 44 and 45, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 46 and 47, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 48 and 49, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 50 and 51, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 52 and 53, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 54 and 55, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 56 and 57, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 58 and 59, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 60 and 61, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 62 and 63, respectively; the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 12 and 17, respectively; or the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 88 and 89, respectively.

[0014] In some of any embodiments, the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively.8MF-365921286217372000640

[0015] In some embodiments, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17. In some of any embodiments, the VH region and the VL region comprises the amino acid sequence set forth in SEQ ID NOs: 12 and 17, respectively.

[0016] In some of any embodiments, the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequences set forth in SEQ ID NOs: 118, 119, and 120, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 121, 122, 123, respectively. In some embodiments, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 88, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 89. In some of any embodiments, the VH region and the VL region comprises the sequence or are the sequence set forth in SEQ ID NOs: 88 and 89, respectively.

[0017] In some of any embodiments, the binding molecule is a full-length antibody. In some of any embodiments, the antibody is a human IgG. In some embodiments, the antibody is IgGl. In some of any embodiments, the antibody comprises a kappa light chain constant region.

[0018] In some of any embodiments, the antibody comprises:(a) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 254; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 255;(b) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 256; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%,9MF-36592128621737200064090%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 257;(c) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 258; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 259;(d) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 260; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 261;(e) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 262; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 263;(f) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 264; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 265;(g) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 266; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 267;10MF-365921286217372000640(h) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 268; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 269;(i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 270; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 271;(j) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 272; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 273;(k) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 274; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 275.

[0019] In some of any embodiments, the antibody comprises:(a) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 254; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 255;(b) a heavy chain comprising the amino acid sequence of SEQ ID NO: 256; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 257;(c) a heavy chain comprising the amino acid sequence of SEQ ID NO: 258; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 259;(d) a heavy chain comprising the amino acid sequence of SEQ ID NO: 260; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 261;11MF-365921286217372000640(e) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 263;(f) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 265;(g) a heavy chain comprising the amino acid sequence of SEQ ID NO: 266; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 267;(h) a heavy chain comprising the amino acid sequence of SEQ ID NO: 268; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 269;(i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 270; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 271;j) a heavy chain comprising the amino acid sequence of SEQ ID NO: 272; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 273; or(k) a heavy chain comprising the amino acid sequence of SEQ ID NO: 274; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 275.

[0020] In some of any embodiments, the binding molecule is an antigen-binding fragment. In some embodiments, the antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, and scFv. In some of any embodiments, the antigenbinding fragment is an scFv. In some embodiments, the scFv comprises a VH-linker-VL arrangement. In some embodiments, the scFv comprises a VL- linker- VH arrangement. In some of any embodiments, the linker is a peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 162) In some of any embodiments, the linker is a peptide linker comprising Gly4Ser (SEQ ID NO: 160). In some of any embodiments, the linker is a peptide linker comprising (Gly4Ser)2 (SEQ ID NO: 161).

[0021] In some of any embodiments, the scFv comprises:(a) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245;(b) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248;(c) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 249; or12MF-365921286217372000640(d) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 252.

[0022] In some of any embodiments, the scFv comprises: (a) the amino acid sequence of SEQ ID NO: 245; (b) the amino acid sequence of SEQ ID NO: 248; (c) the amino acid sequence of SEQ ID NO: 249; or (d) the amino acid sequence of SEQ ID NO: 252. In some of any embodiments, the scFv comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245. In some of any embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 245. In some of any embodiments, the scFv comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248. In some of any embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 248.

[0023] Provided herein is a bispecific antibody comprising (a) a first binding domain that binds CD19 and (b) a second binding domain that binds CD3, wherein: the first binding domain that binds CD 19 comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein: (a) the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; and the VL region comprises a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156; a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15, 122, 126, 25, 138, 144, 149, or 157, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158; or(b) the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within any one of SEQ ID NOs: 12, 32, 34, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, or 88, and the VL13MF-365921286217372000640region comprises a CDR-L1, a CDR-L2), and a CDR-L3 contained within any one of SEQ ID NOs: 17, 33, 35, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, or 89.

[0024] In some embodiments, in the first binding domain:the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; andthe CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15, 122, 126, 25, 138, 144, 149, or 157, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158.

[0025] In some of any embodiments, in the first binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 33;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 35;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 44, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 45;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 46, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 47;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 48, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 49;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 50, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 51;14MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 52, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 53;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 55;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 57;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 59;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 61;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 63;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 12, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 17; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 88, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 89.

[0026] In some of any embodiments, in the first binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 120, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 121, 122, and 123, respectively;15MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 124, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:125, 126, and 127, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 128, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 129, 126, and 130, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 131, 132, and 133, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 134, 25, and 135, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 136, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:137, 138, and 139, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:140, 141, and 142, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 143, 144, and 145, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 146, 119, and 147, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 148, 149, and 150, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 151, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 152, 126, and 153, respectively; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:131, 154, and 155, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 156, 157, and 158, respectively.

[0027] In some of any embodiments, in the first binding domain:16MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 44, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 45;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 46, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 47;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 48, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 49;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 50, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 51;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 52, and the VL region comprises an amino acid sequence that has at 17MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 17; or18MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 88, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 89.

[0028] In some of any embodiments, in the first binding domain:the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 32 and 33, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 34 and 35, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 44 and 45, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 46 and 47, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 48 and 49, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 50 and 51, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 52 and 53, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 54 and 55, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 56 and 57, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 58 and 59, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 60 and 61, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 62 and 63, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 12 and 17, respectively; or19MF-365921286217372000640the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 88 and 89, respectively.

[0029] In some of any embodiments, the first binding domain is an scFv. In some of any embodiments, the first binding domain is an scFv that is a disulfide- stabilized scFv. In some of any embodiments, the scFv comprises a VH-linker-VE arrangement. In some of any embodiments, the scFv comprises a VE-linker-VH arrangement. In some of any embodiments, the linker is a peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 162). In some of any embodiments, the linker is a peptide linker comprising Gly4Ser (SEQ ID NO: 160). In some of any embodiments, the linker is a peptide linker comprising (Gly4Ser)2 (SEQ ID NO: 161).

[0030] In some of any embodiments, the first binding domain comprises:(a) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245;(b) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248;(c) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 249; or(d) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 252.

[0031] In some of any embodiments, the first binding domain comprises: (a) the amino acid sequence of SEQ ID NO: 245; (b) the amino acid sequence of SEQ ID NO: 248; (c) the amino acid sequence of SEQ ID NO: 249; or (d) the amino acid sequence of SEQ ID NO: 252.

[0032] In some of any embodiments, in the first binding domain, the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively.20MF-365921286217372000640

[0033] In some of any embodiments, in the first binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17. In some of any embodiments, the VH region and the VL region comprises the amino acid sequence set forth in SEQ ID NOs: 12 and 17, respectively.

[0034] In some of any embodiments, in the first binding domain, the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 118, 119, and 120, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 121, 122, 123, respectively.

[0035] In some of any embodiments, in the first binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 88, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 89. In some of any embodiments, in the first binding domain, the VH region and the VL region comprises the sequence set forth in SEQ ID NOs: 88 and 89, respectively.

[0036] In some of any embodiments, the second binding domain that binds CD3 comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:the VH comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 198, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 276, and a heavy chain complementarity determining region 3 ( CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 200; andthe VL comprises a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 24, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 201, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth within SEQ ID NO: 277.21MF-365921286217372000640

[0037] In some of any embodiments, in the second binding domain, the VH comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 198, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 199, and a heavy chain complementarity determining region 3 ( CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 200; andthe VL comprises a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 24, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 201, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth within SEQ ID NO: 106.

[0038] In some of any embodiments, in the second binding domain, the VH region binding domain and the VL region comprise, respectively: a VH region sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein X1is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G or A or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9is Y or D; X10is Y or F, X11is I or V, X12is R or G; X13is Y or H; X14is Q or S; X15is Y or H; X16is I or L; and X17is N or D; (SEQ ID NO: 278); and a VL region sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein X1is S or G, X2is N or S; X3is K or N; and X4is Q or C (SEQ ID NO: 197).

[0039] In some of any embodiments, in the second binding domain, the VH region binding domain and the VL region comprise, respectively: a VH region sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein X1is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G or A; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9is Y or D; X10is Y or F, X11is I or V, X12is R or G; X13is Y or H; X14is Q or S; X15is Y or H; X16is I or L; and X17is N or D; (SEQ ID NO: 196); and a VL region sequence of the22MF-365921286217372000640consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein X1is S or G, X2is N or S; X3is K or N; and X4is Q or C (SEQ ID NO: 197).

[0040] In some of any embodiments, in the second binding domain:the CDR-H1 comprises the sequence set forth in any one of SEQ ID NOs: 19, 109, 202, or 203, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 20, 107, 110, 112, or 204-208, and the CDR-H3 comprises the sequence set forth in any one of SEQ ID NOs: 21, 108, 111, 113, or 209-214; andthe CDR-L1 comprises the sequence set forth in SEQ ID NOs: 24, the CDR-L2 comprises the sequence set forth in any one of SEQ ID NOs: 25, 114, 215, or 216, and the CDR-L3 comprises the sequence set forth in any one of SEQ ID NOs: 26 or 115.

[0041] In some of any embodiments, in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 37;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 27;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 68, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;23MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 70, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 72, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 73;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 74, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 78, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 80, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 82, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 84, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 86, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 159, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 195, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 41, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;24MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 64, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 65, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 66, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 67, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 69, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 71, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 75, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 76, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 77, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 79, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 81, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;25MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 83, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 85, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 87, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 90, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 91, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 92, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 93, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 94, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 95, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 96, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 97, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;26MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 98, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 99;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 100;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 101;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37.

[0042] In some of any embodiments, in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;27MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 112, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;28MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 204, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 205, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 206, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 209, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 210, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 211, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;29MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 202, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 203, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 212, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 213, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 214, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;30MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 207, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 208, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 210, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 202, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 214, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;31MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 215, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 216, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 110, 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively.

[0043] In some of any embodiments, wherein in the second binding domain:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at32MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 22, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 68, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 70, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;33MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 72, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 73;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 74, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 78, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 80, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 82, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 84, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 86, and the VL region comprises an amino acid sequence that has at 34MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 159, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 195, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 64, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 65, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 66, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;35MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 67, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 69, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 71, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 75, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 76, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 77, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 79, and the VL region comprises an amino acid sequence that has at 36MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 81, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 83, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 85, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 87, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 90, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 91, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;37MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 92, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 93, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 94, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 95, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 96, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 97, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 98, and the VL region comprises an amino acid sequence that has at 38MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 99;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 100;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 101;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37;39MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37.

[0044] In some of any embodiments, in the second binding domain:the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 40 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 42 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 22 and 27, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 68 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 70 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 72 and 73, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 74 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 78 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 80 and 39, respectively;40MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 82 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 84 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 86 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 159 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 195 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 41 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 64 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 65 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 66 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 67 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 69 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 71 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 75 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 76 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 77 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 79 and 37, respectively;41MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 81 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 83, and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 85 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 87 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 90 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 91 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 92 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 93 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 94 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 95 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 96 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 97 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 98 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 99, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 43, respectively;42MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 100, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 101, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 42 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 40 and 37, respectively.

[0045] In some of any embodiments, in the second binding domain:the VH region comprising a sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTX8X9 YX10X11GX12X13VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5is K, T, or D; X6is K, E, or S; X7is Y or D; X8is R or G; X9is Y or H; X10 is Q or S; Xu is Y or H; X12 is I or L; and X13 is N or D; (SEQ ID NO: 116); andthe VL region comprising a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLEXiGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX2SYPRTFGX3GTKVEIK, wherein Xi is N or S; X2is K or N; and X3is Q or C; (SEQ ID NO: 117).

[0046] In some of any embodiments, in the second binding domain:the VH region comprising a sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTRYY X8X9GX10X11VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5is K, T, or D; X6is K, E, or S; X7is Y or D; X8is Q or S; X9is Y or H; X10is I or L; and X11is N or D; (SEQ ID NO: 192); and the VL region comprising a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX1SYPRTFGX2GTKVEIK, wherein Xi=K or NX2=Q or C; (SEQ ID NO: 193).43MF-365921286217372000640

[0047] In some of any embodiments, in the second binding domain, the VH comprises one or more amino acid residues selected from the group consisting of: an asparagine (N) at position 31, an alanine (A) at position 55, a tyrosine (Y) at position 80, a glycine (G) at position 106, a histidine (H) at position 107, a serine (S) at position 109, a histidine (H) at position 110, a leucine (L) at position 112, and an aspartic acid (D) at position 113 or any combination thereof, wherein the numbering is relative to SEQ ID NO: 36.

[0048] In some of any embodiments, in the second binding domain, the VH comprises:(a) amino acid residues asparagine (N) at position 31, alanine (A) at position 55, and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 36;(b) alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 36; or (c) alanine (A) at position 55, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 36;

[0049] In some of any embodiments, in the second binding domain, the VL region comprises one or more amino acid residues selected from the group consisting of: a serine (S) at position 56, an asparagine (N) at position 92, and a cysteine (C) at position 100, an asparagine (N) at position 108, or any combination thereof in relation to SEQ ID NO: 37. In some of any embodiments, in the second binding domain, the VL region comprises: (a) serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 36; or (b) serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 37.

[0050] In some of any embodiments, in the second binding domain, the VH comprises one or more amino acid residues selected from the group consisting of: a glycine (G) at position 16, a glutamic acid (E) at position 16, a threonine (T) at position 58, an aspartic acid (D) at position 58, a glutamic acid (E) at position 76, a serine (S) at position 76, or any combination thereof in relation to SEQ ID NO: 36.

[0051] In some of any embodiments, the second binding domain is an antigen binding antibody fragment. In some embodiments, the second binding domain is a scFv, is a Fab, or is an Fv. In some embodiments, the second binding domain is an scFv. In some of any embodiments, the second binding domain is a Fab. In some of any embodiments, the second binding domain is an scFv that is a disulfide-stabilized scFv. In some of any embodiments, the scFv comprises a VH-linker-VL arrangement. In some of any embodiments, the scFv comprises a VL-linker-VH arrangement. In some of any embodiments, the scFv comprises a 44MF-365921286217372000640peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 162). In some of any embodiments, the linker is a peptide linker comprising Gly4Ser (SEQ ID NO: 160). In some of any embodiments, the linker is a peptide linker comprising (Gly4Ser)2 (SEQ ID NO: 161).

[0052] In some of any embodiments, in the second binding domain, the VH region comprises cysteine (C) at position 44 and the VL region comprises a cysteine (C) at position 100 in relation to SEQ ID NO: 36.

[0053] In some of any embodiments, in the second binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within any one of SEQ ID NOs: 36, 38, 40, 42, 22, 68, 70, 72, 74, 78, 80, 82, 84, 86, 159 or 195, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within any one of SEQ ID NOs: 27, 37, 39, 43, or 73. In some of any embodiments, in the second binding domain: the CDR-H1 comprises the sequence set forth in any one of SEQ ID NOs: 19, or 109, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 20, 107, 110, or 112, and the CDR-H3 comprises the sequence set forth in any one of SEQ ID NOs: 21, 108, 111, or 113; andthe CDR-L1 comprises the sequence set forth in SEQ ID NOs: 24, the CDR-L2 comprises the sequence set forth in any one of SEQ ID NOs: 25 or 114, and the CDR-L3 comprises the sequence set forth in any one of SEQ ID NOs: 26 or 115.

[0054] In some of any embodiments, in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 37;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;45MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 27;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 68, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 70, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 72, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 73;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 74, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 78, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 80, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 82, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 84, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 86, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 159, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43; or46MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 195, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39.

[0055] In some of any embodiments, in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 112, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;47MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively.

[0056] In some of any embodiments, in the second binding domain:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 22, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 68, and the VL region comprises an amino acid sequence that has at 48MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 70, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 72, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 73;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 74, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 78, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 80, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 82, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;49MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 84, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 86, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 159, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 195, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39.

[0057] In some of any embodiments, in the second binding domain:the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 40 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 42 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 22 and 27, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 68 and 39, respectively;50MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 70 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 72 and 73, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 74 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 78 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 80 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 82 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 84 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 86 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 159 and 43, respectively; orthe VH region and the VL region comprise the sequences set forth in SEQ ID NO: 195 and 39, respectively; or.

[0058] In some of any embodiments, the second binding domain is an scFv comprising:(a) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 246;(b) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 247;(c) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 250; or(d) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 251.51MF-365921286217372000640

[0059] In some of any embodiments, the second binding domain is an scFv comprising: (a) the amino acid sequence of SEQ ID NO: 246; (b) the amino acid sequence of SEQ ID NO: 247; (c) the amino acid sequence of SEQ ID NO: 250; or (d) the amino acid sequence of SEQ ID NO: 251. In some of any embodiments, in the second binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively.

[0060] In some of any embodiments, in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27. In some of any embodiments, in the second binding domain, the VH region and the VL region comprises the sequence or are the sequences set forth in SEQ ID NO: 22 and 27, respectively.

[0061] In some of any embodiments, in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 68, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39. In some of any embodiments, in the second binding domain, the VH region and the VL region comprise the sequences or are the sequences set forth in SEQ ID NO: 68 and 39, respectively.

[0062] In some of any embodiments, in the second binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively. In some of any embodiments, in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 70, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to 52MF-365921286217372000640SEQ ID NO: 43. In some of any embodiments, in the CD3 binding domain, the VH region and the VL region comprise the sequences or are the sequences set forth in SEQ ID NO: 70 and 43, respectively.

[0063] In some of any embodiments, in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 72, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 73. In some of any embodiments, in the second binding domain, the VH region and the VL region comprise the sequences or are the sequences set forth in SEQ ID NO: 72 and 73, respectively.

[0064] In some of any embodiments, the first binding domain comprises the VH set forth in any one of SEQ ID NOs: 12 or 88 and the VL set forth in any one of SEQ ID NO: 17 or 89; and the second binding domain comprises the VH set forth in any one of SEQ ID NOs: 22, 68, 72, or 70 and the VL set forth in any one of SEQ ID NO: 27, 39, 73, or 43. In some of any embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; and the second binding domain comprises the VH set forth in SEQ ID NO: 22 and the VL set forth in SEQ ID NO: 27. In some of any embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; and the second binding domain comprises the VH set forth in SEQ ID NO: 68 and the VL set forth in SEQ ID NO: 39.

[0065] In some of any embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; and the CD3 binding domain comprises the VH set forth in SEQ ID NO: 72 and the VL set forth in SEQ ID NO: 73. In some of any embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; and the second binding domain comprises the VH set forth in SEQ ID NO: 70 and the VL set forth in SEQ ID NO: 43.

[0066] In some of any embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; and the second binding domain comprises the VH set forth in SEQ ID NO: 22 and the VL set forth in SEQ ID NO: 27. In some of any embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; and the second binding domain comprises the VH set forth in SEQ ID NO: 68 and the VL set forth in SEQ ID NO: 39. In some of any 53MF-365921286217372000640embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; and the second binding domain comprises the VH set forth in SEQ ID NO: 72 and the VL set forth in SEQ ID NO: 73. In some of any embodiments, the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; and the second binding domain comprises the VH set forth in SEQ ID NO: 70 and the VL set forth in SEQ ID NO: 43.

[0067] In some of any embodiments, the second binding domain has a KD of 5 to 75 nM to CD3. In some of any embodiments, the second binding domain has a KD of 10 to 70 nM to CD3.

[0068] In some of any embodiments, the first binding domain and the second binding domain are independently selected from a scFv and a Fab. In some of any embodiments, the first binding domain and / or the second binding domain is a scFv. In some of any embodiments, the first and the second binding domain are both an scFv. In some of any embodiments, the first binding domain is a scFv and the second binding domain is a Fab.

[0069] In some of any embodiments, the first binding domain comprises, from N- to C-terminal order: the VH region and the VL region, optionally separated by a linker. In some of any embodiments, the first binding domain comprises, from N- to C- terminal order: the VL region and the VH region, optionally separated by a linker. In some of any embodiments, the first binding domain is a scFv that is disulfide- stabilized such that the VH region and VL region are covalently linked by a disulfide bond, optionally wherein the VH region comprises a cysteine residue at framework region 2 position 44 (Kabat numbering) and the VL region comprises a cysteine residue at framework region 4 position 100 (Kabat numbering).

[0070] In some of any embodiments, the first binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245. In some of any embodiments, the first binding domain comprises the amino acid sequence of SEQ ID NO: 245. In some of any embodiments, the first binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248. In some of any embodiments, the first binding domain comprises the amino acid sequence of SEQ ID NO: 248. In some of any embodiments, the first binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence 54MF-365921286217372000640identity to the amino acid sequence of SEQ ID NO: 249. In some of any embodiments, the first binding domain comprises the amino acid sequence of SEQ ID NO: 249. In some of any embodiments, the first binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 252. In some of any embodiments, the first binding domain comprises the amino acid sequence of SEQ ID NO: 252.

[0071] In some of any embodiments, the second binding domain comprises, from N- to C-terminal order: the VH region and the VL region, optionally separated by a linker. In some of any embodiments, the second binding domain comprises, from N- to C-terminal order: the VL region and the VH region, optionally separated by a linker. In some of any embodiments, the second binding domain is a scFv that is disulfide- stabilized such that the VH region and VL region are covalently linked by a disulfide bond, optionally wherein the VH region comprises a cysteine residue at framework region 2 position 44 (Kabat numbering) and the VL region comprises a cysteine residue at framework region 4 position 100 (Kabat numbering).

[0072] In some of any embodiments, the second binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 246. In some of any embodiments, the second binding domain comprises the amino acid sequence of SEQ ID NO: 246. In some of any embodiments, the second binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 247. In some of any embodiments, the second binding domain comprises the amino acid sequence of SEQ ID NO: 247.

[0073] In some of any embodiments, the antibody comprises a constant region from an IgGl or IgG2. In some of any embodiments, the constant region is a human IgGl heavy chain constant region. In some of any embodiments, the antibody comprises an Fc region comprising a first and second Fc polypeptide each comprising a hinge-CH2-CH3. In some of any embodiments, the first binding domain and the second binding domain are together present on two polypeptide chains.

[0074] In certain embodiments, the constant region comprises the amino acid sequence set forth in any of SEQ ID NOs: 163-166 and 169.55MF-365921286217372000640

[0075] In certain embodiments, the constant region of one heavy chain comprises an amino acid sequence set forth in SEQ ID NOs: 163-166 and the constant region of the other heavy chain independently comprises an amino acid sequence set forth in SEQ ID NOs: 163-166.

[0076] In certain embodiments, the constant region of one heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 165 and the constant region of the other heavy chain comprises the amino acid sequence set forth in SEQ ID NO: 166.

[0077] In certain embodiments, the constant region is a human IgG2 heavy chain constant region.

[0078] In certain embodiments, the constant region comprises the amino acid sequence set forth in any of SEQ ID NO: 167, 168, 170.

[0079] In some of any embodiments, the bispecific antibody comprises a first heavy chain and a second heavy chain, wherein:(a) the first heavy chain comprises (i) the first binding domain that is an scFv comprising the VH region and the VL region and (ii) a first Fc polypeptide comprising a hinge-CH2-CH3; and(b) the second heavy chain comprises (i) the second binding domain that is an scFv comprising the VH region and the VL region and (ii) a second Fc polypeptide comprising a hinge-CH2-CH3.

[0080] In some of any embodiments, the first binding domain and the second binding domain are together present on three polypeptide chains. In some of any embodiments, the bispecific antibody comprises a first heavy chain, a second heavy chain, and a light chain, wherein:(a) the first heavy chain comprises (i) the first binding domain that is an scFv comprising the VH region and the VL region and (ii) a first Fc polypeptide comprising a hinge-CH2-CH3;(b) the second heavy chain comprises (i) the heavy chain of the second binding domain that is the heavy chain of a Fab comprising the VH region and CHI, (ii) and a second Fc polypeptide comprising a hinge-CH2-CH3; and(c) a light chain comprises the light chain of the second binding domain that is the light chain of the Fab comprising the VL region and the constant light chain (CL).

[0081] In some of any embodiments, the first binding domain and the second binding domain are each N-terminal to the Fc region. In some of any embodiments, the Fc region is a 56MF-365921286217372000640heterodimeric Fc region. In some of any embodiments, each of the first and second polypeptide comprises one or more amino acid substitutions in a wild-type Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide. In some embodiments, the wild-type Fc region is an IgGl Fc region or an IgG2 Fc region, optionally wherein the wild- type Fc region is a wildtype IgGl Fc region comprising the amino acid sequence set forth in SEQ ID NO: 253.

[0082] In some of any embodiments, the one more amino acid substitutions are a knob-into-hole modification, a charge mutation to reduce or prevent self-association due to charge repulsion, or disulfide bonding pairing mutation, or combinations thereof. In some of any embodiments, the one or more amino acid substitutions are a knob-into-hole modification and disulfide bond pairing mutation.

[0083] In some of any embodiments, the one or more amino acid substitutions are:(i) amino acid substitution T366W in the first polypeptide of the heterodimeric Fc and amino acid substitutions T366S, L368A and Y407V in the second polypeptide of the heterodimeric Fc; and / or(ii) amino acid substitution S354C on the first polypeptide of the heterodimeric Fc and amino acid substitution Y349C on the second polypeptide of the heterodimeric Fc.

[0084] In some of any embodiments, the heterodimeric Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and / or to reduce effector function, optionally as compared to a wild-type IgGl Fc region. In some embodiments, the wild- type Fc region is a wild- type IgGl Fc region comprising the amino acid sequence set forth in SEQ ID NO: 253. In some of any embodiments, the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering. In some of any embodiments, the one or more amino acid substitution comprises L234A and L235A. In some of any embodiments, the one or more amino acid substitution comprises L234A, L235A, and D265S. In some of any embodiments, the first and second Fc polypeptide is of the human IgGl Glml,17 allotype. In some of any embodiments, the bispecific antibody comprises the amino acid substitutions D356E and L358M. In some of any embodiments, the first Fc polypeptide is an IgGl Fc comprising amino acid substitutions L234A, L235A, D265S, S354C and T366W, and the second Fc polypeptide is an IgGl Fc comprising amino acid substitutions L234A, L235A, D265S, Y349C, T366S, L368A and Y407V.57MF-365921286217372000640

[0085] In some of any embodiments, the first Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 163 or 165; and the second Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 164 or 166. In some of any embodiments, the first Fc polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 164 or 166; and the second Fc polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 163 or 165.

[0086] In some of any embodiments, first Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 164 and the second Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 163. In some of any embodiments, the first Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 166 and the second Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 165.

[0087] In some of any embodiments, the one or more amino acid substitutions are selected from P238K. In some of any embodiments, the first Fc polypeptide is an IgG2 Fc comprising amino acid substitutions P238K, D356E, E358M, Y349C, T366S, E368A and Y407V, and the second Fc polypeptide is an IgG2 Fc comprising amino acid substitutions P238K, D356E, E358M, S354C and T366W.

[0088] In some of any embodiments, the first Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 168; and the second Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 167. In some of any embodiments, the first Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 168 and the second Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 167.

[0089] In some of any embodiments, the bispecific antibody is capable of binding CD19 on B cells and CD3 on T cells. In some of any embodiments, the bispecific antibody results in B cell and / or plasma blast depletion of greater than 90% in the lymph node, bone marrow, and / or blood as determined by an in vitro cell depletion assay.58MF-365921286217372000640

[0090] Provided herein is a bispecific antibody comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 22, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 27, and a Fc region comprising the sequence set forth in SEQ ID NO: 165.

[0091] In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; and the second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:246 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

[0092] In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 172; and(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 173.

[0093] In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 172; and (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 173.

[0094] Provided herein is a bispecific antibody, comprising: (a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 172; and (b) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 173.

[0095] Provided herein is a bispecific antibody, consisting essentially of: (a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 172; and (b) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 173.

[0096] Provided herein is a bispecific antibody, consisting of: (a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 172; and (b) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 173.59MF-365921286217372000640

[0097] Provided herein is a bispecific antibody comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 68 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 39 and a CL comprising the sequence set forth in SEQ ID NO: 171.

[0098] In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166. In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 174;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 175; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 176.

[0099] In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 174; (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 175; and(c) the light chain comprises the amino acid sequence of SEQ ID NO: 176.

[0100] Provided herein is a bispecific antibody, comprising: (a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 174; (b) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 175; and (c) a third polypeptide comprising the amino acid sequence of SEQ ID NO: 176.60MF-365921286217372000640

[0101] Provided herein is a bispecific antibody, consisting essentially of: (a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 174; (b) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 175; and (c) a third polypeptide comprising the amino acid sequence of SEQ ID NO: 176.

[0102] Provided herein is a bispecific antibody, consisting of: (a) a first polypeptide comprising the amino acid sequence of SEQ ID NO: 174; (b) a second polypeptide comprising the amino acid sequence of SEQ ID NO: 175; and (c) a third polypeptide comprising the amino acid sequence of SEQ ID NO: 176.

[0103] Provided herein is a bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 72, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 73, and a Fc region comprising the sequence set forth in SEQ ID NO: 165.

[0104] In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; and the second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:247 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

[0105] In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 177; and (b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 178. In some embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 177; and (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 178.

[0106] Provided herein is a bispecific antibody, comprising:61MF-365921286217372000640(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and (b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 70 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and (c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 43 and a CL comprising the sequence set forth in SEQ ID NO: 171.

[0107] In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166.

[0108] In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 179;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 180; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 181.

[0109] In some embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 179; (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 180; and (c) the light chain comprises the amino acid sequence of SEQ ID NO: 181.

[0110] Provided herein is a bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 22, a linker of SEQ ID NO: 162, a62MF-365921286217372000640VL region comprising the sequence set forth in SEQ ID NO: 27, and a Fc region comprising the sequence set forth in SEQ ID NO: 165.

[0111] In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; and the second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:246 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

[0112] In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 182; and (b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 183. In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 182; and (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 183.

[0113] Provided herein is a bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and (b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 68 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and (c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 39 and a CL comprising the sequence set forth in SEQ ID NO: 171.

[0114] In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166.

[0115] In some embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 184; (b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%,63MF-36592128621737200064094%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 185; and (c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 186. In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 184; (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 185; and (c) the light chain comprises the amino acid sequence of SEQ ID NO: 186.

[0116] Provided herein is a bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and (b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 72, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 73, and a Fc region comprising the sequence set forth in SEQ ID NO: 165. In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; and the second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:247 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

[0117] In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 187; and (b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 188. In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 187; and (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 188.

[0118] Provided herein is a bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence 64MF-365921286217372000640set forth in SEQ ID NO: 166; and (b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 70 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and (c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 43 and a CL comprising the sequence set forth in SEQ ID NO: 171. In some embodiments, the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166.

[0119] In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 189;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 190; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 191.

[0120] In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 189; (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 190; and (c) the light chain comprises the amino acid sequence of SEQ ID NO: 191.

[0121] Provided herein is a bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 168; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 68 and an IgG1 CH1 of SEQ ID NO: 170, and a Fc region comprising the sequence set forth in SEQ ID NO: 167; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 39 and a CL comprising the sequence set forth in SEQ ID NO: 171.65MF-365921286217372000640

[0122] In some embodiments, the first heavy chain polypeptide comprises from N- to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO: 245 and the Fc region comprising the sequence set forth in SEQ ID NO: 168. In some of any embodiments, the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 234; (b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 235; and (c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 236. In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 234; (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 235; and (c) the light chain comprises the amino acid sequence of SEQ ID NO: 236.

[0123] Provided herein is a bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 168; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 70 and an IgG1 CH1 of SEQ ID NO: 170, and a Fc region comprising the sequence set forth in SEQ ID NO: 167; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 43 and a CL comprising the sequence set forth in SEQ ID NO: 171.

[0124] In some embodiments, the first heavy chain polypeptide comprises from N- to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO: 245 and the Fc region comprising the sequence set forth in SEQ ID NO: 168. In some of any embodiments, the bispecific antibody comprises: (a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 237; (b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID 66MF-365921286217372000640NO: 238; and (c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 239. In some of any embodiments, (a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 237; (b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 238; and (c) the light chain comprises the amino acid sequence of SEQ ID NO: 239.

[0125] Provided herein is a polynucleotide comprising a nucleic acid sequence(s) encoding the antibody or antigen-binding fragment disclosed herein or the bispecific antibody disclosed herein. Provided herein is a polynucleotide system comprising a nucleic acid sequence encoding each chain of the antibody or antigen-binding fragment disclosed herein or the bispecific antibody disclosed herein. Provided herein is a polynucleotide system comprising (a) a first nucleic acid sequence encoding the first heavy chain of the bispecific antibody disclosed herein, and (b) a second nucleic acid sequence encoding the second heavy chain of the bispecific antibody disclosed herein.

[0126] An aspect of the invention provides a polynucleotide comprising a nucleic acid comprising a nucleic acid sequence encoding any of the binding molecules or antigen binding fragments thereof described herein. In certain embodiments, the nucleic acid sequences encodes any of the binding molecules or antigen binding fragments thereof described herein including those that contain binding domains or antibodies listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9.

[0127] Provided herein is a vector comprising the polynucleotide disclosed herein. An aspect of the invention provides a vector useful for expressing a binding molecule described herein comprising the polynucleotide. In certain embodiments, the vector is used to express any of the binding molecules or antigen binding fragments thereof described herein including those that comprise a binding domain sequence, or a bispecific antibody sequence, listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9. In some embodiments, the vector is an expression vector. In certain embodiments, the vector is a viral vector. For example, the viral vector is a retroviral vector or a lentiviral vector. Provided herein is a vector system comprising a plurality of vectors, each vector comprising a nucleic acid sequence of the polynucleotide system disclosed herein. In some embodiments, each vector is an expression vector.

[0128] Provided herein is a cell comprising the polynucleotide of disclosed herein or the vector disclosed herein. Provided herein is a cell comprising the polynucleotide system 67MF-365921286217372000640disclosed herein, or the vector system disclosed herein. In some of any embodiments, the cell is a mammalian cell. An aspect of the invention provides a cell useful for expressing any of the binding molecules or antigen binding fragments thereof described herein comprising the polynucleotide, or the vector. In certain embodiments, the cell is used to express any of the binding molecules or antigen binding fragments thereof described herein including those that comprise a binding domain sequence, or a bispecific antibody sequence, listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9. In certain embodiments, the cell is a mammalian cell. In certain embodiments, the cell is a CHO cell. In certain embodiments, the cell is a NSO cell. In certain embodiments, the cell is a SP2 / 0 cell. In certain embodiments, the cell is a HEK293 cell. In certain embodiments, the cell is a PER. C6 cell. In certain embodiments, the cell is a BHK-21 cell.

[0129] Provided herein is a method of producing an antibody comprising culturing the cell disclosed herein under a condition that produces the antibody. An aspect of the invention provides a method of producing any of the binding molecules or antigen binding fragments thereof described herein comprising culturing the cell under a condition that produces the binding molecule. In certain embodiments, the binding molecule is an antibody. In certain embodiments, the binding molecule or antigen binding fragment thereof is described herein including those that comprise a binding domain sequence, or a bispecific antibody sequence, listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9. In certain embodiments, the method further comprises recovering the antibody produced by the cell.

[0130] Provided herein is an antibody or antigen-binding fragment thereof or bispecific antibody produced by the method disclosed herein. An aspect of the invention provides any binding molecule (e.g., antibody) or antigen-binding fragment thereof produced by the method. In certain embodiments, the binding molecule or antigen binding fragment thereof is described herein including those that comprise a binding domain sequence, or a bispecific antibody sequence, listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9.

[0131] Provided herein is a composition comprising the antibody or antigen-binding fragment disclosed herein. Provided herein is a composition comprising the bispecific antibody disclosed herein. An aspect of the invention provides a composition comprising any of the binding molecules or antigen binding fragment thereof described herein. In certain embodiments, the binding molecule or antigen binding fragment thereof is described herein including those that comprise a binding domain sequence, or a bispecific antibody sequence,68MF-365921286217372000640listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9. In certain embodiments, the composition further comprises a pharmaceutically acceptable excipient.

[0132] Provided herein is a method for treating a disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of the antibody or antigen-binding fragment disclosed herein or composition disclosed herein.Provided herein is a method for treating a disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of the bispecific antibody disclosed herein or composition disclosed herein. An aspect of the invention provides a method for treating a subject with a disease or condition, the method comprising administering a therapeutically effective amount of any of the binding molecules or antigen binding fragments thereof described herein. In certain embodiments, the binding molecule or antigen binding fragment thereof is described herein including those that comprise a binding domain sequence, or a bispecific antibody sequence, listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9.

[0133] In certain embodiments of the method, the disease or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer. In certain embodiments of the method, the disease or condition is associated with overexpression of B cells in tissues.

[0134] In certain embodiments of the method, the disease or condition is an autoimmune disease. In certain embodiments, the autoimmune disease in the subject is associated with presence of increased autoantibodies and / or autoreactive B cells in the subject compared to a healthy subject.

[0135] In some of any embodiments, the autoimmune disorder is selected from the group consisting of psoriasis, psoriatic arthritis, Type 1 diabetes mellitus (Type 1 diabetes), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), multiple sclerosis (MS), inflammatory bowel disease (IBD), lymphocytic colitis, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia universalis, ankylosing spondylitisis, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune oophoritis, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Chagas' disease, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Crohn's disease, cicatrical pemphigoid, coeliac sprue- 69MF-365921286217372000640dermatitis herpetiformis, cold agglutinin disease, CREST syndrome, Degos disease, discoid lupus, erythematosus (DLE), dysautonomia, endometriosis, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome (GBS), Hashimoto's thyroiditis, Hidradenitis suppurativa, idiopathic and / or acute thrombocytopenic purpura, idiopathic pulmonary fibrosis, IgA neuropathy, interstitial cystitis, juvenile arthritis, Kawasaki's disease, lichen planus, Lyme disease, Meniere disease, mixed connective tissue disease (MCTD), myasthenia gravis, neuromyotonia, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus vulgaris, pernicious anemia, polychondritis, polymyositis and dermatomyositis, primary biliary cirrhosis, polyarteritis nodosa, polyglandular syndromes, polymyalgia rheumatica, primary agammaglobulinemia, Raynaud phenomenon, Reiter's syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren's syndrome, stiff person syndrome, Takayasu's arteritis, temporal arteritis (also known as “giant cell arteritis”), ulcerative colitis, collagenous colitis, uveitis, vasculitis, vitiligo, vulvodynia (“vulvar vestibulitis”), and Wegener's granulomatosis.

[0136] In certain embodiments of the method, the disease or condition is systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjogren disease, or systemic sclerosis. In some of any embodiments, the autoimmune disorder is SLE.

[0137] In some of any embodiments, the disease or condition is a cancer. In some of any embodiments, the cancer is a solid tumor. In some of any embodiments, the cancer is a melanoma, breast carcinoma, HCC, Renal cell carcinoma, Colorectal carcinoma, non-smallcell lung carcinoma, Cervical cancer or Mesothelioma.

[0138] In some of any embodiments, the cancer is a B-cell-related cancer selected from the group consisting of multiple myeloma, malignant plasma cell neoplasm, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell nonHodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B -lymphoblastic lymphoma, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphatic tissue lymphoma (MALT lymphoma), small cell lymphocytic lymphoma, Primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell / histiocyte-rich large B-cell lymphoma, primary CNS 70MF-365921286217372000640(central nervous system) lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, ALK-positive large B-cell lymphoma, and plasmablastic lymphoma. In some of any embodiments, the disease or condition is an inflammatory disease. In some of any embodiments, the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis (eczema), contact dermatitis and gout.

[0139] Provided herein is a kit comprising the antibody or antigen-binding fragment disclosed herein, or the bispecific antibody disclosed herein and, optionally, instructions for use. An aspect of the invention provides a kit comprising any of the binding molecule or antigen binding fragments thereof described herein. In certain embodiments, the binding molecule or antigen binding fragment thereof is described herein including those that comprise a binding domain sequence, or a bispecific antibody sequence, listed in Table E4, Table E5, Table E6, Table E8, and / or Table E9. In certain embodiments, the kit further comprises instructions for use. In certain embodiments, the instructions for use comprises instructions for performing any of the methods described herein.Brief Description of the Drawings

[0140] FIG. 1A and FIG. 1B depict bispecific antibodies in the scFv-Fc × Fab-Fc format (FIG. 1A; i.e., one arm presenting a single-chain variable fragment (scFv) fused to Fc, the other arm presenting a Fab fragment fused to Fc) and the scFv-Fc × scFv-Fc format (FIG. 1B; i.e., each arm presenting a single-chain variable fragment (scFv) fused to Fc).

[0141] FIG. 2A and FIG. 2B depict two formats of CD 19 TCEs that were generated using binders 13-CD19 with 6-CD3, and 13-CD19 with 5-CD3, respectively.

[0142] FIG. 3A and FIG. 3B depict the ability of TCE constructs with different CD 19 binders and in two different formats (i.e., the scFv-Fc × scFv-Fc TCE format (FIG. 3A); the scFv-Fc × Fab-Fc TCE format (FIG. 3B)) to deplete Raji B cells.

[0143] FIGs. 4A-4D are graphs showing the ability of a selection of TCEs to deplete human B cells (FIG. 4A) and to induce with a lower potency secretion of cytokines including IFNγ (FIG. 4B), TNFα (FIG. 4C) and IL-6 (FIG. 4D) in a human PBMC assay.

[0144] FIGs. 5A-5D are graphs showing the ability of a selection of TCEs to deplete B cells (FIG. 5A) and to induce secretion of cytokines including, IFNγ (FIG. 5B), TNFα (FIG.5C) and IL-6 (FIG. 5D) in a cynomolgus macaques (cyno) PBMC assay.71MF-365921286217372000640

[0145] FIGs. 6A-6C are graphs showing in vivo B cell depletion in whole blood (FIG.6A), spleen (FIG. 6B), and bone marrow (FIG. 6C) of hCD19xhCD3-epitope transgenic mice at 72 hours post subcutaneous administration of selected TCEs including TCE001, TCE009, and TCE003. The mean % B cell depletion is shown at the top of each corresponding bar graph.

[0146] FIG. 7A and FIG. 7B are graphs showing IFNγ and IL-6 and cytokine levels, respectively, in the serum of hCD19 x hCD3e transgenic mice 6 hours post-subcutaneous administration of selected TCE molecules, including TCE001, TCE009, and TCE003.

[0147] FIGs. 8A-8B depict a comparative analysis of the B cell depletion efficiency versus IL-6 secretion levels between TCE001 (FIG. 8A) and blinatumomab bs (FIG. 8B).

[0148] FIGs. 9A-9B depict a comparative analysis of the B cell depletion efficiency versus TNFα secretion levels between TCE001 (FIG. 9A) and blinatumomab bs (FIG. 9B).

[0149] FIGs. 10A-10C depict the results of an in vitro PBMC depletion assay and a cytokine release assay (i.e., IFNγ at B cell depletion EC50(FIG. 10A), TNFα at B cell depletion EC50(FIG. 10B), and IL-6 at B cell depletion EC50(FIG. 10C)) performed using TCE001, blinatumomab bs and tAb0032.DETAILED DESCRIPTION

[0150] The present invention provides a binding molecule or antibody construct comprising a first binding domain which binds to CD 19, and a second binding domain which binds to CD3. In certain embodiments, the binding molecule or antibody construct further comprises two polypeptide monomers, each comprising a hinge, a CH2 domain and a CH3 domain, wherein said two polypeptide monomers are fused to each other via a peptide linker. In some embodiments, the binding molecule is a bispecific antibody. In some embodiments, provided herein are antibodies that bind to human CD3 and human CD 19. The binding molecules, such as bispecific antibodies, described herein are designed to engage and deplete B cells by redirecting T cell cytotoxic activity toward B cells expressing CD19. In some embodiments, the B cells may by any B cell lineage, including immature, mature, and pathogenic B cells. By promoting targeted B cell depletion, these binding molecules can be used to reset the B cell compartment and thereby treat or ameliorate autoimmune diseases and other B cell-associated disorders.

[0151] In certain embodiments, the binding molecules described herein deplete B cells by redirecting T cell cytotoxic activity toward CD19-expressing B lineage cells. B cells play a 72MF-365921286217372000640central role in diseases such as autoimmune disease and cancer. For example, B cells may be involved in autoimmune disease through antibody production, antigen presentation, and cytokine secretion. Dysregulated B cell activation and persistence of autoreactive plasma cells contribute to disease chronicity and relapse. By engaging CD3 on T cells, the binding molecules recruit and activate cytotoxic T lymphocytes in proximity to pathogenic B cells, resulting in targeted elimination of B cells and plasma cells. This mechanism allows for efficient B cell depletion and provides a means to reset the B cell compartment in autoimmune disease.

[0152] In some embodiments, the binding molecules or antibody constructs described herein are administered to a subject having a severe or moderate systemic autoimmune disease, e.g., via adoptive cell therapy, such as adoptive T cell therapy. In some aspects, the disease or condition is a systemic autoimmune disease. In some aspects, the disease or condition is severe or moderate systemic autoimmune disease. Systemic autoimmune diseases are a class of aberrant immune disorders that share similar clinical manifestations and generally are treatable by similar approaches. In addition to Systemic Lupus Erythematosus (SLE), other systemic autoimmune diseases include, for example, Sjogren's’ syndrome, progressive systemic sclerosis (i.e., scleroderma), idiopathic inflammatory myositis (IIM, including dermatomyositis, polymyositis and necrotizing myositis), mixed connective tissue disorder (MCTD), relapsing-remitting multiple sclerosis, ANCA-associated vasculitis (AAV), Crohn’s disease, myasthenia gravis, Behget’s disease, rheumatoid arthritis, multiple sclerosis (MS), IgA nephropathy, pemphigus vulgaris, myasthenia gravis, autoimmune hemolytic anemia, immune thrombocytopenia, IgG4-related diseases, membranous nephropathy, cutaneous lupus erythematosus, sarcoidosis, light chain amyloidosis, rheumatoid arthritis, bullous pemphigoid and chronic inflammatory demyelinating polyneuropathy.

[0153] In some embodiments, the binding molecules or antibody constructs described herein, are used in therapy wherein binding molecules or antibody constructs described herein bind to CD 19 expressed by cells e.g., B cells) that play a role in the manifestation of the systemic autoimmune disease. In some embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of SLE, IIM, SSc, AAV, systemic sclerosis, highly active relapsing remitting multiple sclerosis (MS), primary progressive MS, IgA nephropathy, pemphigus vulgaris, myasthenia gravis, demyelinating polyradiculoneuropathy, autoimmune hemolytic anemia, immune thrombocytopenia, IgG4- 73MF-365921286217372000640related diseases, membranous nephropathy, Primary Sjorgren’s Syndrome, cutaneous lupus erythematosus, sarcoidosis, light chain amyloidosis, rheumatoid arthritis, bullous pemphigoid, acute respiratory distress syndrome, atopic eczema, hereditary angioedema, hidradenitis suppurative, inclusion-body myositis, inflammatory bowel disease, mastocytosis, multifocal motor neuropathy, necrotizing myopathy, neuromyelitis optica spectrum disorder, mixed connective tissue disorder, POEMS syndrome, primary biliary cholangitis, psoriasis, rhesus hemolytic disease, Still’s disease, type 1 diabetes, urticaria, capillary leakage syndrome, cytokine release syndrome, erythema multiforme, pyoderma gangrenosum, antiphospholipid syndrome, or x-linked agammaglobulinemia. In some embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of SLE, IIM, AAV, systemic sclerosis, highly active relapsing remitting multiple sclerosis (MS), primary progressive MS, IgA nephropathy, pemphigus vulgaris, or myasthenia gravis.

[0154] In particular embodiments, CD 19 is expressed by cells, associated with and / or specific to the manifestation of SLE, such as severe refractory SLE. In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of idiopathic inflammatory myopathies (IIM). In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of systemic sclerosis (SSc). In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of multiple sclerosis (MS). In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of rheumatoid arthritis (RA). In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of active secondary progressive MS (aSPMS). In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of Myositis. In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of myasthenia gravis. In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of bullous pemphigoid. In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of immune thrombocytopenia. In particular embodiments, CD 19 is expressed by cells, associated with and / or specific to the manifestation of autoimmune hemolytic anemia. In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of pemphigus vulgaris. In particular embodiments, CD 19 is expressed by cells, associated with and / or specific to the manifestation of demyelinating74MF-365921286217372000640polyradiculoneuropathy. In particular embodiments, CD19 is expressed by cells, associated with and / or specific to the manifestation of membranous nephropathy.

[0155] In some embodiments, the systemic autoimmune disease is SLE, IIM, MS, or SSc. In some aspects, the disease or condition is moderate SLE. In some aspects, the disease or condition is severe refractory SLE. In particular, provided herein are binding molecules or antibody constructs and / or compositions thereof, for the treatment of subjects having severe refractory SLE. In embodiments of the provided methods, the binding molecules or antibody constructs are administered to a subject having severe refractory SLE.

[0156] In immunology, affinity maturation is the process by which B cells produce antibodies with increased affinity for antigen during the course of an immune response. With repeated exposures to the same antigen, a host will produce antibodies of successively greater affinities. Like the natural prototype, the in vitro affinity maturation is based on the principles of mutation and selection. The in vitro affinity maturation has successfully been used to optimize antibodies, antibody constructs, and antibody fragments. Random mutations inside the CDRs are introduced using radiation, chemical mutagens or error-prone PCR. In addition, the genetic diversity can be increased by chain shuffling. Two or three rounds of mutation and selection using display methods like phage display usually results in antibody fragments with affinities in the low nanomolar range.

[0157] A preferred type of an amino acid substitutional variation of the antibody constructs involves substituting one or more hypervariable region residues of a parent antibody (e.g. a humanized or human antibody). Generally, the resulting variant(s) selected for further development will have improved biological properties relative to the parent antibody from which they are generated. A convenient way for generating such substitutional variants involves affinity maturation using phage display. Briefly, several hypervariable region sides (e.g., 6-7 sides) are mutated to generate all possible amino acid substitutions at each side. The antibody variants thus generated are displayed in a monovalent fashion from filamentous phage particles as fusions to the gene III product of M13 packaged within each particle. The phage-displayed variants are then screened for their biological activity (e.g., binding affinity) as herein disclosed. In order to identify candidate hypervariable region sides for modification, alanine scanning mutagenesis can be performed to identify hypervariable region residues contributing significantly to antigen binding. Alternatively, or additionally, it may be beneficial to analyze a crystal structure of the antigen-antibody complex to identify contact points between the binding domain and the antigen, e.g., human CD 19 and human 75MF-365921286217372000640CD3. Such contact residues and neighboring residues are candidates for substitution according to the techniques elaborated herein. Once such variants are generated, the panel of variants is subjected to screening as described herein and antibodies with superior properties in one or more relevant assays may be selected for further development.

[0158] The monoclonal antibodies and antibody constructs of the present invention specifically include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and / or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is / are identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity (U. S. Pat. No. 4,816,567; Morrison et al., Proc. Natl. Acad. Sci. USA, 81: 6851-6855 (1984)). Chimeric antibodies of interest herein include “primitized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g., Old World Monkey, Ape etc.) and human constant region sequences. A variety of approaches for making chimeric antibodies have been described. See e.g., Morrison et al., Proc. Natl. Acad. ScL U. S. A. 81:6851, 1985; Takeda et al., Nature 314:452, 1985, Cabilly et al., U. S. Pat. No.4,816,567; Boss et al., U. S. Pat. No. 4,816,397; Tanaguchi et al., EP 0171496; EP 0173494; and GB 2177096.

[0159] An antibody, antibody construct, antibody fragment or antibody variant may also be modified by specific deletion of human T cell epitopes (a method called “deimmunization”) by the methods disclosed for example in WO 98 / 52976 or WO 00 / 34317. Briefly, the heavy and light chain variable domains of an antibody can be analyzed for peptides that bind to MHC class II; these peptides represent potential T cell epitopes (as defined in WO 98 / 52976 and WO 00 / 34317). For detection of potential T cell epitopes, a computer modeling approach termed “peptide threading” can be applied, and in addition a database of human MHC class II binding peptides can be searched for motifs present in the VH and VL sequences, as described in WO 98 / 52976 and WO 00 / 34317. These motifs bind to any of the 18 major MHC class II DR allotypes, and thus constitute potential T cell epitopes. Potential T cell epitopes detected can be eliminated by substituting small numbers of amino acid residues in the variable domains, or preferably, by single amino acid substitutions. Typically, conservative substitutions are made. Often, but not exclusively, an amino acid common to a position in human germline antibody sequences may be used.76MF-365921286217372000640Human germline sequences are disclosed e.g. in Tomlinson, et al. (1992) J. Mol. Biol.227:776-798; Cook, G. P. et al. (1995) Immunol. Today Vol. 16 (5): 237-242; and Tomlinson et al. (1995) EMBO J. 14: 14:4628-4638. The V BASE directory provides a comprehensive directory of human immunoglobulin variable region sequences (compiled by Tomlinson, L A. et al. MRC Centre for Protein Engineering, Cambridge, UK). These sequences can be used as a source of human sequence, e.g., for framework regions and CDRs. Consensus human framework regions can also be used, for example as described in U. S. Pat. No. 6,300,064.

[0160] “Humanized” antibodies, antibody constructs, variants or fragments thereof (such as Fv, Fab, Fab', F(ab')2 or other antigen-binding subsequences of antibodies) are antibodies or immunoglobulins of mostly human sequences, which contain (a) minimal sequence(s) derived from non-human immunoglobulin. For the most part, humanized antibodies are human immunoglobulins (recipient antibody) in which residues from a hypervariable region (also CDR) of the recipient are replaced by residues from a hypervariable region of a non-human (e.g., rodent) species (donor antibody) such as mouse, rat, hamster or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework region (FR) residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, “humanized antibodies” as used herein may also comprise residues which are found neither in the recipient antibody nor the donor antibody. These modifications are made to further refine and optimize antibody performance. The humanized antibody may also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details, see Jones et al., Nature, 321: 522-525 (1986); Reichmann et al., Nature, 332: 323-329 (1988); and Presta, Curr. Op. Struct. Biol., 2: 593-596 (1992).

[0161] Humanized antibodies or fragments thereof can be generated by replacing sequences of the Fv variable domain that are not directly involved in antigen binding with equivalent sequences from human Fv variable domains. Exemplary methods for generating humanized antibodies or fragments thereof are provided by Morrison (1985) Science 229:1202-1207; by Oi et al. (1986) BioTechniques 4:214; and by U. S. Pat. Nos. 5,585,089; 5,693,761; 5,693,762; 5,859,205; and 6,407,213. Those methods include isolating, manipulating, and expressing the nucleic acid sequences that encode all or part of immunoglobulin Fv variable domains from at least one of a heavy or light chain. Such nucleic acids may be obtained from a hybridoma producing an antibody against a predetermined target, as described above, as well as from other sources. The recombinant 77MF-365921286217372000640DNA encoding the humanized antibody molecule can then be cloned into an appropriate expression vector.

[0162] Humanized antibodies may also be produced using transgenic animals such as mice that express human heavy and light chain genes, but are incapable of expressing the endogenous mouse immunoglobulin heavy and light chain genes. Winter describes an exemplary CDR grafting method that may be used to prepare the humanized antibodies described herein (U. S. Pat. No. 5,225,539). All of the CDRs of a particular human antibody may be replaced with at least a portion of a non-human CDR, or only some of the CDRs may be replaced with non-human CDRs. It is only necessary to replace the number of CDRs required for binding of the humanized antibody to a predetermined antigen.

[0163] A humanized antibody can be optimized by the introduction of conservative substitutions, consensus sequence substitutions, germline substitutions and / or back mutations. Such altered immunoglobulin molecules can be made by any of several techniques known in the art, (e.g., Teng et al., Proc. Natl. Acad. Sci. U. S. A., 80: 7308-7312, 1983; Kozbor et al., Immunology Today, 4: 7279, 1983; Olsson et al., Meth. Enzymol., 92: 3-16, 1982, and EP 239400).

[0164] According to the present invention, binding domains are in the form of one or more polypeptides. Such polypeptides may include proteinaceous parts and non-proteinaceous parts (e.g. chemical linkers or chemical cross-linking agents such as glutaraldehyde). Proteins (including fragments thereof, preferably biologically active fragments, and peptides, usually having less than 30 amino acids) comprise two or more amino acids coupled to each other via a covalent peptide bond (resulting in a chain of amino acids).

[0165] Preferably the binding domain which binds to CD 19 and / or the binding domain which binds to CD3 is / are human binding domains. Antibodies and antibody constructs comprising at least one human binding domain avoid some of the problems associated with antibodies or antibody constructs that possess non-human such as rodent (e.g. murine, rat, hamster or rabbit) variable and / or constant regions. The presence of such rodent derived proteins can lead to the rapid clearance of the antibodies or antibody constructs or can lead to the generation of an immune response against the antibody or antibody construct by a patient. In order to avoid the use of rodent derived antibodies or antibody constructs, human or fully human antibodies / antibody constructs can be generated through the introduction of human antibody function into a rodent so that the rodent produces fully human antibodies.78MF-365921286217372000640

[0166] The ability to clone and reconstruct megabase-sized human loci in YACs and to introduce them into the mouse germline provides a powerful approach to elucidating the functional components of very large or crudely mapped loci as well as generating useful models of human disease. Furthermore, the use of such technology for substitution of mouse loci with their human equivalents could provide unique insights into the expression and regulation of human gene products during development, their communication with other systems, and their involvement in disease induction and progression.

[0167] An important practical application of such a strategy is the “humanization” of the mouse humoral immune system. Introduction of human immunoglobulin (Ig) loci into mice in which the endogenous Ig genes have been inactivated offers the opportunity to study the mechanisms underlying programmed expression and assembly of antibodies as well as their role in B-cell development. Furthermore, such a strategy could provide an ideal source for production of fully human monoclonal antibodies (mAbs) — an important milestone towards fulfilling the promise of antibody therapy in human disease. Fully human antibodies or antibody constructs are expected to minimize the immunogenic and allergic responses intrinsic to mouse or mouse-derivatized mAbs and thus to increase the efficacy and safety of the administered antibodies / antibody constructs. The use of fully human antibodies or antibody constructs can be expected to provide a substantial advantage in the treatment of chronic and recurring human diseases, such as inflammation, autoimmunity, and B cell disorders, which require repeated compound administrations.

[0168] One approach towards this goal was to engineer mouse strains deficient in mouse antibody production with large fragments of the human Ig loci in anticipation that such mice would produce a large repertoire of human antibodies in the absence of mouse antibodies. Large human Ig fragments would preserve the large variable gene diversity as well as the proper regulation of antibody production and expression. By exploiting the mouse machinery for antibody diversification and selection and the lack of immunological tolerance to human proteins, the reproduced human antibody repertoire in these mouse strains should yield high affinity antibodies against any antigen of interest, including human antigens. Using the hybridoma technology, antigen- specific human mAbs with the desired specificity could be readily produced and selected. This general strategy was demonstrated in connection with the generation of the first XenoMouse mouse strains (see Green et al. Nature Genetics 7:13-21 (1994)). The XenoMouse strains were engineered with yeast artificial chromosomes (YACs) containing 245 kb and 190 kb-sized germline configuration fragments of the human heavy 79MF-365921286217372000640chain locus and kappa light chain locus, respectively, which contained core variable and constant region sequences. The human Ig containing YACs proved to be compatible with the mouse system for both rearrangement and expression of antibodies and were capable of substituting for the inactivated mouse Ig genes. This was demonstrated by their ability to induce B cell development, to produce an adult-like human repertoire of fully human antibodies, and to generate antigen- specific human mAbs. These results also suggested that introduction of larger portions of the human Ig loci containing greater numbers of V genes, additional regulatory elements, and human Ig constant regions may recapitulate substantially the full repertoire that is characteristic of the human humoral response to infection and immunization. The work of Green et al. was recently extended to the introduction of greater than approximately 80% of the human antibody repertoire through introduction of megabase sized, germline configuration YAC fragments of the human heavy chain loci and kappa light chain loci, respectively. See Mendez et al. Nature Genetics 15:146-156 (1997) and U. S. patent application Ser. No. 08 / 759,620.

[0169] The production of the XenoMouse mice is further discussed and delineated in U. S. patent application Ser. No. 07 / 466,008, Ser. No. 07 / 610,515, Ser. No. 07 / 919,297, Ser. No.07 / 922,649, Ser. No. 08 / 031,801, Ser. No. 08 / 112,848, Ser. No. 08 / 234,145, Ser. No.08 / 376,279, Ser. No. 08 / 430,938, Ser. No. 08 / 464,584, Ser. No. 08 / 464,582, Ser. No.08 / 463,191, Ser. No. 08 / 462,837, Ser. No. 08 / 486,853, Ser. No. 08 / 486,857, Ser. No.08 / 486,859, Ser. No. 08 / 462,513, Ser. No. 08 / 724,752, and Ser. No. 08 / 759,620; and U. S. Pat. Nos. 6,162,963; 6,150,584; 6,114,598; 6,075,181, and 5,939,598 and Japanese Patent Nos. 3 068 180 B2, 3 068506 B2, and 3 068507 B2. See also Mendez et al. Nature Genetics 15:146-156 (1997) and Green and Jakobovits J. Exp. Med. 188:483-495 (1998), EP 0463 151 Bl, WO 94 / 02602, WO 96 / 34096, WO 98 / 24893, WO 00 / 76310, and WO 03 / 47336.

[0170] In an alternative approach, others, including GenPharm International, Inc., have utilized a “minilocus” approach. In the minilocus approach, an exogenous Ig locus is mimicked through the inclusion of pieces (individual genes) from the Ig locus. Thus, one or more VH genes, one or more DH genes, one or more JH genes, a mu constant region, and a second constant region (preferably a gamma constant region) are formed into a construct for insertion into an animal. This approach is described in U. S. Pat. No. 5,545,807 to Surani et al. and U. S. Pat. Nos. 5,545,806; 5,625,825; 5,625,126; 5,633,425; 5,661,016; 5,770,429;5,789,650; 5,814,318; 5,877,397; 5,874,299; and 6,255,458 each to Lonberg and Kay, U. S. Pat. Nos. 5,591,669 and 6,023,010 to Krimpenfort and Berns, U. S. Pat. Nos. 5,612,205;80MF-3659212862173720006405,721,367; and U. S. Pat. No. 5,789,215 to Berns et al., and U. S. Pat. No. 5,643,763 to Choi and Dunn, and GenPharm International U. S. patent application Ser. No. 07 / 574,748, Ser. No.07 / 575,962, Ser. No. 07 / 810,279, Ser. No. 07 / 853,408, Ser. No. 07 / 904,068, Ser. No.07 / 990,860, Ser. No. 08 / 053,131, Ser. No. 08 / 096,762, Ser. No. 08 / 155,301, Ser. No.08 / 161,739, Ser. No. 08 / 165,699, Ser. No. 08 / 209,741. See also EP 0546073 Bl, WO 92 / 03918, WO 92 / 22645, WO 92 / 22647, WO 92 / 22670, WO 93 / 12227, WO 94 / 00569, WO 94 / 25585, WO 96 / 14436, WO 97 / 13852, and WO 98 / 24884 and U. S. Pat. No. 5,981,175. See further Taylor et al. (1992), Chen et al. (1993), Tuaillon et al. (1993), Choi et al. (1993), Lonberg et al. (1994), Taylor et al. (1994), and Tuaillon et al. (1995), Fishwild et al. (1996).

[0171] Kirin has also demonstrated the generation of human antibodies from mice in which, through microcell fusion, large pieces of chromosomes, or entire chromosomes, have been introduced. See European Patent Application Nos. 773288 and 843 961. Xenerex Biosciences is developing a technology for the potential generation of human antibodies. In this technology, SCID mice are reconstituted with human lymphatic cells, e.g., B and / or T cells. Mice are then immunized with an antigen and can generate an immune response against the antigen. See U. S. Pat. Nos. 5,476,996; 5,698,767; and 5,958,765.

[0172] Human anti-mouse antibody (HAMA) responses have led the industry to prepare chimeric or otherwise humanized antibodies. It is however expected that certain human antichimeric antibody (HACA) responses will be observed, particularly in chronic or multi-dose utilizations of the antibody. Thus, it would be desirable to provide antibody constructs comprising a human binding domain against CD 19 and a human binding domain against CD3 in order to vitiate concerns and / or effects of HAMA or HACA response.

[0173] By way of example, for the treatment of B cell disorders, a therapeutically effective amount or dosage of the drug or therapeutic agent (e.g., an anti-CD19 antibody or antigen binding portion thereof, or a CD19 / CD3 binding molecule or antibody construct) reduces B cells by at least about 20%, by at least about 30% by at least about 40%, by at least about 50%, by at least about 60%, by at least above 70%, by at least about 80%, or by at least about 90% relative to untreated subjects. In some aspects, a therapeutically effective amount or dosage of the drug or therapeutic agent completely depletes B cells, i.e., inhibits B cell populations or B cell growth by 100%. The ability of a drug or therapeutic agent, including an antibody, to deplete B cells can be evaluated using the assays described herein.Alternatively, this property of a composition comprising the compound or therapeutic agent81MF-365921286217372000640can be evaluated by examining the ability of the composition to inhibit B growth; such inhibition can be measured in vitro by assays known to the skilled practitioner.

[0174] A method for epitope mapping is described in the following: When a region (a contiguous amino acid stretch) in the human CD 19 protein is exchanged / replaced with its corresponding region of a non-human and non-primate CD 19 (e.g., mouse CD 19, but others like chicken, rat, hamster, rabbit etc. may also be conceivable), a decrease in the binding of the binding domain is expected to occur, unless the binding domain is cross -reactive for the non-human, non-primate CD19 used. Said decrease is preferably at least 10%, 20%, 30%, 40%, or 50%; more preferably at least 60%, 70%, or 80%, and most preferably 90%, 95% or even 100% in comparison to the binding to the respective region in the human CD 19 protein, whereby binding to the respective region in the human CD 19 protein is set to be 100%. It is envisaged that the aforementioned human CD19 / non-human CD19 chimeras are expressed in CHO cells.

[0175] In an alternative or additional method for epitope mapping, several truncated versions of the human CD 19 extracellular domain can be generated in order to determine a specific region that is recognized by a binding domain. In these truncated versions, the different extracellular CD 19 domains / sub-domains or regions are stepwise deleted, starting from the N-terminus. It is envisaged that the truncated CD19 versions may be expressed in CHO cells. It is also envisaged that the truncated CD19 versions may be fused with a transmembrane domain and / or cytoplasmic domain of a different membrane-bound protein. It is also envisaged that the truncated CD 19 versions may encompass a signal peptide domain at their N-terminus, for example a signal peptide derived from mouse IgG heavy chain signal peptide. It is furthermore envisaged that the truncated CD 19 versions may encompass a v5 domain at their N-terminus (following the signal peptide) which allows verifying their correct expression on the cell surface. A decrease or a loss of binding is expected to occur with those truncated CD 19 versions which do not encompass any more the CD 19 region that is recognized by the binding domain. The decrease of binding is preferably at least 10%, 20%, 30%, 40%, 50%; more preferably at least 60%, 70%, 80%, and most preferably 90%, 95% or even 100%, whereby binding to the entire human CD19 protein (or its extracellular region or domain) is set to be 100.

[0176] A further method to determine the contribution of a specific residue of CD 19 to the recognition by an antibody construct or binding domain is alanine scanning (see e.g. Morrison K L & Weiss G A. Cur Opin Chem Biol. 2001 June; 5(3):302-7), where each 82MF-365921286217372000640residue to be analyzed is replaced by alanine, e.g. via site-directed mutagenesis. Alanine is used because of its non-bulky, chemically inert, methyl functional group that nevertheless mimics the secondary structure references that many of the other amino acids possess.Sometimes bulky amino acids such as valine or leucine can be used in cases where conservation of the size of mutated residues is desired. Alanine scanning is a mature technology which has been used for a long period of time. The interaction between the binding domain and the epitope or the region comprising the epitope implies that a binding domain exhibits appreciable affinity for the epitope / the region comprising the epitope on a particular protein or antigen (here: CD 19 and CD3, respectively) and, generally, does not exhibit significant reactivity with proteins or antigens other than the CD 19 or CD3.

[0177] Specific binding is believed to be affected by specific motifs in the amino acid sequence of the binding domain and the antigen. Thus, binding is achieved as a result of their primary, secondary and / or tertiary structure as well as the result of secondary modifications of said structures. The specific interaction of the antigen-interaction- side with its specific antigen may result in a simple binding of said side to the antigen. Moreover, the specific interaction of the antigen-interaction-side with its specific antigen may alternatively or additionally result in the initiation of a signal, e.g., due to the induction of a change of the conformation of the antigen, an oligomerization of the antigen, etc.

[0178] Variability is not evenly distributed throughout the variable domains of antibodies; it is concentrated in sub-domains of each of the heavy and light chain variable regions. These sub-domains are called “hypervariable regions” or “complementarity determining regions” (CDRs). The more conserved (i.e., non-hypervariable) portions of the variable domains are called the “framework” regions (FRM or FR) and provide a scaffold for the six CDRs in three-dimensional space to form an antigen-binding surface. The variable domains of naturally occurring heavy and light chains each comprise four FRM regions (FR1, FR2, FR3, and FR4), largely adopting a P-sheet configuration, connected by three hypervariable regions, which form loops connecting, and in some cases forming part of, the P-sheet structure. The hypervariable regions in each chain are held together in close proximity by the FRM and, with the hypervariable regions from the other chain, contribute to the formation of the antigen-binding side (see Kabat et al., loc. cit.).

[0179] Typically, CDRs form a loop structure that can be classified as a canonical structure. The term “canonical structure” refers to the main chain conformation that is adopted by the antigen binding (CDR) loops. From comparative structural studies, it has been 83MF-365921286217372000640found that five of the six antigen binding loops have only a limited repertoire of available conformations. Each canonical structure can be characterized by the torsion angles of the polypeptide backbone. Correspondent loops between antibodies may, therefore, have very similar three-dimensional structures, despite high amino acid sequence variability in most parts of the loops (Chothia and Lesk, J. Mol. Biol., 1987, 196: 901; Chothia et al., Nature, 1989, 342: 877; Martin and Thornton, J. Mol. Biol, 1996, 263: 800). Furthermore, there is a relationship between the adopted loop structure and the amino acid sequences surrounding it. The conformation of a particular canonical class is determined by the length of the loop and the amino acid residues residing at key positions within the loop, as well as within the conserved framework (i.e., outside of the loop). Assignment to a particular canonical class can therefore be made based on the presence of these key amino acid residues.

[0180] The CDR3 of the light chain and, particularly, the CDR3 of the heavy chain may constitute the most important determinants in antigen binding within the light and heavy chain variable regions. In some antibody constructs, the heavy chain CDR3 appears to constitute the major area of contact between the antigen and the antibody. In vitro selection schemes in which CDR3 alone is varied can be used to vary the binding properties of an antibody or determine which residues contribute to the binding of an antigen. Hence, CDR3 is typically the greatest source of molecular diversity within the antibody-binding side. H3, for example, can be as short as two amino acid residues or greater than 26 amino acids.

[0181] In a classical full-length antibody or immunoglobulin, each light (L) chain is linked to a heavy (H) chain by one covalent disulfide bond, while the two H chains are linked to each other by one or more disulfide bonds depending on the H chain isotype. The CH domain most proximal to VH is usually designated as CHI. The constant (“C”) domains are not directly involved in antigen binding, but exhibit various effector functions, such as antibody-dependent, cell-mediated cytotoxicity and complement activation. The Fc region of an antibody is comprised within the heavy chain constant domains and is for example able to interact with cell surface located Fc receptors.

[0182] The sequence of antibody genes after assembly and somatic mutation is highly varied, and these varied genes are estimated to encode 1010different antibody molecules (Immunoglobulin Genes, 2nded., eds. Jonio et al., Academic Press, San Diego, Calif., 1995). Accordingly, the immune system provides a repertoire of immunoglobulins. The term “repertoire” refers to at least one nucleotide sequence derived wholly or partially from at least one sequence encoding at least one immunoglobulin. The sequence(s) may be generated by 84MF-365921286217372000640rearrangement in vivo of the V, D, and J segments of heavy chains, and the V and J segments of light chains. Alternatively, the sequence(s) can be generated from a cell in response to which rearrangement occurs, e.g., in vitro stimulation. Alternatively, part or all of the sequence(s) may be obtained by DNA splicing, nucleotide synthesis, mutagenesis, and other methods, see, e.g., U. S. Pat. No. 5,565,332. A repertoire may include only one sequence or may include a plurality of sequences, including ones in a genetically diverse collection. An " Fc region,” “Fc domain,” or " Fc" refers to the C-terminal region of the heavy chain of an antibody. Thus, an Fc region comprises the constant region of an antibody excluding the first constant region immunoglobulin domain (e.g., CHI or CL).

[0183] Bispecific single chain antibody constructs are known in the art and are described in WO 99 / 54440, Mack, J. Immunol. (1997), 158, 3965-3970, Mack, PNAS, (1995), 92, 7021-7025, Kufer, Cancer Immunol. Immunother., (1997), 45, 193-197, Loffler, Blood, (2000), 95, 6, 2098-2103, Briihl, Immunol., (2001), 166, 2420-2426, Kipriyanov, J. Mol. Biol., (1999), 293, 41-56. Techniques described for the production of single chain antibodies (see, inter alia, U. S. Pat. No. 4,946,778, Kontermann and Diibel (2010), loc. cit. and Little (2009), loc. cit.) can be adapted to produce single chain antibody constructs specifically recognizing (an) elected target(s).

[0184] Bivalent (also called divalent) or bispecific single-chain variable fragments (bi-scFvs or di-scFvs) having the format (scFv)2can be engineered by linking two scFv molecules (e.g. with linkers as described hereinbefore). If these two scFv molecules have the same binding specificity, the resulting (scFv)2 molecule will preferably be called bivalent (i.e. it has two valences for the same target epitope). If the two scFv molecules have different binding specificities, the resulting (scFv)2 molecule will preferably be called bispecific. The linking can be done by producing a single peptide chain with two VH regions and two VL regions, yielding tandem scFvs (see e.g., Kufer P. et al., (2004) Trends in Biotechnology 22(5):238-244). Another possibility is the creation of scFv molecules with linker peptides that are too short for the two variable regions to fold together (e.g. about five amino acids), forcing the scFvs to dimerize. This type is known as diabodies (see e.g. Hollinger, Philipp et al., (July 1993) Proceedings of the National Academy of Sciences of the United States of America 90 (14): 6444-8).

[0185] The monoclonal antibodies herein also include camelized single domain antibodies. See, e.g., Muyldermans et al. (2001) Trends Biochem. Sci. 26:230; Reichmann et al. (1999) J. Immunol. Methods 231:25; WO 94 / 04678; WO 94 / 25591; U. S. Pat. No.85MF-3659212862173720006406,005,079, which are hereby incorporated by reference in their entireties). In one aspect, provided herein are single domain antibodies comprising two VHdomains with modifications such that single domain antibodies are formed.

[0186] T cells or T lymphocytes are a type of lymphocyte (itself a type of white blood cell) that play a central role in cell-mediated immunity. There are several subsets of T cells, each with a distinct function. T cells can be distinguished from other lymphocytes, such as B cells and NK cells, by the presence of a T cell receptor (TCR) on the cell surface. The TCR is responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules and is composed of two different protein chains. In 95% of the T cells, the TCR consists of an alpha (a) and beta (0) chain. When the TCR engages with antigenic peptide and MHC (peptide / MHC complex), the T lymphocyte is activated through a series of biochemical events mediated by associated enzymes, co-receptors, specialized adaptor molecules, and activated or released transcription factors.

[0187] The CD3 receptor complex is a protein complex and is composed of four chains. In mammals, the complex contains a CD3y (gamma) chain, a CD36 (delta) chain, and two CD3e (epsilon) chains. These chains associate with the T cell receptor (TCR) and the so-called, (zeta) chain to form the T cell receptor CD3 complex and to generate an activation signal in T lymphocytes. The CD3y (gamma), CD36 (delta), and CD3e (epsilon) chains are highly related cell- surface proteins of the immunoglobulin superfamily containing a single extracellular immunoglobulin domain. The intracellular tails of the CD3 molecules contain a single conserved motif known as an immunoreceptor tyrosine-based activation motif or IT AM for short, which is essential for the signaling capacity of the TCR. The CD3 epsilon molecule is a polypeptide which in humans is encoded by the CD3E gene which resides on chromosome 11. An epitope of CD3 epsilon that has been investigated is comprised within amino acid residues 1-27 of the human CD3 epsilon extracellular domain. It is envisaged that binding molecules or antibody constructs according to the present invention typically and advantageously show less unspecific T cell activation.

[0188] The redirected lysis of target cells via the recruitment of T cells by a multispecific, e.g., bispecific construct, involves cytolytic synapse formation and delivery of perforin and granzymes. The engaged T cells are capable of serial target cell lysis, and are not affected by immune escape mechanisms interfering with peptide antigen processing and presentation, or clonal T cell differentiation. See, for example, WO 2007 / 042261.86MF-365921286217372000640

[0189] Cytotoxicity mediated by antibody constructs of the invention can be measured in various ways. Effector cells can be e.g. stimulated enriched (human) CD8 positive T cells or unstimulated (human) peripheral blood mononuclear cells (PBMC). If the target cells are of macaque origin or express or are transfected with macaque CD 19 which is bound by the first domain, the effector cells should also be of macaque origin such as a macaque T cell line, e.g.4119LnPx. The target cells should express (at least the extracellular domain of) CD19, e.g. human or macaque CD19. Target cells can be a cell line (such as CHO) which is stably or transiently transfected with CD19, e.g., human or macaque CD19. Alternatively, the target cells can be a CD 19 positive natural expresser cell line such as the human multiple myeloma cell line L363 or NCI-H929. Usually EC50values are expected to be lower with target cell lines expressing higher levels of CD 19 on the cell surface. The effector to target cell (E: T) ratio is usually about 10:1, but can also vary. Cytotoxic activity of CD19×CD3 bispecific antibody constructs can be measured in a51Cr-release assay (incubation time of about 18 hours) or in a in a FACS-based cytotoxicity assay (incubation time of about 48 hours).Modifications of the assay incubation time (cytotoxic reaction) are also possible. Other methods of measuring cytotoxicity are well-known to the skilled person and comprise MTT or MTS assays, ATP-based assays including bioluminescent assays, the sulforhodamine B (SRB) assay, WST assay, clonogenic assay and the ECIS technology.

[0190] Covalent modifications of the constructs are also included within the scope of this invention, and are generally, but not always, done post-translationally. For example, several types of covalent modifications of the antibody construct are introduced into the molecule by reacting specific amino acid residues of the antibody construct with an organic derivatizing agent that is capable of reacting with selected side chains or the N- or C-terminal residues.

[0191] Cysteinyl residues most commonly are reacted with a-haloacetates (and corresponding amines), such as chloroacetic acid or chloroacetamide, to give carboxymethyl or carboxyamidomethyl derivatives. Cysteinyl residues also are derivatized by reaction with bromotrifluoroacetone, a-bromo-P-(5-imidozoyl)propionic acid, chloroacetyl phosphate, N-alkylmaleimides, 3-nitro-2-pyridyl disulfide, methyl 2-pyridyl disulfide, p-chloromercuribenzoate, 2-chloromercuri-4-nitrophenol, or chloro-7-nitrobenzo-2-oxa-l,3-diazole.

[0192] Histidyl residues are derivatized by reaction with diethylpyrocarbonate at pH 5.5-7.0 because this agent is relatively specific for the histidyl side chain. Para-bromophenacyl bromide also is useful; the reaction is preferably performed in 0.1 M sodium cacodylate at pH 87MF-3659212862173720006406.0. Lysinyl and amino terminal residues are reacted with succinic or other carboxylic acid anhydrides. Derivatization with these agents has the effect of reversing the charge of the lysinyl residues. Other suitable reagents for derivatizing alpha-amino-containing residues include imidoesters such as methyl picolinimidate; pyridoxal phosphate; pyridoxal; chloroborohydride; trinitrobenzenesulfonic acid; O-methylisourea; 2,4-pentanedione; and transaminase-catalyzed reaction with glyoxylate.

[0193] Arginyl residues are modified by reaction with one or several conventional reagents, among them phenylglyoxal, 2,3-butanedione, 1,2-cyclohexanedione, and ninhydrin. Derivatization of arginine residues requires that the reaction be performed in alkaline conditions because of the high pKa of the guanidine functional group. Furthermore, these reagents may react with the groups of lysine as well as the arginine epsilon-amino group.

[0194] The specific modification of tyrosyl residues may be made, with particular interest in introducing spectral labels into tyrosyl residues by reaction with aromatic diazonium compounds or tetranitromethane. Most commonly, N-acetylimidizole and tetranitromethane are used to form 0-acetyl tyrosyl species and 3-nitro derivatives, respectively. Tyrosyl residues are iodinated using125I or131I to prepare labeled proteins for use in radioimmunoassay, the chloramine T method described above being suitable.

[0195] Carboxyl side groups (aspartyl or glutamyl) are selectively modified by reaction with carbodiimides (R' — N=C=N — R'), where R and R' are optionally different alkyl groups, such as l-cyclohexyl-3-(2-morpholinyl-4-ethyl) carbodiimide or l-ethyl-3-(4-azonia-4,4-dimethylpentyl) carbodiimide. Furthermore, aspartyl and glutamyl residues are converted to asparaginyl and glutaminyl residues by reaction with ammonium ions.

[0196] Derivatization with bifunctional agents is useful for crosslinking the antibody constructs of the present invention to a water-insoluble support matrix or surface for use in a variety of methods. Commonly used crosslinking agents include, e.g., l,l-bis(diazoacetyl)-2-phenylethane, glutaraldehyde, N-hydroxy succinimide esters, for example, esters with 4-azidosalicylic acid, homobifunctional imidoesters, including disuccinimidyl esters such as 3,3'-dithiobis(succinimidylpropionate), and bifunctional maleimides such as bis-N-maleimido-l,8-octane. Derivatizing agents such as methyl-3-[(p-azidophenyl)dithio]propioimidate yield photoactivatable intermediates that are capable of forming crosslinks in the presence of light.

[0197] Alternatively, reactive water-insoluble matrices such as cyanogen bromide-activated carbohydrates and the reactive substrates as described in U. S. Pat. Nos. 3,969,287;88MF-3659212862173720006403,691,016; 4,195,128; 4,247,642; 4,229,537; and 4,330,440 are employed for protein immobilization.

[0198] Glutaminyl and asparaginyl residues are frequently deamidated to the corresponding glutamyl and aspartyl residues, respectively. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues falls within the scope of this invention.

[0199] Other modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the a-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W. H. Freeman & Co., San Francisco, 1983, pp. 79-86), acetylation of the N-terminal amine, and amidation of any C-terminal carboxyl group.

[0200] Another type of covalent modification of the antibody constructs included within the scope of this invention comprises altering the glycosylation pattern of the protein. As is known in the art, glycosylation patterns can depend on both the sequence of the protein (e.g., the presence or absence of particular glycosylation amino acid residues, discussed below), or the host cell or organism in which the protein is produced. Particular expression systems are discussed below.

[0201] Glycosylation of polypeptides is typically either N-linked or O-linked. N-linked refers to the attachment of the carbohydrate moiety to the side chain of an asparagine residue. The tri-peptide sequences asparagine -X- serine and asparagine-X-threonine, where X is any amino acid except proline, are the recognition sequences for enzymatic attachment of the carbohydrate moiety to the asparagine side chain. Thus, the presence of either of these tripeptide sequences in a polypeptide creates a potential glycosylation site. O-linked glycosylation refers to the attachment of one of the sugars N-acetylgalactosamine, galactose, or xylose, to a hydroxyamino acid, most commonly serine or threonine, although 5-hydroxyproline or 5-hydroxy lysine may also be used.

[0202] Addition of glycosylation sites to the antibody construct is conveniently accomplished by altering the amino acid sequence such that it contains one or more of the above-described tri-peptide sequences (for N-linked glycosylation sites). The alteration may also be made by the addition of, or substitution by, one or more serine or threonine residues to the starting sequence (for O-linked glycosylation sites). For ease, the amino acid sequence of an antibody construct is preferably altered through changes at the DNA level, particularly89MF-365921286217372000640by mutating the DNA encoding the polypeptide at preselected bases such that codons are generated that will translate into the desired amino acids.

[0203] Another means of increasing the number of carbohydrate moieties on the antibody construct is by chemical or enzymatic coupling of glycosides to the protein. These procedures are advantageous in that they do not require production of the protein in a host cell that has glycosylation capabilities for N- and O-linked glycosylation. Depending on the coupling mode used, the sugar(s) may be attached to (a) arginine and histidine, (b) free carboxyl groups, (c) free sulfhydryl groups such as those of cysteine, (d) free hydroxyl groups such as those of serine, threonine, or hydroxyproline, (e) aromatic residues such as those of phenylalanine, tyrosine, or tryptophan, or (f) the amide group of glutamine. These methods are described in WO 87 / 05330, and in Aplin and Wriston, 1981, CRC Crit. Rev. Biochem., pp. 259-306.

[0204] Removal of carbohydrate moieties present on the starting binding molecule or antibody construct may be accomplished chemically or enzymatically. Chemical deglycosylation requires exposure of the protein to the compound trifluoromethanesulfonic acid, or an equivalent compound. This treatment results in the cleavage of most or all sugars except the linking sugar (N-acetylglucosamine or N-acetylgalactosamine), while leaving the polypeptide intact. Chemical deglycosylation is described by Hakimuddin et al., 1987, Arch. Biochem. Biophys. 259:52 and by Edge et al., 1981, Anal. Biochem. 118:131. Enzymatic cleavage of carbohydrate moieties on polypeptides can be achieved by the use of a variety of endo- and exo-glycosidases as described by Thotakura et al., 1987, Meth. Enzymol. 138:350. Glycosylation at potential glycosylation sites may be prevented by the use of the compound tunicamycin as described by Duskin et al., 1982, J. Biol. Chem. 257:3105. Tunicamycin blocks the formation of protein-N-glycoside linkages.

[0205] Other modifications of the binding molecule or antibody construct are also contemplated herein. For example, another type of covalent modification of the antibody construct comprises linking the antibody construct to various non-proteinaceous polymers, including, but not limited to, various polyols such as polyethylene glycol, polypropylene glycol, polyoxyalkylenes, or copolymers of polyethylene glycol and polypropylene glycol, in the manner set forth in U. S. Pat. Nos. 4,640,835; 4,496,689; 4,301,144; 4,670,417; 4,791,192 or 4,179,337. In addition, as is known in the art, amino acid substitutions may be made in various positions within the antibody construct, e.g., in order to facilitate the addition of polymers such as PEG.90MF-365921286217372000640

[0206] In some embodiments, the covalent modification of the binding molecules or antibody constructs of the invention comprises the addition of one or more labels. The labelling group may be coupled to the antibody construct via spacer arms of various lengths to reduce potential steric hindrance. Various methods for labelling proteins are known in the art and can be used in performing the present invention. The term “label” or “labelling group” refers to any detectable label. In general, labels fall into a variety of classes, depending on the assay in which they are to be detected — the following examples include, but are not limited to:• a) isotopic labels, which may be radioactive or heavy isotopes, such as radioisotopes or radionuclides(e.g.,3H,14C,15N,35S,89Zr,90Y,99Tc,111In,125I,131I)• b) magnetic labels (e.g., magnetic particles)• c) redox active moieties• d) optical dyes (including, but not limited to, chromophores, phosphors and fluorophores) such as fluorescent groups (e.g., FITC, rhodamine, lanthanide phosphors), chemiluminescent groups, and fluorophores which can be either “small molecule” fluores or proteinaceous fluores• e) enzymatic groups (e.g. horseradish peroxidase, β-galactosidase, luciferase, alkaline phosphatase)• f) biotinylated groups• g) predetermined polypeptide epitopes recognized by a secondary reporter (e.g., leucine zipper pair sequences, binding sides for secondary antibodies, metal binding domains, epitope tags, etc.)

[0207] The binding molecule or antibody construct of the invention may also comprise additional domains, which are e.g. helpful in the isolation of the molecule or relate to an adapted pharmacokinetic profile of the molecule. Domains helpful for the isolation of an antibody construct may be selected from peptide motives or secondarily introduced moieties, which can be captured in an isolation method, e.g., an isolation column. Non-limiting embodiments of such additional domains comprise peptide motives known as Myc-tag, HAT-tag, HA-tag, TAP-tag, GST-tag, chitin binding domain (CBD-tag), maltose binding protein (MBP-tag), Flag-tag, Strep-tag and variants thereof (e.g., StrepII-tag) and His-tag. All herein disclosed binding molecules or antibody constructs may comprise a His-tag domain, which is generally known as a repeat of consecutive His residues in the amino acid sequence of a 91MF-365921286217372000640molecule, preferably of five, and more preferably of six His residues (hexa- histidine). The His-tag may be located e.g., at the N- or C-terminus of the antibody construct, preferably it is located at the C-terminus. Most preferably, a hexa-histidine tag (HHHHHH; SEQ ID NO: 222) is linked via peptide bond to the C-terminus of the antibody construct according to the invention. Additionally, a conjugate system of PLGA-PEG-PLGA may be combined with a poly-histidine tag for sustained release application and improved pharmacokinetic profile.

[0208] Amino acid sequence modifications of the binding molecules or antibody constructs described herein are also contemplated. For example, it may be desirable to improve the binding affinity and / or other biological properties of the binding molecule or antibody construct. Amino acid sequence variants of the binding molecule or antibody constructs are prepared by introducing appropriate nucleotide changes into the binding molecule or antibody constructs nucleic acid, or by peptide synthesis. All of the below described amino acid sequence modifications should result in an binding molecule or antibody construct which still retains the desired biological activity (e.g., binding to CD19 and to CD3) of the unmodified parental molecule.

[0209] The sites of greatest interest for substitutional mutagenesis include (but are not limited to) the CDRs of the heavy and / or light chain, in particular the hypervariable regions, but FR alterations in the heavy and / or light chain are also contemplated. The substitutions are preferably conservative substitutions as described herein. Preferably, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acids may be substituted in a CDR, while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids may be substituted in the framework regions (FRs), depending on the length of the CDR or FR. For example, if a CDR sequence encompasses 6 amino acids, it is envisaged that one, two or three of these amino acids are substituted. Similarly, if a CDR sequence encompasses 15 amino acids it is envisaged that one, two, three, four, five or six of these amino acids are substituted.

[0210] A useful method for identification of certain residues or regions of the binding molecules or antibody constructs that are preferred locations for mutagenesis is called “alanine scanning mutagenesis” as described by Cunningham and Wells in Science, 244: 1081-1085 (1989). Here, a residue or group of target residues within the antibody construct is / are identified e.g., charged residues such as arg, asp, his, lys, and glu) and replaced by a neutral or negatively charged amino acid (most preferably alanine or polyalanine) to affect the interaction of the amino acids with the epitope.92MF-365921286217372000640

[0211] Those amino acid locations demonstrating functional sensitivity to the substitutions are then refined by introducing further or other variants at, or for, the sites of substitution. Thus, while the site or region for introducing an amino acid sequence variation is predetermined, the nature of the mutation per se needs not to be predetermined. For example, to analyze or optimize the performance of a mutation at a given site, alanine scanning or random mutagenesis may be conducted at a target codon or region, and the expressed antibody construct variants are screened for the optimal combination of desired activity. Techniques for making substitution mutations at predetermined sites in the DNA having a known sequence are well known, for example, M13 primer mutagenesis and PCR mutagenesis. Screening of the mutants is done using assays of antigen binding activities, such as CD19 or CD3 binding.

[0212] Generally, if amino acids are substituted in one or more or all of the CDRs of the heavy and / or light chain, it is preferred that the then-obtained “substituted” sequence is at least 60% or 65%, more preferably 70% or 75%, even more preferably 80% or 85%, and particularly preferably 90% or 95% identical to the “original” CDR sequence. This means that it is dependent of the length of the CDR to which degree it is identical to the “substituted” sequence. For example, a CDR having 5 amino acids is preferably 80% identical to its substituted sequence in order to have at least one amino acid substituted. Accordingly, the CDRs of the antibody construct may have different degrees of identity to their substituted sequences, e.g., CDR-L1 may have 80%, while CDR-L3 may have 90%.

[0213] Preferred substitutions (or replacements) are conservative substitutions. However, any substitution (including non-conservative substitution or one or more from the “exemplary substitutions” described herein) is envisaged as long as the antibody construct retains its capability to bind to CD 19 via the first domain and to CD3 epsilon via the second domain and / or its CDRs have an identity to the then substituted sequence (at least 60% or 65%, more preferably 70% or 75%, even more preferably 80% or 85%, and particularly preferably 90% or 95% identical to the “original” CDR sequence).

[0214] Also provided are “conservative sequence modifications” of the sequences set forth herein, e.g., amino acid sequence modifications which do not abrogate the binding of the antibody encoded by the nucleotide sequence or containing the amino acid sequence, to the antigen. Such conservative sequence modifications include conservative nucleotide and amino acid substitutions, as well as nucleotide and amino acid additions and deletions. For example, modifications can be introduced into a sequence by standard techniques known in 93MF-365921286217372000640the art, such as site-directed mutagenesis and PCR-mediated mutagenesis. Conservative amino acid substitutions include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, a predicted nonessential amino acid residue in an anti-CD19 or anti-CD3 antibody is preferably replaced with another amino acid residue from the same side chain family. Methods of identifying nucleotide and amino acid conservative substitutions which do not eliminate antigen binding are well-known in the art (see, e.g., Brummell et al., Biochem. 32:1180-1187 (1993); Kobayashi et al. Protein Eng. 12(10):879-884 (1999); and Burks et al. Proc. Natl. Acad. Sci. USA 94:412-417 (1997)). Alternatively, in another aspect, mutations can be introduced randomly along all or part of an anti-CD19 or anti-CD3 antibody antibody coding sequence, such as by saturation mutagenesis, and the resulting modified antibodies can be screened for binding activity.

[0215] The nucleic acid and protein sequences described herein can further be used as a “query sequence” to perform a search against public databases to, for example, identify related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al. (1990) J. Mol. Biol. 215:403-10. BLAST nucleotide searches can be performed with the NBLAST program, score = 100, wordlength = 12 to obtain nucleotide sequences homologous to the nucleic acid molecules described herein. BLAST protein searches can be performed with the XBLAST program, score = 50, wordlength = 3 to obtain amino acid sequences homologous to the protein molecules described herein. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al., (1997) Nucleic Acids Res. 25(17):3389-3402. When utilizing BLAST and Gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used. See www.ncbi.nlm.nih.gov.94MF-365921286217372000640I. DEFINITIONS

[0216] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or for ready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art

[0217] As used herein, "comprising" is synonymous with "including," "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the claim element. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the claim. In each instance herein any of the terms "comprising," "consisting essentially of," and "consisting of" may be optionally replaced with either of the other two terms, thus describing alternative aspects of the scope of the subject matter. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0218] As used herein, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. The use of "or" or "and" means "and / or" unless stated otherwise. Furthermore, use of the term "including" as well as other forms, such as "include," "includes," and "included," is not limiting.

[0219] The term "about" as used herein when referring to a measurable value such as an amount, a temporal duration and the like, encompasses variations of up to ± 10% from the specified value. Unless otherwise indicated, all numbers expressing e.g., quantities of ingredients or properties (e.g., molecular weight, reaction conditions) described herein are to be understood as being modified by the term "about".

[0220] As used herein, “and / or” is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” as used in a phrase such as “A and / or B” includes “A and B,” “A or B,” “A” alone, and “B” alone. Likewise, the term “and / or” as used in a phrase such as “A, B, and / or C” encompasses each95MF-365921286217372000640of the following: 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. I ma

[0221] As used herein, recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. For example, if a concentration range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3% are expressly enumerated in this specification. These are only examples of what is specifically intended, and all possible combinations of numerical values between and including the lowest value and the highest value enumerated are to be considered to be expressly stated in this disclosure.

[0222] Table 1 lists exemplary position boundaries of CDR-L1, CDR-L2, CDR-L3 and CDR-H1, CDR-H2, CDR-H3 as identified by Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-H1, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between CDRs, for example, with FR-L1 located before CDR-L1, FR-L2 located between CDR-L1 and CDR-L2, FR-L3 located between CDR-L2 and CDR-L3 and so forth. It is noted that because the shown Kabat numbering scheme places insertions at H35A and H35B, the end of the Chothia CDR-H1 loop when numbered using the shown Kabat numbering convention varies between H32 and H34, depending on the length of the loop.Table 1. Boundaries of CDRs according to various numbering schemes.CDR Kabat Chothia AbM Contact IMGT CDR-L1 L24-L34 L24-L34 L24-L34 L30-L36 L27-L38 CDR-L2 L50-L56 L50-L56 L50-L56 L46-L55 L56-L65 CDR-L3 L89-L97 L89-L97 L89-L97 L89-L96 L105-L117 CDR-H1 H31- H27-H38 (Kabat Numbering1) H35B H26-H32.34 H26-H35B H30-H35BCDR-H1 H27-H38 (Chothia Numbering2) H31-H35 H26-H32 H26-H35 H30-H35CDR-H2 H50-H65 H52-H56 H50-H58 H47-H58 H56-H65CDR-H3 H95-H102 H95-H102 H95-H102 H93-H101 H105-H117 1 - Kabat et al. (1991), “Sequences of Proteins of Immunological Interest,” 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD2 - Al-Lazikani et al., (1997) JMB 273,927-94896MF-365921286217372000640

[0223] Thus, unless otherwise specified, a “CDR” or “complementary determining region,” or individual specified CDRs (e.g., CDR-H1, CDR-H2, CDR-H3), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) complementary determining region as defined by any of the aforementioned schemes, or other known schemes. For example, where it is stated that a particular CDR (e.g., a CDR-H3) contains the amino acid sequence of a corresponding CDR in a given VH or VL region amino acid sequence, it is understood that such a CDR has a sequence of the corresponding CDR (e.g., CDR-H3) within the variable region, as defined by any of the aforementioned schemes, or other known schemes. In some embodiments, the provided binding molecule, comprises a CDR-H1, a CDR-H2, and a CDR-H3 as contained within a given VH region amino acid sequence and defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes, and a CDR-L1, a CDR-L2, and a CDR-L3 as contained within a given VL region amino acid sequence and defined by any of the aforementioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In some embodiments, specific CDR sequences are specified. In some embodiments, specific CDR sequences are specified. Exemplary CDR sequences of provided antibodies are described using various numbering schemes (see e.g. Table 1), although it is understood that a provided antibody can include CDRs as described according to any of the other aforementioned numbering schemes or other known numbering schemes.

[0224] As used herein, the term "framework" or " FR" residues refers to those variable domain residues other than the hypervariable region residues defined herein as CDR residues. Unless otherwise specified, a FR or individual specified FR(s) (e.g., FR-H1, FR-H2, FR-H3, FR-H4), of a given antibody or region thereof, such as a variable region thereof, should be understood to encompass a (or the specific) framework region as defined by any of the known schemes. In some instances, the scheme for identification of a particular CDR, FR, or FRs or CDRs is specified, such as the CDR as defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method, or other known schemes. In other cases, the particular amino acid sequence of a CDR or FR is given.

[0225] The term “variable region” or “variable domain” refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to antigen. The variable regions of the heavy chain and light chain (VH and VL, respectively) of a native antibody generally have similar structures, with each domain comprising four conserved framework 97MF-365921286217372000640regions (FRs) and three CDRs. (See, e.g., Kindt et al. Kuby Immunology, 6th ed., W. H. Freeman and Co., page 91 (2007). A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind a particular antigen may be isolated using a VH or VL domain from an antibody that binds the antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0226] Among the provided antibodies are antibody fragments. An “antibody fragment” or “antigen-binding fragment” refers to a molecule other than an intact or full-length antibody that comprises a portion of an intact or full-length antibody that binds the antigen to which the intact antibody binds. The term thus refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., human CD3 or human CD 19). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of antibody fragments include but are not limited to Fv, Fab, Fab’, Fab’-SH, F(ab’)2; diabodies; linear antibodies; VH regions, single-chain antibody molecules such as scFvs and single-domain antibodies comprising only the VH region; and multispecific antibodies formed from antibody fragments. In some embodiments, the antibody is or comprises an antibody fragment comprising a VH and a VL region. In some embodiments, the antibodies are single-chain antibody fragments comprising a heavy chain variable VH region and / or a VL region, such as Fvs or scFvs. In some embodiments, the antibodies are Fab composed of an entire light chain (i.e. VL region and a constant light chain (CL)) and the VH region and the first constant domain of one heavy chain (CHI).

[0227] Antibody fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. For instance, papain digestion of full-length antibodies produces two identical antigenbinding fragments, called " Fab" fragments, and a residual " Fc" fragment, a designation reflecting the ability to crystallize readily. Pepsin treatment of an antibody yields a single large F(ab')2 fragment which roughly corresponds to two disulfide linked Fab fragments having different antigen-binding activity and is still capable of cross-linking antigen. Fab' fragments differ from Fab fragments by having a few additional residues at the carboxy terminus of the CHI domain including one or more cysteines from the antibody hinge region. Fab'-SH is the designation herein for Fab' in which the cysteine residue(s) of the constant domains bear a free thiol group. F(ab')2 antibody fragments originally were produced as pairs of Fab' fragments which have hinge cysteines between them. Other chemical couplings of 98MF-365921286217372000640antibody fragments are also known. In some embodiments, the antibodies are recombinantly-produced fragments. For instance, the chains of an antibody or antigen-binding fragment can be incorporated into an expression vector and expressed from a host cell to produce the antibody. In some instances, a recombinantly-produced antibody fragments also can include fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and / or that are may not be produced by enzyme digestion of a naturally- occurring intact antibody. In some aspects, the antibody fragments are scFvs. For example, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as 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 within the term “antigen-binding portion” of an antibody. Antigen-binding portions can be produced by recombinant DNA techniques, or by enzymatic or chemical cleavage of intact immunoglobulins.

[0228] The term “human antibody”, “human antibody construct” and “human binding domain” includes antibodies, antibody constructs and binding domains having antibody regions such as variable and constant regions or domains which correspond substantially to human germline immunoglobulin sequences known in the art, including, for example, those described by Kabat et al. (1991) (loc. cit.). The human antibodies, antibody constructs or binding domains of the invention may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or side-specific mutagenesis in vitro or by somatic mutation in vivo), for example in the CDRs, and in particular, in CDR3. The human antibodies, antibody constructs or binding domains can have at least one, two, three, four, five, or more positions replaced with an amino acid residue that is not encoded by the human germline immunoglobulin sequence. The definition of human antibodies, antibody constructs and binding domains as used herein, however, also contemplates “fully human antibodies”, which include only non- artificially and / or genetically altered human sequences of antibodies as those can be derived by using technologies or systems such as the Xenomouse. Preferably, a “fully human antibody” does not include amino acid residues not encoded by human germline immunoglobulin sequences.99MF-365921286217372000640

[0229] Furthermore, the definition of the term “antibody construct” includes monovalent, bivalent and polyvalent / multivalent constructs and, thus, bispecific constructs, the latter which specifically bind to only two antigenic structure, as well as polyspecific / multispecific constructs, which specifically bind more than two antigenic structures, e.g. three, four or more, through distinct binding domains. Moreover, the definition of the term “antibody construct” includes molecules consisting of only one polypeptide chain as well as molecules consisting of more than one polypeptide chain, which chains can be either identical (homodimers, homotrimers or homo oligomers) or different (heterodimer, heterotrimer or heterooligomer). Examples for the above identified antibodies and variants or derivatives thereof are described inter alia in Harlow and Lane, Antibodies a laboratory manual, CSHL Press (1988) and Using Antibodies: a laboratory manual, CSHL Press (1999), Kontermann and Diibel, Antibody Engineering, Springer, 2nd ed. 2010 and Little, Recombinant Antibodies for Immunotherapy, Cambridge University Press 2009.

[0230] The term “bispecific” as used herein refers to an antibody construct which is that comprises at least a first binding domain and a second binding domain, wherein the first binding domain binds to one antigen or target (e.g., CD19 as disclosed herein), and the second binding domain binds to another antigen or target (e.g, CD3 as disclosed herein). Accordingly, antibody constructs according to the invention comprise specificities for at least two different antigens or targets. A bispecific antibody can be a monoclonal antibody that has binding specificity for two different epitopes. Bispecific antibodies can be prepared as full length antibodies or antibody fragments. Given that the antibody constructs are (at least) bispecific, they do not occur naturally and they are markedly different from naturally occurring products. A “bispecific” antibody construct or immunoglobulin is hence an artificial hybrid antibody or immunoglobulin having at least two distinct binding sides with different specificities. Bispecific antibody constructs can be produced by a variety of methods including fusion of hybridomas or linking of Fab' fragments. See, e.g., Songsivilai & Lachmann, Clin. Exp. Immunol. 79:315-321 (1990).

[0231] The term “target cell surface antigen” refers to an antigenic structure expressed by a cell and which is present at the cell surface such that it is accessible for an antibody construct as described herein. It may be a protein, preferably the extracellular portion of a protein, or a carbohydrate structure, preferably a carbohydrate structure of a protein, such as a glycoprotein.100MF-365921286217372000640

[0232] As used herein, "administering" refers to the physical introduction of a CD 19 binding molecule, such as an anti-CD19 antibody or an anti-CD19 and anti-CD3 bispecific antibody, including antibody fragments thereof, or a nucleic acid or expression vector as described herein encoding the same, alone or in combination with another therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art. Preferred routes of administration for antibodies described herein include intravenous, intraperitoneal, intramuscular, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intraperitoneal, intramuscular, intraarterial, intrathecal, intra-lymphatic, intralesional, intracap sular, intraorbital, intracardiac, intradermal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion, as well as in vivo electroporation. Alternatively, an antibody described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically. Administering can also be performed, for example, once, a plurality of times, and / or over one or more extended periods.

[0233] The terms “treat,” “treating,” and “treatment,” as used herein, refer to any type of intervention or process performed on, or administering an active agent (e.g., an anti-CD19 binding molecule, such as an anti-CD19 antibody or an anti-CD19 and anti-CD3 bispecific antibody, including antibody fragments thereof) to, the subject with the objective of preventing, reversing, alleviating, ameliorating, inhibiting, or slowing down or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease. Treatment can be of a subject having a disease or a subject who does not have a disease (e.g., for prophylaxis).

[0234] As used herein, the term “subject” includes any human or non-human animal. The term “non-human animal” includes all vertebrates, e.g., a mammals and non-mammals, such as non-human primates, sheep, cats, dogs, cows, chickens, amphibians, and reptiles.

[0235] The term “patient” includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment.

[0236] The terms “detection” or “detected”, as used herein refer to qualitative and / or quantitative detection (measuring levels) with or without reference to a control.101MF-365921286217372000640

[0237] The term “diagnosing”, as used herein, means the determination of the nature of a medical condition intended to identify a pathology which affects the subject from a number of collected data.

[0238] The terms “(specifically) binds to”, (specifically) recognizes”, “is (specifically) directed to”, and “(specifically) reacts with” mean in accordance with this invention that a binding domain interacts or specifically interacts with a given epitope or a given target side on the target molecules (antigens), e.g., CD19 and / or CD3 as disclosed herein.

[0239] The term “epitope” refers to a side on an antigen to which a binding domain, such as an antibody or immunoglobulin, or a derivative, fragment or variant of an antibody or an immunoglobulin, specifically binds. An “epitope” is antigenic and thus the term epitope is sometimes also referred to herein as “antigenic structure” or “antigenic determinant”. Thus, the binding domain is an “antigen interaction side”. Said binding / interaction is also understood to define a “specific recognition”.

[0240] “Epitopes” can be formed both by contiguous amino acids or non-contiguous amino acids juxtaposed by tertiary folding of a protein. A “linear epitope” is an epitope where an amino acid primary sequence comprises the recognized epitope. A linear epitope typically includes at least 3 or at least 4, and more usually, at least 5 or at least 6 or at least 7, for example, about 8 to about 10 amino acids in a unique sequence.

[0241] A “conformational epitope”, in contrast to a linear epitope, is an epitope wherein the primary sequence of the amino acids comprising the epitope is not the sole defining component of the epitope recognized (e.g., an epitope wherein the primary sequence of amino acids is not necessarily recognized by the binding domain). With regard to recognition of conformational epitopes, the binding domain recognizes a three-dimensional structure of the antigen, preferably a peptide or protein or fragment thereof (in the context of the present invention, the antigenic structure for one of the binding domains is comprised within the target cell surface antigen protein). For example, when a protein molecule folds to form a three-dimensional structure, certain amino acids and / or the polypeptide backbone forming the conformational epitope become juxtaposed enabling the antibody to recognize the epitope. Methods of determining the conformation of epitopes include, but are not limited to, x-ray crystallography, two-dimensional nuclear magnetic resonance (2D-NMR) spectroscopy and site-directed spin labelling and electron paramagnetic resonance (EPR) spectroscopy.

[0242] “Appreciable affinity” includes binding with an affinity of about 10−6M (KD) or stronger. Preferably, binding is considered specific when the binding affinity is about 10−12to 102MF-36592128621737200064010−8M, 10−12to 10−9M, 10−12to 10−10M, 10−11to 10−8M, preferably of about 10−11to 10−9M. Whether a binding domain specifically reacts with or binds to a target can be tested readily by, inter alia, comparing the reaction of said binding domain with a target protein or antigen with the reaction of said binding domain with proteins or antigens other than the CD 19 or CD3. Preferably, a binding domain of the invention does not essentially or substantially bind to proteins or antigens other than CD19 or CD3 (i.e., the first binding domain is not capable of binding to proteins other than CD 19 and the second binding domain is not capable of binding to proteins other than CD3). It is an envisaged characteristic of the antibody constructs according to the present invention to have superior affinity characteristics in comparison to other HLE formats. Such a superior affinity, in consequence, suggests a prolonged half-life in vivo. The longer half-life of the antibody constructs according to the present invention may reduce the duration and frequency of administration which typically contributes to improved patient compliance. This is of particular importance as the antibody constructs of the present invention are particularly beneficial for highly weakened or even treatment resistant B cell disorder patients.

[0243] The term “does not essentially / substantially bind” or “is not capable of binding” means that a binding domain of the present invention does not bind a protein or antigen other than the CD19 or CD3, i.e., does not show reactivity of more than 30%, preferably not more than 20%, more preferably not more than 10%, particularly preferably not more than 9%, 8%, 7%, 6% or 5% with proteins or antigens other than CD19 or CD3, whereby binding to the CD19 or CD3, respectively, is set to be 100%.

[0244] As used herein, “isotype” refers to the antibody class (e.g., IgG (including IgGl, IgG2, IgG3, and IgG4), IgM, IgA (including IgAl and IgA2), IgD, and IgE antibody) that is encoded by the heavy chain constant region genes of the antibody.

[0245] An antibody may be from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM. The IgG isotype is divided in subclasses in certain species: IgGl, IgG2, IgG3 and IgG4 in humans, and IgGl, IgG2a, IgG2b and IgG3 in mice. Immunoglobulins, e.g., IgGl, exist in several allotypes, which differ from each other in at most a few amino acids.

[0246] As used herein, the term “allotype” refers to naturally occurring variants within a specific isotype group, where the variants differ in a few amino acids. Anti- antibodies described herein can be of any allotype. The mutation of certain residues would modulate103MF-365921286217372000640(i.e., eliminate or decrease) the binding of the antibodies to Fcγ receptors and / or Clq, and thus reduce activator efficacy of the Fc domain of the IgG component of an antibody.

[0247] For nucleic acids, the term “substantial homology” indicates that two nucleic acids, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate nucleotide insertions or deletions, in at least about 80% of the nucleotides, usually at least about 80% to 85%, 85% to 90% or 90% to 95%, and more preferably at least about 98% to 99.5% of the nucleotides. Alternatively, substantial homology exists when the segments will hybridize under selective hybridization conditions, to the complement of the strand. For polypeptides, the term “substantial homology” indicates that two polypeptides, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate amino acid insertions or deletions, in at least about 80% of the amino acids, usually at least about 80% to 85%, 85% to 90%, 90% to 95%, and more preferably at least about 98% to 99.5% of the amino acids.

[0248] The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = # of identical positions / total # of positions x 100), considering the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described in the non-limiting examples below.

[0249] The percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at http: / / www.gcg.com), using a NWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6. The percent identity between two nucleotide or two amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CAB IOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM 120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. In addition, the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.

[0250] The term “monoclonal antibody” (mAb) or monoclonal antibody construct as used herein refers to an antibody obtained from a population of substantially homogeneous 104MF-365921286217372000640antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and / or post-translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic side or determinant on the antigen, in contrast to conventional (polyclonal) antibody preparations which typically include different antibodies directed against different determinants (or epitopes). The modifier “monoclonal” indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. A monoclonal antibody may be made by a variety of techniques, including but not limited to generation from a hybridoma, recombinant DNA methods, phage-display and other antibody display methods.

[0251] The term “amino acid” or “amino acid residue” typically refers to an amino acid having its art recognized definition such as an amino acid selected from the group consisting of: alanine (Ala or A); arginine (Arg or R); asparagine (Asn or N); aspartic acid (Asp or D); cysteine (Cys or C); glutamine (Gin or Q); glutamic acid (Glu or E); glycine (Gly or G); histidine (His or H); isoleucine (Ile or I): leucine (Leu or L); lysine (Lys or K); methionine (Met or M); phenylalanine (Phe or F); pro line (Pro or P); serine (Ser or S); threonine (Thr or T); tryptophan (Trp or W); tyrosine (Tyr or Y); and valine (Vai or V), although modified, synthetic, or rare amino acids may be used as desired. Generally, amino acids can be grouped as having a nonpolar side chain (e.g., Ala, Cys, He, Leu, Met, Phe, Pro, Vai); a negatively charged side chain (e.g., Asp, Glu); a positively charged sidechain (e.g., Arg, His, Lys); or an uncharged polar side chain (e.g., Asn, Cys, Gin, Gly, His, Met, Phe, Ser, Thr, Trp, and Tyr).

[0252] Amino acid modifications include, for example, deletions from, and / or insertions into, and / or substitutions of, residues within the amino acid sequences of the antibody constructs. Any combination of deletion, insertion, and substitution is made to arrive at the final construct, provided that the final construct possesses the desired characteristics. The amino acid changes also may alter post-translational processes of the antibody constructs, such as changing the number or position of glycosylation sites.

[0253] For example, 1, 2, 3, 4, 5, or 6 amino acids may be inserted, substituted or deleted in each of the CDRs (of course, dependent on their length), while 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 25 amino acids may be inserted, substituted or deleted in each of the FRs. Preferably, amino acid sequence insertions into the binding molecule or antibody construct include amino- and / or carboxyl-terminal fusions ranging in 105MF-365921286217372000640length from 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 residues to polypeptides containing a hundred or more residues, as well as intra-sequence insertions of single or multiple amino acid residues. Corresponding modifications may also performed within the third domain of the antibody construct of the invention. An insertional variant of the antibody construct of the invention includes the fusion to the N-terminus or to the C-terminus of the antibody construct of an enzyme or the fusion to a polypeptide.

[0254] The term “polypeptide” as used herein describes a group of molecules, which usually consist of more than 30 amino acids. Polypeptides may further form multimers such as dimers, trimers and higher oligomers, i.e., consisting of more than one polypeptide molecule. Polypeptide molecules forming such dimers, trimers etc. may be identical or nonidentical. The corresponding higher order structures of such multimers are, consequently, termed homo- or heterodimers, homo- or heterotrimers etc. An example for a hereteromultimer is an antibody molecule, which, in its naturally occurring form, consists of two identical light polypeptide chains and two identical heavy polypeptide chains. The terms “peptide”, “polypeptide” and “protein” also refer to naturally modified peptides / polypeptides / proteins wherein the modification is effected e.g. by post-translational modifications like glycosylation, acetylation, phosphorylation and the like. A “peptide”, “polypeptide” or “protein” when referred to herein may also be chemically modified such as pegylated. Such modifications are well known in the art and described herein below.II. CD19 BINDING MOLECULES INCLUDING CD3- AND CD19- BINDING MOLECULES

[0255] Also provided are polynucleotides containing nucleic acids sequences encoding all or a portion of any of the provided binding molecules or antibody constructs, including any of the provided antibodies or antigen-binding fragments or other binding molecules incorporating the same. The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) constructs, such as those that can be introduced into cells for expression thereof.

[0256] Antibody fragments within the scope of the present invention also include F(ab’)2 fragments which may be produced by enzymatic cleavage of an IgG by, for example, pepsin. Fab fragments may be produced by, for example, reduction of F(ab’)2 with dithiothreitol or mercaptoethylamine. A Fab fragment is a VL-CL chain appended to a VH-CH1 chain by a disulfide bridge. A F(ab’)2 fragment is two Fab fragments which, in turn, are appended by 106MF-365921286217372000640two disulfide bridges. The Fab portion of an F(ab’)2 molecule includes a portion of the Fc region between which disulfide bridges are located.A. CD19 antibody binding domain

[0257] Provided are binding molecules that contain an anti-CD19 antibody binding domain, including full-length antibodies and functional antigen-binding fragments. In some embodiments, the antibodies include antibodies that specifically bind to CD 19, e.g., human CD19. Exemplary antibodies are described below. In some embodiments, the antibody, e.g., the anti-CD19 antibody, such as a full-length antibody or antigen-binding antibody fragment, contains a VH sequence and a VL sequence as described. In some embodiments, the antiCD 19 antibody is an antigen-binding antibody fragment that is a single chain fragment, such as a scFv fragment. In some aspects, the scFv comprises a VH region and a VL region. In some embodiments, the anti-CD19 antibody is an antigen-binding antibody fragment that is an Fv fragment containing a VH region and a VL region. In some embodiments, the Fv fragment is a dsFv. In some embodiments, the anti-CD19 antibody is an antigen-binding antibody fragment that is a Fab. In some embodiments, the antibodies provided herein bind to human CD19 with the amino acid sequence set forth in SEQ ID NO: 1, such as is encoded by the nucleotide sequence set forth in SEQ ID NO: 2.

[0258] In some embodiments, the anti-CD19 binding region includes one or more copies of an antibody or an antigen-binding fragment thereof selected from the group consisting of a Fab fragment, a F(ab')2 fragment, an Fv fragment, or an a scFv. In some embodiments, the anti-CD19 binding region is monovalent for binding CD19. In some embodiments, the antiCD 19 binding region is a Fab. In some embodiments, the anti-CD19 binding region is a disulfide stabilized Fv fragment.

[0259] Among the provided antibodies, e.g., antigen-binding fragments, are human antibodies. In some embodiments of a provided human anti-CD19 antibody, e.g., antigenbinding fragments, the human antibody contains a VH region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and / or contains a VL region 107MF-365921286217372000640that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment.

[0260] Among the provided antibodies, e.g., antigen-binding fragments, are human antibodies. In some embodiments of a provided human anti- CD19 antibody, e.g., antigenbinding fragments, the human antibody contains a VH region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment; and contains a VL region that comprises a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100 % sequence identity to an amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment. In some embodiments, the portion of the VH region corresponds to the CDR-H1, the CDR-H2 and / or the CDR-H3. In some embodiments, the portion of the VH region corresponds to the CDR-H1, the CDR-H2 and the CDR-H3. In some embodiments, the portion of the VL region corresponds to the CDR-L1, the CDR-L2 and / or the CDR-L3. In some embodiments, the portion of the VL region corresponds to the CDR-L1, the CDR-L2 and the CDR-L3.

[0261] Among the provided antibodies are monoclonal antibodies, including monoclonal antibody fragments.

[0262] In some embodiments, the anti- CD19 antibody, e.g., antigen-binding antibody fragment, contains a VH region sequence that contains a CDR-H1, a CDR-H2 and a CDR-H3 as described and contains a VL region sequence that contains a CDR-L1, a CDR-L2 and / or a CDR-L3 as described. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 108MF-36592128621737200064099% identical to such a sequence, e.g., any of the CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, CDR-L3 sequences of the antibodies described herein. Also among the provided antibodies and fragment thereof are those having sequences at least at or about 85%, at or about 86%, at or about 87%, at or about 88%, at or about 89%, at or about 90%, at or about 91%, at or about 92%, at or about 93%, at or about 94%, at or about 95%, at or about 96%, at or about 97%, at or about 98%, or at or about 99% identical to such a sequence, e.g., any of the VH and VL sequences, respectively, of the antibodies described herein.

[0263] The disclosed binding molecules include anti-CD19 antibodies, including antigen binding fragments, comprising specified paratope resides that interact with the human CD19. In some embodiments, the provided anti-CD19 antibodies, including antibody fragments, comprises a VH region comprising a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3) present in (or contained in) a VH amino acid sequence set forth in any one of SEQ ID NOS: 12, 32, 34, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, or 88, and a VL region comprising a light chain complementarity determining region 1 (CDR-L1), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3) present in (or contained in) a VL amino acid sequence set forth in any one of SEQ ID NO: 17, 33, 35, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, or 89.

[0264] In some embodiments, the VH region of an antibody or antigen-binding fragment thereof comprises a CDR-H1, a CDR-H2 and a CDR-H3 according to Kabat numbering. In some embodiments, the VL region of an antibody or antigen-binding fragment thereof comprises a CDR-L1, a CDR-L2 and a CDR-L3 according to Kabat numbering.

[0265] In some embodiments, the CDR-H1 comprises the amino acid sequence set forth in set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155. In some embodiments, the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15, 122, 126, 25, 138, 144, 149, or 157, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158.109MF-365921286217372000640

[0266] In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 33. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 35. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 44, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 45. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 46, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 48, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 49. In some embodiments, the VH region comprises a CDR-Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 50, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 51. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 52, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 53. In some embodiments, the VH region comprises a CDR-Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 55. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 57. In some embodiments, the VH region comprises a CDR-Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 59. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 61. In some embodiments, the VH region comprises the CDR-Hl, the CDR- H2, and the CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 63. In some embodiments, the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 12, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 17. In some embodiments, the VH region comprises a CDR- 110MF-365921286217372000640Hl, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 88, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89.

[0267] In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 120, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 121, 122, and 123, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 124, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:125, 126, and 127, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 128, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 129, 126, and 130, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 131, 132, and 133, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 134, 25, and 135, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 136, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:137, 138, and 139, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:140, 141, and 142, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 143, 144, and 145, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 146, 119, and 147, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3111MF-365921286217372000640comprising the amino acid sequence set forth in SEQ ID NOS: 148, 149, and 150, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 151, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 152, 126, and 153, respectively. In some embodiments, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:131, 154, and 155, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 156, 157, and 158, respectively.

[0268] In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 44, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 45. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 46, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 47. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 48, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%,112MF-36592128621737200064092%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 49. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 50, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 51. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 52, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%,113MF-36592128621737200064088%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 17. In some embodiments, the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 88, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 89.

[0269] In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 32 and 33, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 34 and 35, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 44 and 45, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 46 and 47, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 48 and 49, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 50 and 51, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 52 and 53, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 54 and 55, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 56 and 57, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 58 and 59, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 60 and 61, respectively. In some embodiments, the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 62 and 63respectively. In some embodiments, the VH region and the VL region of the CD 19 binding domain comprises the sequence or are the sequence set forth in SEQ ID NOs: 12 and 17, respectively. In some embodiments, the114MF-365921286217372000640VH region and the VL region of the CD 19 binding domain comprises the sequence or are the sequence set forth in SEQ ID NOs: 88 and 89, respectively.

[0270] In some embodiments, the VH region of the CD 19 binding domain comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively. In some embodiments the VH region of the CD 19 binding domain is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17. In some embodiments, the VH region and the VL region of the CD19 binding domain comprises the sequence or are the sequence set forth in SEQ ID NOs: 12 and 17, respectively.

[0271] In some embodiments, the VH region of the CD 19 binding domain comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 118, 119, and 120, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 121, 122, 123, respectively. In some embodiments, the VH region of the CD19 binding domain is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 88, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 89. In some embodiments, the VH region and the VL region of the CD19 binding domain comprises the sequence or are the sequence set forth in SEQ ID NOs: 88 and 89, respectively.

[0272] In some embodiments, a provided binding molecule is an antibody or an antigenbinding fragment thereof that comprises a VH region and VL region, and their combinations, described above. In some embodiments, the antibody or antigen-binding fragment further includes human immunoglobulin constant regions. In some embodiments, the antibody or antigen-binding fragment is an antigen-binding fragment. In some embodiments, the antigenbinding fragment format retains CD 19 binding conferred by the VH and VL regions. In some embodiments, the antigen-binding fragment may be an Fv, scFv, Fab, Fab', F(ab')2, or other 115MF-365921286217372000640antigen-binding fragment of antibodies. In some embodiments, the antibody or antigenbinding fragment is a full-length antibody that comprises human immunoglobulin constant regions, including an Fc region.

[0273] Antigen-binding fragments can be made by various techniques, including but not limited to proteolytic digestion of an intact antibody as well as production by recombinant host cells. In some embodiments, the antibodies are recombinantly-produced fragments, such as fragments comprising arrangements that do not occur naturally, such as those with two or more antibody regions or chains joined by synthetic linkers, e.g., peptide linkers, and / or that may not be produced by enzyme digestion of a naturally-occurring intact antibody.

[0274] In some embodiments, the antibody is an scFv containing any of the above VH and VL regions. In some embodiments, the scFv includes a linker joining the two antibody VH and VL region. The linker typically is a peptide linker, e.g., a flexible and / or soluble peptide linker, such as one rich in glycine and serine. In some aspects, the linker that is rich in glycine and serine (and / or threonine) includes at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% glycine, serine, and / or threonine amino acid(s). In some embodiments, the linker includes at least at or about 50%, 55%, 60%, 70%, or 75%, glycine, serine, and / or threonine. In some embodiments, the linker is comprised substantially entirely of glycine, serine, and / or threonine. The linkers generally are between about 5 and about 50 amino acids in length, typically between at or about 10 and at or about 30, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some examples between 10 and 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS; SEQ ID NO: 160) or GGGS (3GS; SEQ ID NO: 217), such as between 2, 3, 4 and 5 repeats of such a sequence. Exemplary linkers include those having the sequence set forth in SEQ ID NO: 162 (GGGGSGGGGSGGGGS). Exemplary linkers further include those having the sequence set forth in SEQ ID NO: 161 (GGGGSGGGGS). Exemplary linkers further include those having the sequence set forth in SEQ ID NO: 218 (GSTSGSGKPGSGEGSTKG). Exemplary linkers further include those having or consisting of the sequence set forth in SEQ ID NO: 219 (SRGGGGSGGGGSGGGGSLEMA). An exemplary linker includes those having or consisting of the sequence set forth in SEQ ID NO: 220 (GSRGGGGSGGGGSGGGGSLEMA). In some embodiments, the VH region may be amino terminal to the VL region. In some embodiments, the VH region may be carboxy terminal to the VL region. In particular embodiments, the fragment, e.g., scFv, may include a VH region 116MF-365921286217372000640or portion thereof, followed by the linker, followed by a VL region or portion thereof. In other embodiments, the fragment, e.g., the scFv, may include the VL region or portion thereof, followed by the linker, followed by the VH region or portion thereof.

[0275] In some embodiments, the scFv is a disulfide- stabilized Fv (ds-scFv) in which the VH and VL contain a first and second engineered cysteine residue, respectively, that form a disulfide bond. In some embodiments, the VH region comprises a cysteine residue at framework region 2 position 44 (Kabat numbering) and the VL region comprises a cysteine residue at framework region 4 position 100 (Kabat numbering).

[0276] In some embodiments, the CD 19 binding domain is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 245. In some embodiments, the CD19 binding domain is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 248. In some embodiments, the CD19 binding domain is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 249. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 249. In some embodiments, the CD19 binding domain is an scFv comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 252. In some embodiments, the scFv comprises the amino acid sequence of SEQ ID NO: 252.

[0277] In some embodiments, the antibody is an antigen-binding fragment comprising the VH and VL regions that further comprises at least a portion of an immunoglobulin constant region of the heavy chain and at least a portion of an immunoglobulin constant region of the light chain. In some embodiments, the CD 19 binding domain is an anti-CD19 antibody that is a Fab containing any of the above VH and VL regions. In some embodiments, the Fab contains a heavy chain comprising any one of the above VH regions and an immunoglobulin constant heavy chain domain 1 (CHI domain) and a light chain comprising any one of the above VL regions and an immunoglobulin constant light chain (CL).117MF-365921286217372000640

[0278] In some embodiments, the CHI is from an IgGl antibody. In some embodiments, the CHI is set forth by the sequence in SEQ ID NO: 221 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% identity to SEQ ID NO:221. In some embodiments, the CHI is set forth by the sequence in SEQ ID NO: 223 or a sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 9...

Claims

1. 217372000640CLAIMS1. A bispecific antibody comprising (a) a first binding domain that binds CD 19 and (b) a second binding domain that binds CD3, wherein:the first binding domain that binds CD 19 comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:(a) the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; andthe VL region comprises a light chain complementarity determining region 1 (CDR-Ll) comprising the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156; a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 15, 122, 126, 25, 138, 144, 149, or 157, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158; or(b) the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within any one of SEQ ID NOs: 12, 32, 34, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, or 88, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within any one of SEQ ID NOs: 17, 33, 35, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, or 89.

2. The bispecific antibody of claim 1, wherein in the first binding domain: the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; and316MF-365921286217372000640the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15, 122, 126, 25, 138, 144, 149, or 157, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158.

3. The bispecific antibody of claim 1 or claim 2, wherein in the first binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 33;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 35;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 44, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 45;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 46, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 47;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 48, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 49;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 50, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 51;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 52, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 53;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 55;317MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 57;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 59;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 61;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 63;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 12, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 17; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 88, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 89.

4. The bispecific antibody of any one of claims 1-3, wherein in the first binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 120, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 121, 122, and 123, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 124, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:125, 126, and 127, respectively;318MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 128, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 129, 126, and 130, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 131, 132, and 133, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 134, 25, and 135, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 136, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:137, 138, and 139, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:140, 141, and 142, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 143, 144, and 145, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 146, 119, and 147, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 148, 149, and 150, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 151, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 152, 126, and 153, respectively; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:131, 154, and 155, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 156, 157, and 158, respectively.

5. The bispecific antibody of any one of claims 1-4, wherein in the first binding domain:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence 319MF-365921286217372000640identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 44, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 45;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 46, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 47;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 48, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 49;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 50, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 51;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 52, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53;320MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 17; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 88, and the VL region comprises an amino acid sequence that has at 321MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 89.

6. The bispecific antibody of any one of claims 1-5, wherein in the first binding domain:the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 32 and 33, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 34 and 35, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 44 and 45, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 46 and 47, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 48 and 49, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 50 and 51, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 52 and 53, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 54 and 55, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 56 and 57, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 58 and 59, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 60 and 61, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 62 and 63, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 12 and 17, respectively; orthe VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 88 and 89, respectively.322MF-3659212862173720006407. The bispecific antibody of any one of claims 1-6, wherein the first binding domain is an scFv.

8. The bispecific antibody of claim 7, wherein the scFv comprises a VH-linker-VL arrangement.

9. The bispecific antibody of claim 7, wherein the scFv comprises a VL-linker-VH arrangement.

10. The bispecific antibody of any claim 8 or 9, wherein the linker is a peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 162).

11. The bispecific antibody of any of claims 1-10, wherein the first binding domain is an scFv that is a disulfide- stabilized scFv.

12. The bispecific antibody of any one of claims 1-11, wherein the first binding domain comprises:(a) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245;(b) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248;(c) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 249; or(d) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 252.

13. The bispecific antibody of any one of claims 1-12, wherein the first binding domain comprises:323MF-365921286217372000640(a) the amino acid sequence of SEQ ID NO: 245;(b) the amino acid sequence of SEQ ID NO: 248;(c) the amino acid sequence of SEQ ID NO: 249; or(d) the amino acid sequence of SEQ ID NO: 252.

14. The bispecific antibody of any one of claims 1-6, wherein, in the first binding domain, the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively.

15. The bispecific antibody of any one of claims 1-6 and 14, wherein, in the first binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17.

16. The bispecific antibody of any one of claims 1-6, 14 and 15, wherein the VH region and the VL region comprises the amino acid sequences set forth in SEQ ID NOs: 12 and 17, respectively.

17. The bispecific antibody of any one of claims 1-6, wherein, in the first binding domain, the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 118, 119, and 120, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 121, 122, 123, respectively.

18. The bispecific antibody of any one of claims 1-6 and 17, wherein, in the first binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 88, and the VL region that is or comprises an amino acid324MF-365921286217372000640sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 89.

19. The bispecific antibody of any one of claims 1-6, 17 and 18, wherein, in the first binding domain, the VH region and the VL region comprises the sequence set forth in SEQ ID NOs: 88 and 89, respectively.

20. The bispecific antibody of any one of claims 1-19, wherein the second binding domain that binds CD3 comprises a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:the VH comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 198, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 276, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 200; andthe VL comprises a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 24, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 201, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth within SEQ ID NO: 277.

21. The bispecific antibody of any one of claims 1-20, wherein in the second binding domain, the VH comprises a heavy chain complementarity determining region 1 (CDR-H1) comprising the amino acid sequence set forth in SEQ ID NO: 198, a heavy chain complementarity determining region 2 (CDR-H2) comprising the amino acid sequence set forth in SEQ ID NO: 199, and a heavy chain complementarity determining region 3 (CDR-H3) comprising the amino acid sequence set forth in SEQ ID NO: 200; andthe VL comprises a light chain complementarity determining region 1 (CDR-L1) comprising the amino acid sequence set forth in SEQ ID NO: 24, a light chain complementarity determining region 2 (CDR-L2) comprising the amino acid sequence set forth in SEQ ID NO: 201, and a light chain complementarity determining region 3 (CDR-L3) comprising the amino acid sequence set forth within SEQ ID NO: 106.325MF-36592128621737200064022. The bispecific antibody of any one of claims 1-21, wherein, in the second binding domain, the VH region binding domain and the VL region comprise, respectively: a VH region sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein X1is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G or A or S; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9is Y or D; X10is Y or F, X11is I or V, X12is R or G; X13is Y or H; X14is Q or S; X15is Y or H; X16is I or L; and X17is N or D; (SEQ ID NO: 278); anda VL region sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein Xi is S or G, X2is N or S; X3is K or N; and X4is Q or C (SEQ ID NO: 197).

23. The bispecific antibody of any one of claims 1-22, wherein, in the second binding domain, the VH region binding domain and the VL region comprise, respectively: a VH region sequence of the consensus sequence set forth in QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2X3GIHWVRQAPGKX4LEWVAAIWY DX5SX6X7YYADSVKGRFTISRDNSX8NTLX9LQMNSLRAEDTAVYYCARSNX10DX11L TX12X13YX14X15GX16X17VWGQGTTVTVSS, wherein X1is R, G, or E; X2is R or N; X3is Y or H, X4is G or C; X5is G or A; X6is K, H, or N, X7is K, T, or D; X8is K, E, or S; X9is Y or D; X10is Y or F, X11is I or V, X12is R or G; X13is Y or H; X14is Q or S; X15is Y or H; X16is I or L; and X17is N or D; (SEQ ID NO: 196); anda VL region sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASX1LEX2G VPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX3SYPRTFGX4GTKVEIK, wherein Xi is S or G, X2is N or S; X3is K or N; and X4is Q or C (SEQ ID NO: 197).

24. The bispecific antibody of any one of claims 20-23, wherein in the second binding domain:the CDR-H1 comprises the sequence set forth in any one of SEQ ID NOs: 19, 109, 202, or 203, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 20,326MF-365921286217372000640107, 110, 112, or 204-208, and the CDR-H3 comprises the sequence set forth in any one of SEQ ID NOs: 21, 108, 111, 113, or 209-214; andthe CDR-L1 comprises the sequence set forth in SEQ ID NOs: 24, the CDR-L2 comprises the sequence set forth in any one of SEQ ID NOs: 25, 114, 215, or 216, and the CDR-L3 comprises the sequence set forth in any one of SEQ ID NOs: 26 or 115.

25. The bispecific antibody of any one of claims 20-24, wherein in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 37;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 27;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 68, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 70, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 72, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 73;327MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 74, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 78, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 80, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 82, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 84, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 86, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 159, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 195, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 41, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 64, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 65, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;328MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 66, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 67, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 69, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 71, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 75, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 76, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 77, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 79, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 81, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 83, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 85, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;329MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 87, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 90, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 91, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 92, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 93, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 94, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 95, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 96, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 97, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 98, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37, 39, or 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 39;330MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 99;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 100;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 101;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NOs: 37.

26. The bispecific antibody of any one of claims 20-25, wherein in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;331MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 112, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 204, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;332MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 205, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 206, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 209, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 210, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 211, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;333MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 202, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 203, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 212, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 213, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 214, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 207, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;334MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 208, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectivelythe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 210, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 202, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 214, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 115, respectively;335MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 215, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 216, and 115, respectively;.the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 110, 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively.

27. The bispecific antibody of any one of claims 20-26, wherein in the second binding domain:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37;336MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 22, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 68, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 70, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 72, and the VL region comprises an amino acid sequence that has at 337MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 73;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 74, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 78, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 80, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 82, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 84, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 86, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;338MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 159, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 195, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 41, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 64, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 65, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 66, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 67, and the VL region comprises an amino acid sequence that has at 339MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 69, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 71, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 75, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 76, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 77, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 79, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;340MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 81, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 83, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 85, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 87, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 90, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 91, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 92, and the VL region comprises an amino acid sequence that has at 341MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 93, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 94, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 95, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 96, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 97, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 98, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NOs: 37, 39, or 43;342MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 99;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 100;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 101;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at 343MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37.

28. The bispecific antibody of any one of claims 20-27, wherein in the second binding domain:the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 40 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 42 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 22 and 27, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 68 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 70 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 72 and 73, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 74 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 78 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 80 and 39, respectively;344MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 82 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 84 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 86 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 159 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 195 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 41 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 64 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 65 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 66 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 67 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 69 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 71 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 75 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 76 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 77 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 79 and 37, respectively;345MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 81 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 83, and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 85 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 87 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 90 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 91 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 92 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 93 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 94 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 95 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 96 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 97 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 98 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 99, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 43, respectively;346MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 100, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 101, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 42 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 40 and 37, respectively.

29. The bispecific antibody of any one of claims 20-28, wherein in the second binding domain:the VH region comprising a sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTX8X9 YX10X11GX12X13VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5is K, T, or D; X6is K, E, or S; X7is Y or D; X8is R or G; X9is Y or H; X10 is Q or S; Xu is Y or H; X12 is I or L; and X13 is N or D; (SEQ ID NO: 116); andthe VL region comprising a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLEXiGV PSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX2SYPRTFGX3GTKVEIK, wherein Xi is N or S; X2is K or N; and X3is Q or C; (SEQ ID NO: 117).

30. The bispecific antibody of any one of claims 20-29, wherein in the second binding domain:the VH region comprising a sequence of the consensus sequence QVQLVESGGGVVQPGX1SLRLSCAASGFTFSX2YGIHWVRQAPGKX3LEWVAAIWYD X4SKX5YYADSVKGRFTISRDNSX6NTLX7LQMNSLRAEDTAVYYCARSNYDILTRYY X8X9GX10X11VWGQGTTVTVSS, wherein Xi is R, G, or E; X2is R or N; X3is G or C; X4is G or A; X5is K, T, or D; X6is K, E, or S; X7is Y or D; X8is Q or S; X9is Y or H; X10is I or L; and X11is N or D; (SEQ ID NO: 192); and347MF-365921286217372000640the VL region comprising a sequence of the consensus sequence set forth in AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVP SRFSGSGSGTDFTLTISSLQPEDFATYYCQQFX1SYPRTFGX2GTKVEIK, wherein Xi=K or NX2=Q or C; (SEQ ID NO: 193).

31. The bispecific antibody of any one of claims 20-30, wherein in the second binding domain, the VH comprises one or more amino acid residues selected from the group consisting of: an asparagine (N) at position 31, an alanine (A) at position 55, a tyrosine (Y) at position 80, a glycine (G) at position 106, a histidine (H) at position 107, a serine (S) at position 109, a histidine (H) at position 110, a leucine (L) at position 112, and an aspartic acid (D) at position 113 or any combination thereof, wherein the numbering is relative to SEQ ID NO: 36.

32. The bispecific antibody of any one of claims 20-31, wherein, in the second binding domain, the VH comprises:(a) amino acid residues asparagine (N) at position 31, alanine (A) at position 55, and tyrosine (Y) at position 80, wherein the numbering is relative to SEQ ID NO: 36;(b) alanine (A) at position 55, tyrosine (Y) at position 80, leucine (L) at position 112, and aspartic acid (D) at position 113, wherein the numbering is relative to SEQ ID NO: 36; or (c) alanine (A) at position 55, tyrosine (Y) at position 80, serine (S) at position 109, and histidine (H) at position 110, wherein the numbering is relative to SEQ ID NO: 36;33. The bispecific antibody of any one of claims 20-32, wherein, in the second binding domain, the VL region comprises one or more amino acid residues selected from the group consisting of: a serine (S) at position 56, an asparagine (N) at position 92, and a cysteine (C) at position 100, an asparagine (N) at position 108, or any combination thereof in relation to SEQ ID NO: 37.

34. The bispecific antibody of any of claims 20-33, wherein, in the second binding domain, the VL region comprises:(a) serine (S) at position 56, wherein the numbering is relative to SEQ ID NO: 36; or348MF-365921286217372000640(b) serine (S) at position 56 and asparagine (N) at position 92, wherein the numbering is relative to SEQ ID NO: 37.

35. The bispecific antibody of any one of claims 20-34, wherein, in the second binding domain, the VH comprises one or more amino acid residues selected from the group consisting of: a glycine (G) at position 16, a glutamic acid (E) at position 16, a threonine (T) at position 58, an aspartic acid (D) at position 58, a glutamic acid (E) at position 76, a serine (S) at position 76, or any combination thereof in relation to SEQ ID NO: 36.

36. The bispecific antibody of any of claims 1-35, wherein the second binding domain is an antigen binding antibody fragment.

37. The bispecific antibody of any of claims 1-35, wherein the second binding domain is a scFv, is a Fab, or is an Fv.

38. The bispecific antibody of claim 36 or claim 37, wherein the second binding domain is an scFv.

39. The bispecific antibody of any one of claims 37-38, wherein the scFv comprises a VH-linker-VL arrangement.

40. The bispecific antibody of any one of claims 37-39, wherein the scFv comprises a VL-linker-VH arrangement.

41. The bispecific antibody of claim 39 or claim 40, wherein the scFv comprises a peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 162).

42. The bispecific antibody of any of claims 1-41, wherein the second binding domain is an scFv that is a disulfide-stabilized scFv.

43. The bispecific antibody of claim 39, wherein, in the second binding domain, the VH region comprises cysteine (C) at position 44 and the VL region comprises a cysteine (C) at position 100 in relation to SEQ ID NO: 36.349MF-36592128621737200064044. The bispecific antibody of any one of claims 1-43, wherein, in the second binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within any one of SEQ ID NOs: 36, 38, 40, 42, 22, 68, 70, 72, 74, 78, 80, 82, 84, 86, 159 or 195, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within any one of SEQ ID NOs: 27, 37, 39, 43, or 73.

45. The bispecific antibody of any one of claims 1-44, wherein, in the second binding domain,:the CDR-H1 comprises the sequence set forth in any one of SEQ ID NOs: 19, or 109, the CDR-H2 comprises the sequence set forth in any one of SEQ ID NOs: 20, 107, 110, or 112, and the CDR-H3 comprises the sequence set forth in any one of SEQ ID NOs: 21, 108, 111, or 113; andthe CDR-L1 comprises the sequence set forth in SEQ ID NOs: 24, the CDR-L2 comprises the sequence set forth in any one of SEQ ID NOs: 25 or 114, and the CDR-L3 comprises the sequence set forth in any one of SEQ ID NOs: 26 or 115.

46. The bispecific antibody of any one of claims 1-45, wherein in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 36, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 37;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 38, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 40, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 42, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;350MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 22, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 27;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 68, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 70, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 72, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 73;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 74, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 78, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 80, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 82, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 84, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 86, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 159, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 43; or351MF-365921286217372000640the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 contained within SEQ ID NO: 195, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 contained within SEQ ID NO: 39.

47. The bispecific antibody of any one of claims 1-46, wherein in the second binding domain:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 107, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 114, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 109, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 110, and 108, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 112, and 21, respectively, and the VL region352MF-365921286217372000640comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOS: 19, 20, and 113, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively.

48. The bispecific antibody of any one of claims 1-47, wherein in the second binding domain:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 36, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 37;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 38, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 40, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 42, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 22, and the VL region comprises an amino acid sequence that has at353MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 27;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 68, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 70, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 72, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 73;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 74, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 78, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 80, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;354MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 82, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 84, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 86, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 159, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 43; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 195, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 39.

49. The bispecific antibody of any one of claims 1-48, wherein in the second binding domain:the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 36 and 37, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 38 and 39, respectively;355MF-365921286217372000640the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 40 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 42 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 22 and 27, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 68 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 70 and 43, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 72 and 73, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 74 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 78 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 80 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 82 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 84 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 86 and 39, respectively;the VH region and the VL region comprise the sequences set forth in SEQ ID NO: 159 and 43, respectively; orthe VH region and the VL region comprise the sequences set forth in SEQ ID NO: 195 and 39, respectively.

50. The bispecific antibody of any one of claims 1-49, wherein the second binding domain is an scFv comprising:356MF-365921286217372000640(a) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 246;(b) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 247;(c) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 250; or(d) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 251.

51. The bispecific antibody of any one of claims 1-50, wherein the second binding domain is an scFv comprising:(a) the amino acid sequence of SEQ ID NO: 246;(b) the amino acid sequence of SEQ ID NO: 247;(c) the amino acid sequence of SEQ ID NO: 250; or(d) the amino acid sequence of SEQ ID NO: 251.

52. The bispecific antibody of any one of claims 1-51, wherein in the second binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 21, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 26, respectively.

53. The bispecific antibody of any one of claims 1-52, wherein in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 22, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 27.357MF-36592128621737200064054. The bispecific antibody of any one of claims 1-53 wherein in the second binding domain, the VH region and the VL region comprises the sequence or are the sequences set forth in SEQ ID NO: 22 and 27, respectively.

55. The bispecific antibody of any one of claims 1-52, wherein in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 68, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 39.

56. The bispecific antibody of any one of claims 1-51, and 55, wherein in the second binding domain, the VH region and the VL region comprise the sequences or are the sequences set forth in SEQ ID NO: 68 and 39, respectively.

57. The bispecific antibody of any one of claims 1-51, wherein in the second binding domain, the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the sequence set forth in SEQ ID NOs: 19, 20, and 111, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the sequence set forth in SEQ ID NOS: 24, 25, and 115, respectively.

58. The bispecific antibody of any one of claims 1-51 and 57, wherein in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 70, and the VL region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 43.

59. The bispecific antibody of any one of claims 1-51, 57 and 58, wherein in the CD3 binding domain, the VH region and the VL region comprise the sequences or are the sequences set forth in SEQ ID NO: 70 and 43, respectively.358MF-36592128621737200064060. The bispecific antibody of any one of claims 1-51 and 59, wherein in the second binding domain, the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 72, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 73.

61. The bispecific antibody of any one of claims 1-51, 59 and 60, wherein in the second binding domain, the VH region and the VL region comprise the sequences or are the sequences set forth in SEQ ID NO: 72 and 73, respectively.

62. The bispecific antibody of any one of claims 1-61, wherein:the first binding domain comprises the VH set forth in any one of SEQ ID NOs: 12 or 88 and the VL set forth in any one of SEQ ID NO: 17 or 89; andthe second binding domain comprises the VH set forth in any one of SEQ ID NOs: 22, 68, 72, or 70 and the VL set forth in any one of SEQ ID NO: 27, 39, 73, or 43.

63. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; andthe second binding domain comprises the VH set forth in SEQ ID NO: 22 and the VL set forth in SEQ ID NO: 27.

64. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; andthe second binding domain comprises the VH set forth in SEQ ID NO: 68 and the VL set forth in SEQ ID NO: 39.

65. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; and359MF-365921286217372000640the CD3 binding domain comprises the VH set forth in SEQ ID NO: 72 and the VL set forth in SEQ ID NO: 73.

66. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 12 and the VL set forth in SEQ ID NO: 17; andthe second binding domain comprises the VH set forth in SEQ ID NO: 70 and the VL set forth in SEQ ID NO: 43.

67. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; andthe second binding domain comprises the VH set forth in SEQ ID NO: 22 and the VL set forth in SEQ ID NO: 27.

68. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; andthe second binding domain comprises the VH set forth in SEQ ID NO: 68 and the VL set forth in SEQ ID NO: 39.

69. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; andthe second binding domain comprises the VH set forth in SEQ ID NO: 72 and the VL set forth in SEQ ID NO: 73.

70. The bispecific antibody of any of claims 1-62, wherein:the first binding domain comprises the VH set forth in SEQ ID NO: 88 and the VL set forth in SEQ ID NO: 89; andthe second binding domain comprises the VH set forth in SEQ ID NO: 70 and the VL set forth in SEQ ID NO: 43.360MF-36592128621737200064071. The bispecific antibody of any of claims 1-70, wherein the second binding domain has a KD of 5 to 75 nM to CD3.

72. The bispecific antibody of any of claims 1-71, wherein the second binding domain has a KD of 10 to 70 nM to CD3.

73. The bispecific antibody of any one of claims 1-72, wherein the first binding domain and the second binding domain are independently selected from a scFv and a Fab.

74. The bispecific antibody of any one of claims 1-73, wherein the first binding domain and / or the second binding domain is a scFv.

75. The bispecific antibody of any one of claims 1-74, wherein the first and the second binding domain are both an scFv.

76. The bispecific antibody of any one of claims 1-74, wherein the first binding domain is a scFv and the second binding domain is a Fab.

77. The bispecific antibody of any one of claims 1-76, wherein the first binding domain comprises, from N- to C-terminal order: the VH region and the VL region, optionally separated by a linker.

78. The bispecific antibody of any one of claims 1-77, wherein the first binding domain is a scFv that is disulfide- stabilized such that the VH region and VL region are covalently linked by a disulfide bond, optionally wherein the VH region comprises a cysteine residue at framework region 2 position 44 (Kabat numbering) and the VL region comprises a cysteine residue at framework region 4 position 100 (Kabat numbering).

79. The bispecific antibody of any one of claims 1-16, 20-66 and 71-78, wherein the first binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245.361MF-36592128621737200064080. The bispecific antibody of any one of claims 1-16, 20-66 and 71-79, wherein the first binding domain comprises the amino acid sequence of SEQ ID NO: 245.

81. The bispecific antibody of any one of claims 1-16, 20-62 and 67-78, wherein the first binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248.

82. The bispecific antibody of any one of claims 1-16, 20-62, 67-78 and 81, wherein the first binding domain comprises the amino acid sequence of SEQ ID NO: 248.

83. The bispecific antibody of any one of claims 1-82, wherein the second binding domain comprises, from N- to C-terminal order: the VH region and the VL region, optionally separated by a linker.

84. The bispecific antibody of any one of claims 1-83, wherein the second binding domain is a scFv that is disulfide-stabilized such that the VH region and VL region are covalently linked by a disulfide bond, optionally wherein the VH region comprises a cysteine residue at framework region 2 position 44 (Kabat numbering) and the VL region comprises a cysteine residue at framework region 4 position 100 (Kabat numbering).

85. The bispecific antibody of any one of claims 1-54, 62-63, 67, 71-75 and 77-84, wherein the second binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 246.

86. The bispecific antibody of any one of claims 1-54, 62-63, 67, 71-75 and 77-84, wherein the second binding domain comprises the amino acid sequence of SEQ ID NO: 246.

87. The bispecific antibody of any one of claims 1-49, 57, 60, 61, 62, 65, 69, 71-75 and 77-84, wherein the second binding domain comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 247.362MF-36592128621737200064088. The bispecific antibody of any one of claims 1-49, 57, 60, 61, 62, 65, 69, 71-75 and 77-84 and 87, wherein the second binding domain comprises the amino acid sequence of SEQ ID NO: 247.

89. The bispecific antibody of any of claims 1-88, wherein the antibody comprises a constant region from an IgGl or IgG2.

90. The bispecific antibody of claim 89, wherein the constant region is a human IgGl heavy chain constant region.

91. The bispecific antibody of any one of claims 1-89, wherein the antibody comprises an Fc region comprising a first and second Fc polypeptide each comprising a hinge-CH2-CH3.

92. The bispecific antibody of any one of claims 1-75 and 77-91, wherein the first binding domain and the second binding domain are together present on two polypeptide chains.

93. The bispecific antibody of any one of claims 1-75 and 77-92, comprising a first heavy chain and a second heavy chain, wherein:(a) the first heavy chain comprises (i) the first binding domain that is an scFv comprising the VH region and the VE region and (ii) a first Fc polypeptide comprising a hinge-CH2-CH3; and(b) the second heavy chain comprises (i) the second binding domain that is an scFv comprising the VH region and the VL region and (ii) a second Fc polypeptide comprising a hinge-CH2-CH3.

94. The bispecific antibody of any one of claims 1-75 and 77-91, wherein the first binding domain and the second binding domain are together present on three polypeptide chains.363MF-36592128621737200064095. The bispecific antibody of any one of claims 1-75, 77-91 and 94, comprising a first heavy chain, a second heavy chain, and a light chain, wherein:(a) the first heavy chain comprises (i) the first binding domain that is an scFv comprising the VH region and the VL region and (ii) a first Fc polypeptide comprising a hinge-CH2-CH3;(b) the second heavy chain comprises (i) the heavy chain of the second binding domain that is the heavy chain of a Fab comprising the VH region and CHI, (ii) and a second Fc polypeptide comprising a hinge-CH2-CH3; and(c) a light chain comprises the light chain of the second binding domain that is the light chain of the Fab comprising the VL region and the constant light chain (CL).

96. The bispecific antibody of any one of claims 1-95, wherein the first binding domain and the second binding domain are each N-terminal to the Fc region.

97. The bispecific antibody of any one of claims 91-96, wherein the Fc region is a heterodimeric Fc region.

98. The bispecific antibody of any one of claims 91-97, wherein each of the first and second polypeptide comprises one or more amino acid substitutions in a wild-type Fc polypeptide region to effect heterodimer formation between the first polypeptide and the second polypeptide.

99. The bispecific antibody of claim 98, wherein the wild-type Fc region is an IgGl Fc region or an IgG2 Fc region, optionally wherein the wild- type Fc region is a wildtype IgGl Fc region comprising the amino acid sequence set forth in SEQ ID NO: 253.

100. The bispecific antibody of claim 98 or claim 99, wherein the one more amino acid substitutions are a knob-into-hole modification, a charge mutation to reduce or prevent self-association due to charge repulsion, or disulfide bonding pairing mutation, or combinations thereof.364MF-365921286217372000640101. The bispecific antibody of any of claims 98-100, wherein the one or more amino acid substitutions are a knob-into-hole modification and disulfide bond pairing mutation.

102. The bispecific antibody of any of claims 98-101, wherein the one or more amino acid substitutions are:(i) amino acid substitution T366W in the first polypeptide of the heterodimeric Fc and amino acid substitutions T366S, L368A and Y407V in the second polypeptide of the heterodimeric Fc; and / or(ii) amino acid substitution S354C on the first polypeptide of the heterodimeric Fc and amino acid substitution Y349C on the second polypeptide of the heterodimeric Fc.

103. The bispecific antibody of any of claims 98-102, wherein the heterodimeric Fc region comprises one or more amino acid substitutions to reduce binding affinity to an Fc receptor and / or to reduce effector function, optionally as compared to a wild- type IgGl Fc region.

104. The bispecific antibody of claim 99, wherein the wild-type Fc region is a wildtype IgGl Fc region comprising the amino acid sequence set forth in SEQ ID NO: 253.

105. The bispecific antibody of claim 103, wherein the one or more amino acid substitutions are selected from L234A, L234V, L235A, L235E, G237A, D265S, S267K, R292C, N297G, V302C, and P329G by EU numbering.

106. The bispecific antibody of claim 105, wherein the one or more amino acid substitution comprises L234A and L235A.

107. The bispecific antibody of any of claims 104-106, wherein the one or more amino acid substitution comprises L234A, L235A, and D265S.

108. The bispecific antibody of any one of claims 91-107, wherein the first and second Fc polypeptide is of the human IgGl G Im 1,17 allotype.365MF-365921286217372000640109. The bispecific antibody of any one of claims 91-108, wherein the first and second Fc polypeptide comprise the amino acid substitutions D356E and L358M.

110. The bispecific antibody of any one of claims 91-109, wherien:the first Fc polypeptide is an IgGl Fc comprising amino acid substitutions L234A, L235A, D265S, S354C and T366W, and the second Fc polypeptide is an IgGl Fc comprising amino acid substitutions L234A, L235A, D265S, Y349C, T366S, L368A and Y407V; or the first Fc polypeptide is an IgGl Fc comprising amino acid substitutions L234A, L235A, G237A, S354C and T366W, and the second Fc polypeptide is an IgGl Fc comprising amino acid substitutions L234A, L235E, Y349C, T366S, L368A and Y407V.

111. The bispecific antibody of any of claims 91-110, wherein:the first Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 163 or 165; andthe second Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 164 or 166.

112. The bispecific antibody of any of claims 91-111, wherein:the first Fc polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 164 or 166; andthe second Fc polypeptide comprises the amino acid sequence set forth in SEQ ID NO: 163 or 165.

113. The bispecific antibody of any of claims 91-112, wherein the first Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 164 and the second Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 163.

114. The bispecific antibody of any of claims 91-113, wherein the first Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ366MF-365921286217372000640ID NO: 166 and the second Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 165.

115. The bispecific antibody of claim 103-109, wherein the one or more amino acid substitutions are selected from P238K.

116. The bispecific antibody of any one of claims 91-109 and 115, wherien the first Fc polypeptide is an IgG2 Fc comprising amino acid substitutions P238K, D356E, L358M, Y349C, T366S, L368A and Y407V, and the second Fc polypeptide is an IgG2 Fc comprising amino acid substitutions P238K, D356E, L358M, S354C and T366W.

117. The bispecific antibody of any of claims 91-109, 115 and 116, wherein: the first Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 168; andthe second Fc polypeptide comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity SEQ ID NO: 167.

118. The bispecific antibody of any of claims 91-109 and 115-117, wherein the first Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 168 and the second Fc polypeptide of the heterodimeric Fc region comprises the amino acid sequence set forth in SEQ ID NO: 167.

119. The bispecific antibody of any of claims 1-118, wherein the bispecific antibody is capable of binding CD 19 on B cells and CD3 on T cells.

120. The bispecific antibody of any of claims 1-119, wherein the bispecific antibody results in B cell and / or plasma blast depletion of greater than 90% in the lymph node, bone marrow, and / or blood as determined by an in vitro cell depletion assay.

121. A bispecific antibody, comprising:367MF-365921286217372000640(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 22, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 27, and a Fc region comprising the sequence set forth in SEQ ID NO: 165.

122. The bispecific antibody of claim 121, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; andthe second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:246 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

123. The bispecific antibody of claim 121 or claim 122, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 172; and(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 173.

124. The bispecific antibody of any one of claims 121-123, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 172; and(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 173.

125. A bispecific antibody, comprising:368MF-365921286217372000640(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 68 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 39 and a CL comprising the sequence set forth in SEQ ID NO: 171.

126. The bispecific antibody of claim 125, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166.

127. The bispecific antibody of claim 125 and 126, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 174;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 175; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 176.

128. The bispecific antibody of any one of claims 125-127, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 174;(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 175; and369MF-365921286217372000640(c) the light chain comprises the amino acid sequence of SEQ ID NO: 176.

129. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 72, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 73, and a Fc region comprising the sequence set forth in SEQ ID NO: 165.

130. The bispecific antibody of claim 129, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; andthe second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:247 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

131. The bispecific antibody of claim 129 or claim 130, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 177; and(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 178.

132. The bispecific antibody of any one of claims 129-131, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 177; and370MF-365921286217372000640(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 178.

133. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 70 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 43 and a CL comprising the sequence set forth in SEQ ID NO: 171.

134. The bispecific antibody of claim 133, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 166.

135. The bispecific antibody of claim 133 and 134, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 179;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 180; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 181.

136. The bispecific antibody of any one of claims 133-135, wherein:371MF-365921286217372000640(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 179;(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 180; and(c) the light chain comprises the amino acid sequence of SEQ ID NO: 181.

137. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 22, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 27, and a Fc region comprising the sequence set forth in SEQ ID NO: 165.

138. The bispecific antibody of claim 137, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; andthe second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:246 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

139. The bispecific antibody of claim 137 or claim 138, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 182; and(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 183.372MF-365921286217372000640140. The bispecific antibody of any one of claims 137-139, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 182; and(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 183.

141. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 68 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 39 and a CL comprising the sequence set forth in SEQ ID NO: 171.

142. The bispecific antibody of claim 141, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166.

143. The bispecific antibody of claim 141 and 142, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 184;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 185; and373MF-365921286217372000640(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 186.

144. The bispecific antibody of any one of claims 141-143, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 184;(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 185; and(c) the light chain comprises the amino acid sequence of SEQ ID NO: 186.

145. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 72, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 73, and a Fc region comprising the sequence set forth in SEQ ID NO: 165.

146. The bispecific antibody of claim 145, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166; andthe second heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:247 and the Fc region comprising the sequence set forth in SEQ ID NO: 165.

147. The bispecific antibody of claim 145 or claim 146, wherein the bispecific antibody comprises:374MF-365921286217372000640(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 187; and(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 188.

148. The bispecific antibody of any one of claims 145-147, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 187; and(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 188.

149. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 88, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 89, and a Fc region comprising the sequence set forth in SEQ ID NO: 166; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 70 and an IgG1 CH1 of SEQ ID NO: 169, and a Fc region comprising the sequence set forth in SEQ ID NO: 165; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 43 and a CL comprising the sequence set forth in SEQ ID NO: 171.

150. The bispecific antibody of claim 149, wherein:the first heavy chain polypeptide comprises from N-to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:248 and the Fc region comprising the sequence set forth in SEQ ID NO: 166.

151. The bispecific antibody of claim 149 and 150, wherein the bispecific antibody comprises:375MF-365921286217372000640(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 189;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 190; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 191.

152. The bispecific antibody of any one of claims 149-151, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 189;(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 190; and(c) the light chain comprises the amino acid sequence of SEQ ID NO: 191.

153. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 168; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 68 and an IgG1 CH1 of SEQ ID NO: 170, and a Fc region comprising the sequence set forth in SEQ ID NO: 167; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 39 and a CL comprising the sequence set forth in SEQ ID NO: 171.

154. The bispecific antibody of claim 153, wherein:the first heavy chain polypeptide comprises from N- to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 168.376MF-365921286217372000640155. The bispecific antibody of claim 153 and 154, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 234;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 235; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 236.

156. The bispecific antibody of any one of claims 153-155, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 234;(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 235; and(c) the light chain comprises the amino acid sequence of SEQ ID NO: 236.

157. A bispecific antibody, comprising:(a) a first heavy chain polypeptide comprising from N- to C-terminal order: a VH region comprising the sequence set forth in SEQ ID NO: 12, a linker of SEQ ID NO: 162, a VL region comprising the sequence set forth in SEQ ID NO: 17, and a Fc region comprising the sequence set forth in SEQ ID NO: 168; and(b) a second heavy chain polypeptide comprising from N- to C-terminal order: a Fab comprising a VH region comprising the sequence set forth in SEQ ID NO: 70 and an IgG1 CH1 of SEQ ID NO: 170, and a Fc region comprising the sequence set forth in SEQ ID NO: 167; and(c) a light chain comprises a VL region comprising the sequence set forth in SEQ ID NO: 43 and a CL comprising the sequence set forth in SEQ ID NO: 171.

158. The bispecific antibody of claim 157, wherein:377MF-365921286217372000640the first heavy chain polypeptide comprises from N- to C-terminal order the scFv comprising the sequence set forth in SEQ ID NO:245 and the Fc region comprising the sequence set forth in SEQ ID NO: 168.

159. The bispecific antibody of claim 157 and 158, wherein the bispecific antibody comprises:(a) a first heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 237;(b) a second heavy chain polypeptide comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 238; and(c) a light chain comprising an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 239.

160. The bispecific antibody of any one of claims 157-159, wherein:(a) the first heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 237;(b) the second heavy chain polypeptide comprises the amino acid sequence of SEQ ID NO: 238; and(c) the light chain comprises the amino acid sequence of SEQ ID NO: 239.

161. An isolated anti-CD19 antibody, or an antigen-binding fragment thereof, comprising a heavy chain variable (VH) region and a light chain variable (VL) region, wherein:(a) the VH region comprises a heavy chain complementarity determining region 1 (CDR-H1), a heavy chain complementarity determining region 2 (CDR-H2), and a heavy chain complementarity determining region 3 (CDR-H3), wherein the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; and378MF-365921286217372000640the VL region comprises a light chain complementarity determining region 1 (CDR-Ll), a light chain complementarity determining region 2 (CDR-L2), and a light chain complementarity determining region 3 (CDR-L3), wherein the CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs:, 15, 122, 126, 25, 138, 144, 149, or 157, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158; or (b) the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within any one of SEQ ID NOs: 12, 32, 34, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, or 88, and the VL region comprises a CDR-L1, a CDR-L2), and a CDR-L3 contained within any one of SEQ ID NOs: 17, 33, 35, 45, 47, 49, 51, 53, 55, 57, 59, 61, 63, or 89.

162. The anti-CD19 antibody, or an antigen-binding fragment thereof, of claim 161, wherein:the CDR-H1 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 9, 118, 131, 140, or 146, the CDR-H2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 10, 119, 132, 141, or 154, and the CDR-H3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 11, 120, 124, 128, 133, 136, 142, 147, 151, or 155; andthe CDR-L1 comprises the amino acid sequence set forth in SEQ ID NOs: 14, 121, 125, 129, 134, 137, 143, 148, 152, or 156, the CDR-L2 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 15, 122, 126, 25, 138, 144, 149, or 157, and the CDR-L3 comprises the amino acid sequence set forth in any one of SEQ ID NOs: 16, 123, 127, 130, 135, 139, 145, 150, 153, or 158.

163. The anti-CD19 antibody, or an antigen-binding fragment thereof, of claim 161, wherein:the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 32, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 33;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 34, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 35;379MF-365921286217372000640the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 44, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 45;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 46, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 47;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 48, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 49;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 50, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 51;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 52, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 53;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 54, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 55;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 56, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 57;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 58, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 59;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 60, and the VL region comprises a CDR-L1, a CDR-L2, a CDR-L3 contained within SEQ ID NO: 61;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 62, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 63;the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 12, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 17; or380MF-365921286217372000640the VH region comprises a CDR-H1, a CDR-H2, and a CDR-H3 contained within SEQ ID NO: 88, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 contained within SEQ ID NO: 89.

164. The anti-CD19 antibody, or an antigen-binding fragment thereof, of any of claims 161-163, wherein:the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 9, 10, and 11, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 120, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 121, 122, and 123, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 124, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:125, 126, and 127, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:118, 119, and 128, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 129, 126, and 130, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 131, 132, and 133, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 134, 25, and 135, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 136, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS:137, 138, and 139, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 140, 141, and 142, respectively, and the VL381MF-365921286217372000640region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 143, 144, and 145, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 146, 119, and 147, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 148, 149, and 150, respectively;the VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS: 118, 119, and 151, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 152, 126, and 153, respectively; orthe VH region comprises the CDR-H1, the CDR-H2, and the CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOS:131, 154, and 155, respectively, and the VL region comprises the CDR-L1, the CDR-L2, and the CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 156, 157, and 158, respectively.

165. The anti-CD19 antibody, or an antigen-binding fragment thereof, of any of claims 161-164, wherein:the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 32, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 33;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 34, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 35;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 44, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 45;382MF-365921286217372000640the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 46, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 47;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 48, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 49;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 50, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 51;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 52, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 53;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 54, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 55;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 56, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 57;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 58, and the VL region comprises an amino acid sequence that has at 383MF-365921286217372000640least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 59;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 60, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 61;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 62, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 63;the VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 12, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 17; orthe VH region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 88, and the VL region comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO: 89.

166. The anti-CD19 antibody, or an antigen-binding fragment thereof, of any of claims 161-165, wherein:the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 32 and 33, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 34 and 35, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 44 and 45, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 46 and 47, respectively;384MF-365921286217372000640the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 48 and 49, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 50 and 51, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 52 and 53, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 54 and 55, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 56 and 57, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 58 and 59, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 60 and 61, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 62 and 63, respectively;the VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 12 and 17, respectively; orthe VH region and the VL region comprise the amino acid sequences set forth in SEQ ID NO: 88 and 89, respectively.

167. The anti-CD19 antibody, or an antigen-binding fragment thereof, of any of claims 161-166, wherein the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NOs: 9, 10, and 11, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NOS: 14, 15, and 16, respectively.

168. The anti-CD19 antibody, or an antigen-binding fragment thereof, of claim 167, wherein the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 12, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 17.385MF-365921286217372000640169. The anti-CD19 antibody, or an antigen-binding fragment thereof, of claim 167 or claim 168, wherein the VH region and the VL region comprises the amino acid sequence set forth in SEQ ID NOs: 12 and 17, respectively.

170. The anti-CD19 antibody, or an antigen-binding fragment thereof, of any of claims 161-166, wherein the VH region comprises the CDR-H1, a CDR-H2, and a CDR-H3 comprising the sequence set forth in SEQ ID NOs: 118, 119, and 120, respectively, and the VL region comprises a CDR-L1, a CDR-L2, and a CDR-L3 comprising the sequence set forth in SEQ ID NOS: 121, 122, 123, respectively.

171. The anti-CD19 antibody, or an antigen-binding fragment thereof, of claim 170, wherein the VH region is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 88, and the VL region that is or comprises an amino acid sequence having at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 89.

172. The anti-CD19 antibody, or an antigen-binding fragment thereof, of claim 170 or claim 171, wherein the VH region and the VL region comprises the sequence or are the sequence set forth in SEQ ID NOs: 88 and 89, respectively.

173. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 161-172 that is a full-length antibody.

174. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 161-173, wherein the antibody is a human IgG.

175. The anti-CD19 antibody, or an antigen binding fragment thereof, of claim 174, wherein the antibody is IgGl.

176. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 161-175, wherein the antibody comprises a kappa light chain constant region.386MF-365921286217372000640177. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 161-176, wherein the antibody comprises:(a) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 254; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 255;(b) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 256; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 257;(c) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 258; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 259;(d) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 260; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 261;(e) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 262; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 263;387MF-365921286217372000640(f) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 264; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 265;(g) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 266; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 267;(h) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 268; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 269;(i) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 270; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 271;j) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 272; and (ii) a light chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 273;(k) (i) a heavy chain comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 274; and (ii) a light chain 388MF-365921286217372000640comprising an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 275.

178. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 161-177, wherein the antibody comprises:(a) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 254; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 255;(b) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 256; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 257;(c) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 258; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 259;(d) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 260; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 261;(e) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 262; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 263;(f) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 264; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 265;(g) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 266; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 267;(h) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 268; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 269;(i) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 270; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 271;j) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 272; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 273; or(k) (i) a heavy chain comprising the amino acid sequence of SEQ ID NO: 274; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO: 275.

179. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 161-172, that is an antigen-binding fragment.389MF-365921286217372000640180. The anti-CD19 antibody, or an antigen binding fragment thereof, of claim 179, wherein the antigen-binding fragment is selected from the group consisting of Fab, Fab', F(ab')2, Fv, and scFv.

181. The anti-CD19 antibody, or an antigen binding fragment thereof, of claim 179 or claim 180, wherein the antigen-binding fragment is an scFv.

182. The anti-CD19 antibody, or an antigen binding fragment thereof, of claim 181, wherein the scFv comprises a VH-linker-VL arrangement.

183. The anti-CD19 antibody, or an antigen binding fragment thereof, of claim 181, wherein the scFv comprises a VL-linker-VH arrangement.

184. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 182 or 183, wherein the linker is a peptide linker comprising (Gly4Ser)3 (SEQ ID NO: 162).

185. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 181-184, wherein the scFv comprises:(a) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245;(b) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248;(c) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 249; or(d) an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 252.390MF-365921286217372000640186. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 181-185, wherein the scFv comprises:(a) the amino acid sequence of SEQ ID NO: 245;(b) the amino acid sequence of SEQ ID NO: 248;(c) the amino acid sequence of SEQ ID NO: 249; or(d) the amino acid sequence of SEQ ID NO: 252.

187. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 181-186, wherein the scFv comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 245.

188. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 181-187, wherein the scFv comprises the amino acid sequence of SEQ ID NO: 245.

189. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 181-186, wherein the scFv comprises an amino acid sequence that has at least at or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the amino acid sequence of SEQ ID NO: 248.

190. The anti-CD19 antibody, or an antigen binding fragment thereof, of any one of claims 181-186 or 189, wherein the scFv comprises the amino acid sequence of SEQ ID NO: 248.

191. A polynucleotide comprising a nucleic acid sequence(s) encoding the bispecific antibody of any of claims 1-160 or the anti-CD19 antibody or an antigen-binding fragment thereof of any one of claims 161-190.

192. A polynucleotide system comprising a nucleic acid sequence encoding each chain of the bispecific antibody of any one of claims 1-160 or the anti-CD19 antibody or an antigen-binding fragment thereof of any one of claims 161-190.391MF-365921286217372000640193. A polynucleotide system comprising (a) a first nucleic acid sequence encoding the first heavy chain of the bispecific antibody of any one of claims 1-160, and (b) a second nucleic acid sequence encoding the second heavy chain of the bispecific antibody of any one of claims 1-160.

194. A vector comprising the polynucleotide of claim 191.

195. The vector of claim 194, wherein the vector is an expression vector.

196. A vector system comprising a plurality of vectors, each vector comprising a nucleic acid sequence of the polynucleotide system of claim 192 or claim 193.

197. The vector system of claim 196, wherein each vector is an expression vector.

198. A cell comprising the polynucleotide of claim 191 or the vector of any of claims 194-195.

199. A cell comprising the polynucleotide system of claim 192 or claim 193 or the vector system of claim 196 or claim 197.

200. The cell of claim 198 or claim 199, wherein the cell is a mammalian cell.

201. A method of producing an antibody comprising culturing the cell of any one of claims 198-200 under a condition that produces the antibody.

202. The method of claim 201, further comprising recovering the antibody produced by the cell.

203. An antibody or antigen-binding fragment thereof or bispecific antibody produced by the method of claim 201 or claim 202.

204. A composition comprising the bispecific antibody of any of claims 1-160.392MF-365921286217372000640205. A composition comprising the anti-CD19 antibody or an antigen-binding fragment thereof of any of claims 161-190.

206. The composition of claim 204 or claim 205, further comprising a pharmaceutically acceptable excipient.

207. A method for treating a disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of the bispecific antibody of any of claims 1-160 or composition of claim 204 or claim 206.

208. A method for treating a disease or condition in a subject in need thereof, the method comprising administering a therapeutically effective amount of the anti-CD19 antibody or an antigen-binding fragment thereof of any of claims 161-190 or composition of claim 205 or claim 206.

209. The method of claim 207 or claim 208, wherein the disease or condition is an infectious disease or disorder, an autoimmune disease, an inflammatory disease, or a tumor or a cancer.

210. The method of any one of claims 207-209, wherein the disease or condition is associated with overexpression of B cells in tissues.

211. The method of any of claims 207-210, wherein the disease or condition is an autoimmune disorder.

212. The method of claim 211, wherein the autoimmune disorder is associated with presence of increased autoantibodies and / or autoreactive B cells in the subject compared to a healthy subject.

213. The method of claim 211 or claim 212, wherein the autoimmune disorder is selected from the group consisting of psoriasis, psoriatic arthritis, Type 1 diabetes mellitus (Type 1 diabetes), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), cutaneous lupus erythematosus (CLE), multiple sclerosis (MS), inflammatory bowel disease (IBD),393MF-365921286217372000640lymphocytic colitis, acute disseminated encephalomyelitis (ADEM), Addison's disease, alopecia universalis, ankylosing spondylitisis, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune inner ear disease (AIED), autoimmune lymphoproliferative syndrome (ALPS), autoimmune oophoritis, Balo disease, Behcet's disease, bullous pemphigoid, cardiomyopathy, Chagas' disease, chronic fatigue immune dysfunction syndrome (CFIDS), chronic inflammatory demyelinating polyneuropathy, Crohn's disease, cicatrical pemphigoid, coeliac spruedermatitis herpetiformis, cold agglutinin disease, CREST syndrome, Degos disease, discoid lupus erythematosus (DLE), dysautonomia, endometriosis, essential mixed cryoglobulinemia, fibromyalgia-fibromyositis, Goodpasture's syndrome, Grave's disease, Guillain-Barre syndrome (GBS), Hashimoto's thyroiditis, Hidradenitis suppurativa, idiopathic and / or acute thrombocytopenic purpura, idiopathic pulmonary fibrosis, IgA neuropathy, interstitial cystitis, juvenile arthritis, Kawasaki's disease, lichen planus, Lyme disease, Meniere disease, mixed connective tissue disease (MCTD), myasthenia gravis, neuromyotonia, opsoclonus myoclonus syndrome (OMS), optic neuritis, Ord's thyroiditis, pemphigus vulgaris, pernicious anemia, polychondritis, polymyositis and dermatomyositis, primary biliary cirrhosis, polyarteritis nodosa, polyglandular syndromes, polymyalgia rheumatica, primary agammaglobulinemia, Raynaud phenomenon, Reiter's syndrome, rheumatic fever, sarcoidosis, scleroderma, Sjogren's syndrome, stiff person syndrome, Takayasu's arteritis, temporal arteritis (also known as “giant cell arteritis”), ulcerative colitis, collagenous colitis, uveitis, vasculitis, vitiligo, vulvodynia (“vulvar vestibulitis”), and Wegener's granulomatosis.

214. The method of any of claims 211-213, wherein the autoimmune disorder is systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjogren disease, or systemic sclerosis.

215. The method of any of claims 211-214, wherein the autoimmune disorder is SLE.

216. The method of any of claims 207-210, wherein the disease or condition is a cancer.

217. The method of claim 209 or claim 216, wherein the cancer is a solid tumor.394MF-365921286217372000640218. The method of claim 209, 216 or 217, wherein the cancer is a melanoma, breast carcinoma, HCC, Renal cell carcinoma, Colorectal carcinoma, non-small-cell lung carcinoma, Cervical cancer or Mesothelioma.

219. The method of claim 209, 216 or 217, wherein the cancer is a B -cell-related cancer selected from the group consisting of multiple myeloma, malignant plasma cell neoplasm, plasma cell leukemia, plasmacytoma, B-cell prolymphocytic leukemia, hairy cell leukemia, B-cell non-Hodgkin's lymphoma (NHL), chronic lymphocytic leukemia (CLL), follicular lymphoma, Burkitt's lymphoma, marginal zone lymphoma, mantle cell lymphoma, large cell lymphoma, precursor B -lymphoblastic lymphoma, Waldenstrom's macroglobulinemia, diffuse large B-cell lymphoma (DLBCL), mucosa-associated lymphatic tissue lymphoma (MALT lymphoma), small cell lymphocytic lymphoma, Primary mediastinal (thymic) large B-cell lymphoma, lymphoplasmacytic lymphoma, nodal marginal zone B cell lymphoma, splenic marginal zone lymphoma, intravascular large B-cell lymphoma, primary effusion lymphoma, lymphomatoid granulomatosis, T cell / histiocyte-rich large B-cell lymphoma, primary CNS (central nervous system) lymphoma, primary cutaneous diffuse large B-cell lymphoma (leg type), EBV positive diffuse large B-cell lymphoma of the elderly, diffuse large B-cell lymphoma associated with inflammation, ALK-positive large B-cell lymphoma, and plasmablastic lymphoma.

220. The method of any of claims 207-210, wherein the disease or condition is an inflammatory disease.

221. The method of claim 209 or 219, wherein the inflammatory disease is selected from the group consisting of asthma, atopic dermatitis (eczema), contact dermatitis and gout.

222. A kit comprising the bispecific antibody of any of claims 1-160 or the antiCD 19 antibody or an antigen-binding fragment thereof of any of claims 161-190 and, optionally, instructions for use.395MF-365921286