Baffr x CD3 bispecific antibodies and methods of use

Abstract

The present invention relates to antibodies that specifically bind human BAFFR, to bispecific antibodies that specifically bind to both human BAFFR and human CD3, compositions comprising such antibodies, and methods of using the same.

Description

BAFFR x CD3 BISPECIFIC ANTIBODIES AND METHODS OF USE

[0001] The present disclosure relates to antibodies that specifically bind human BAFFR, to bispecific antibodies that specifically bind to both human BAFFR and human CD3, compositions comprising such antibodies, and methods of using such antibodies for the treatment of B-cell cancers and other diseases.BACKGROUND

[0002] The number of newly diagnosed lymphoma and leukemia cases in the U.S. in 2024 is projected to be approximately 89,190 and 62,770 respectively (Siegel, R. et al., Cancer Statistics Jan 2024). Currently there are five marketed T cell engager (TCE) therapies to address some of these diseases: Blincyto® - blinatumomab a CD19 / CD3 (Amgen), Lunsumio® - mosunetuzumab a CD20 / CD3 (Genentech-Roche), Epkinly® - epcoritamab a CD20 / CD3 (Genmab-Abbvie), Columvi® - glofitamab a CD20 / CD3 (Roche), and Tecvayli® - teclistamab a BCMA / CD3 (Janssen) (see Tapia-Galisteo, A. et al., J Hematol Oncol 2023).

[0003] One of the earliest approved TCE therapies is blinatumomab (Blincyto®), a CD19 / CD3 BiTE, indicated for R / R B-cell precursor acute lymphocytic leukemia (ALL), see Tapia-Galisteo 2023. However, there are drawbacks to this therapy, such as toxicity and short half-life in the serum. Severe cytokine release syndrome (CRS) and neurological adverse events are the main reasons for the interruption of blinatumomab therapy, which appears to be attributed to abnormal activation of effector T cells and macrophages induced, see Jain, T. and Litzow, M., Ther Adv Hematol v.ll 2020. Other limitations are that the short half-life of blinatumomab requires a continuous infusion over 6-8 weeks which is a major hurdle of use in the clinic, see Viardot A. et al., Ann Hematol. 2020 and Bukhari Al and Lee ST,. Expert Rev Hematol. 2019.

[0004] Similarly, mosunetuzumab (Lunsumio®) is a CD20 / CD3 T cell dependent bispecific (TDB) approved in 2022 for relapsed or refractory (R / R) follicular lymphoma (FL). This TDB is a humanized IgGl -based bispecific antibody, generated using knob-in-hole technology, with an aglycosylated, nonfunctional Fc domain. In non-human primates (NHP), mosunetuzumab potently depleted B cells while exhibiting pharmacokinetics similar to those of conventional antibodies. In a pivotal Phase II study, mosunetuzumab demonstrated CRS as the most common adverse event (AE) (44% patients), but only two patients (2%) presented grade > 3 CRS (Budde, L. et al., Lancet Oncol 2022).

[0005] Another challenge with both CD 19 and CD20 therapies is the phenomenon of antigen loss after treatment which can cause patients to relapse, see Mejstrikova, E. et al., Blood Cancer J 2017 Dec; 7(12):659. With blinatumomab, approximately 20% of B cell acute lymphoblastic leukemia (B-ALL) patients experienced relapse after last treatment with blinatumomab, see Zhou, T. and Wang, H-W. Clin Lab Med 2021 Sep; 41(3). In a retrospective study, authors studied CD20 expression prior to mosunetuzumabtreatment, during treatment and upon progression in R / R NHL during a Phase 1 / 2 trial CD20 expression was abundant in 95% of patients. At disease progression, 34% of relapsed patients showed CD20 loss (Schuster, S. et al., Blood 2024; 143(9):822-832).

[0006] Therefore, there is a need to identify alternative targets, improve efficacy and mitigate CRS. The present disclosure provides an advance in the art by providing compositions and methods useful in the treatment of B-cell cancers using a human BAFFR / human CD3 bispecific antibody.DESCRIPTION OF THE FIGURES

[0007] Figures 1A-B shows the binding activity of hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE3, TCE4 and TCE5 and negative controls: Controls A, B, C, TTx38E4vl and positive controls C90x38E4vl and Lunsumio® to a human BAFFR expressing Jeko-1 cell line (Fig. 1A) and the relative EC50s in nM of each tested antibody (Fig. IB), where “NA” indicates that the tested antibody showed minimal binding such that a relative EC50 was not applicable. See Example 2.

[0008] Figures 2A-B shows the binding activity of the same hBAFFR x hCD3 bispecifics and same controls as described in Figures 1 A-B to a human CD3 expressing Jurkat cell line (Fig. 2 A) and the relative EC50s in nM of each tested antibody (Fig. 2B), where “NA” indicates that the tested antibody showed minimal binding such that a relative EC50 was not applicable. See Example 2.

[0009] Figures 3 A-B shows ELISA results of binding activity hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE3, TCE4 and TCE5 and negative controls: Controls A, B, C, TTx38E4vl and positive controls C90x38E4vl and Lunsumio® to human recombinant BAFFR-his (Fig. 3A) and the corresponding EC50 (nM) (Fig. 3B), where “NA” indicates that the tested antibody showed minimal binding such that a relative EC50 was not applicable. See Example 3.

[0010] Figures 4A-B show ELISA results of binding activity of hBAFFR x hCD3 bispecifics and controls as described above in Figure 3A-B to human CD3 heterodimer E8 His (Fig. 4A) and the corresponding EC50 (nM) (Fig. 4B), where “NC” indicates that the tested antibody did not saturate at the highest concentration such that an EC50 could not be calculated. See Example 3.

[0011] Figures 5A-B show ELISA results of binding activity of hBAFFR x hCD3 bispecifics and controls as described above in Figure 3A-B to human CD3 heterodimer ey His (Fig. 5A) and the corresponding EC50 (nM) (Fig. 5B), where “NC” indicates that the tested antibody did not saturate at the highest concentration such that an EC50 could not be calculated. See Example 3.

[0012] Figure 6 shows intracellular antibody accumulation (IAA) of hBAFFR x hCD3 bispecifics: TCE1, TCE2, TCE3, TCE4 and TCE5 and negative controls: Control A, B and C in BAFFR-expressing Jeko-1 cells at 24 hours. See Example 4.

[0013] Figure 7 shows intracellular antibody accumulation (IAA) of hBAFFR x hCD3 bispecifics and controls as described above in Figure 6 in CD3-expressing Jurkat cells at 24 hours. See Example 4.

[0014] Figures 8 A-B show relative levels of IFNy (Fig. 8 A) and TNFa (Fig. 8B) cytokine induction by hBAFFR x hCD3 bispecifics: TCE1, TCE2, TCE4 and TCE5 and negative controls Control A, B and C in BAFFR-expressing Jeko-1 cells co-cultured with representative healthy donor PBMCs at 48 hours. See Example 5.

[0015] Figures 9A-B show relative levels of IFNy (Fig. 9A) and TNFa (Fig. 9B) cytokine induction by hBAFFR x hCD3 bispecifics and controls as described above in Figure 8 in BAFFR-expressing Z-138 cells co-cultured with representative healthy donor PBMCs at 48 hours. See Example 5.

[0016] Figures 10A-B show relative levels of IFNy (Fig. 10A) and TNFa (Fig. 10B) cytokine induction by hBAFFR x hCD3 bispecifics and controls as described above in Figure 8 in BAFFR-expressing Nalm- 6 cells co-cultured with representative healthy donor PBMCs at 48 hours. See Example 5.

[0017] Figures 11 A-B show relative levels of IFNy (Fig. 11 A) and TNFa (Fig. 11 B) cytokine induction by hBAFFR x hCD3 bispecifics and controls as described above in Figure 11A-B in BAFFR-knock outs in Nalm-6 cells co-cultured with representative healthy donor PBMCs at 48 hours. See Example 5.

[0018] Figures 12A-F show T-cell killing by hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 and negative controls Control A, B and C, on autologous B cells (PBMC donor RV504) at 48 hours (Fig. 12A-C). Positive controls of Lunsumio® (Fig. 12E) and C90x38E4vl (Fig. 12D), along with a negative control TTx38E4vl. Relative EC50s of the study are summarized in Fig. 12F. where “NA” indicates that the tested TCE or control showed minimal binding such that a relative EC50 was not applicable. See Example 6.

[0019] Figures 13A-F show T-cell killing by hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 on autologous B cells (PBMC donor #110044241) at 48 hours (Fig. 13A-C). Positive controls of Lunsumio® (Fig. 13E) and C90x38E4vl (Fig. 13D), along with a negative control TTx38E4vl. Relative EC50s of the study are summarized in Fig. 13F, where “NA” indicates that the tested TCE or control showed minimal binding such that a relative EC50 was not applicable. See Example 6.

[0020] Figures 14A-F show T-cell killing by hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 on autologous B cells (PBMC donor #3464) at 48 hours (Fig. 14A-C). Positive controls of Lunsumio® (Fig. 14E) and C90x38E4vl (Fig. 14D), along with a negative control TTx38E4vl. Relative EC50s of the study are summarized in Fig. 14F, where “NA” indicates that the tested TCE or control showed minimal binding such that a relative EC50 was not applicable. See Example 6.

[0021] Figures 15A-C show the ability of hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 along with positive controls of Lunsumio® and C90x38E4vl, and negative controls Control A, B, C, and TTx38E4vl to activate T cells by utilizing Jurkat-NFAT-RE luciferase reporter cells cultured with Jeko-1cells at 24 hours (Fig. 15A-B). Relative EC50s and maximum activity in RLU of this study are summarized in Fig. 15C, where “NA” indicates that the tested antibody showed minimal binding such that a relative EC50 was not applicable. See Example 7.

[0022] Figures 16A-C show the ability of hBAFFR x hCD3 bispecifics and controls as described in Figure 15 to activate T cells by utilizing Jurkat-NFAT-RE luciferase reporter cells cultured with Z-138 cells at 24 hours (Fig. 16A-B). Relative EC50s and maximum activity in RLU of this study are summarized in Fig. 16C, where “NA” indicates that the tested antibody showed minimal binding such that a relative EC50 was not applicable. See Example 7.

[0023] Figures 17A-C show the ability of hBAFFR x hCD3 bispecifics and controls as described in Figure 15 to activate T cells by utilizing Jurkat-NFAT-RE luciferase reporter cells cultured with Nalm-6 (DSMZ) cells at 24 hours (Fig. 17A-B). Relative EC50s and maximum activity in RLU of this study are summarized in Fig. 17C, where “NA” indicates that the tested antibody showed minimal binding such that a relative EC50 was not applicable. See Example 7.

[0024] Figures 18A-D show isolated effector T cells labeled with CFSE co-cultured with PKH-26 labeled target Jeko-1 cells at E:T ratio of 5:1 in the presence of hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B, C and positive controls of mosunetuzumab and C90x38E4vl for 48 hrs (Figs. 18A, C) or 96 hrs (Figs. 18B, D). Percent (%) activity data shown as the mean with standard deviation. See Example 8.

[0025] Figures 19A-H show CFSE-labeled T cells co-cultured with Jeko-1 cells (E:T = 5: 1) in the presence of hBAFFR x hCD3 bispecifics and controls as described in Figure 18 for 48 hrs (Figs. 19A, C. E and G) or 96 hrs (Figs. 19B, D, F and H). Percent proliferation was taken from CFSE-population of live CD4+ (Figs. 19A, B, E, F) or CD8+ (Figs. 19C, D, G, H) T cells and plotted on GraphPad Prism, data shown as the mean with standard deviation. See Example 8.

[0026] Figures 20A-H show CFSE-labeled T cells co-cultured with Jeko-1 cells (E:T = 5: 1) in the presence of hBAFFR x hCD3 bispecifics and controls as described in Figure 18 for 48 hrs (Figs. 20A, C, E and G) or 96 hrs (Figs. 19C, D, G and H). The percentage of the early T cell activation marker CD69 was taken from live CD4+ (Figs. 20A, B, E, F) or CD8+ (Figs. 20C, D, G, H) T cells and plotted on GraphPad Prism, data shown as mean with standard deviation. See Example 8.

[0027] Figures 21 A-H show CFSE-labeled T cells co-cultured with Jeko-1 cells (E:T = 5: 1) in the presence of hBAFFR x hCD3 bispecifics and controls as described in Figure 18 for 48 hrs (Figs. 21A, C, E and G) or 96 hrs (Figs. 21C, D, G and H). The percentage of the late T cell activation marker CD25 was taken from live CD4+ (Figs. 21A, B, E, F) or CD8+ (Figs. 21C, D, G, H) T cells and plotted on GraphPad Prism, data shown as mean with standard deviation. Sec Example 8.

[0028] Figures 22A-B show cytotoxic activity of hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B and C in high hB AFFR-expressing Jeko-1 cells co-cultured with representative healthy donor PBMC at 48 hours at an effector-to-target ratio of 10:1 (Fig. 22 A) and 5:1 (Fig. 22B). Graphs shows average values of quadruplicate dose response curves with standard deviation. See Example 9.

[0029] Figures 23A-B show cytotoxic activity of hBAFFR x hCD3 bispecifics and controls as described in Figure 22 in high hB AFFR-expressing Z-138 cells co-cultured with representative healthy donor PBMC at 48 hours at an effector-to-target ratio of 10: 1 (Fig. 23A) and 5: 1 (Fig. 23B). Graphs shows average values of quadruplicate dose response curves with standard deviation. See Example 9.

[0030] Figures 24A-B show cytotoxic activity of hBAFFR x hCD3 bispecifics and controls as described in Figure 22 in low hB AFFR-expressing Nalm-6 cells co-cultured with representative healthy donor PBMC at 48 hours at an effector-to-target ratio of 10: 1 (Fig. 24A) and 5: 1 (Fig. 24B). Graphs shows average values of quadruplicate dose response curves with standard deviation. See Example 9.

[0031] Figures 25A-B show cytotoxic activity of hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B and C in BAFFR-knock out Nalm-6 cells co-cultured with representative healthy donor PBMC at 48 hours at an effector-to-target ratio of 10:1 (Fig. 25 A) and 5: 1 (Fig. 25B). Graphs shows average values of quadruplicate dose response curves with standard deviation. See Example 9.

[0032] Figure 26 summarizes the maximum activity % and the EC50 in nM of the cytotoxic activity of tested hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B and C in target cells Jeko-1, Z-138 or Nalm-6 co-cultured with representative healthy donor PBMC at 48 hours at an effector-to-target ratio of 10:1 and 5:1. Maximum activity % (Max. act.) and the half maximal effective concentration (EC50) were calculated in Graphpad Prism 10. See Example 9.

[0033] Figures 27A-C show ex-vivo serum human cytokine levels in a 10-plex as produced by humanized mice treated with hBAFFR x hCD3 bispecifics in a Jeko-1 luciferase tumor model: Fig. 27A depicts from top to bottom: hlFNg, hIL4, hIL8, and hIL22; Fig. 27B depicts from top to bottom: hILIb, hIL5, hILlO and hTNFa; and Fig. 27C depicts from top to bottom: hIL2, hIL6 and hIL12p70. Standard curve for each analyte was manually and minimally adjusted to ensure that TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B and C and positive controls C90x38E4vl and Lunsumio® had a curve fit close to 1 and error bars representing one standard deviation of the average concentration per group. See Example 10.

[0034] Figures 28A-C show ex-vivo serum human cytokine levels 2 hours post-treatment in a 10-plex as produced by humanized mice treated with hBAFFR x hCD3 bispccifics TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B and C and positive controls C90x38E4vl and Lunsumio® in a Z-138 xenograft tumor model. Fig. 28A depicts from top to bottom: hlFNg, hIL4, hIL8, and hIL22; Fig. 28B depicts from top to bottom: hILIb, hIL5, hILlO and hTNFa; and Fig. 28C depicts from top to bottom: hIL2, hIL6 and hIL12p70. Standard curve for each analyte was manually and minimally adjusted to ensure a curve fit close to 1 and error bars representing one standard deviation of the average concentration per group. See Example 11.

[0035] Figures 29A-C show ex- vivo serum human cytokine levels 24 hours post-treatment in a 10-plex as produced by humanized mice treated with hBAFFR x hCD3 bispecifics TCE1. TCE2. TCE4 and TCE5 along with negative controls Control A, B, C and positive controls C90x38E4vl and Lunsumio® in a Z- 138 xenograft tumor model. Fig. 29A depicts from top to bottom: hlFNg, hIL4, hIL8, and hIL22; Fig. 29B depicts from top to bottom: hILIb, hIL5, hILlO and hTNFa; and Fig. 29C depicts from top to bottom: hIL2, hIL6 and hIL12p70. Standard curve for each analyte was manually and minimally adjusted to ensure a curve fit close to 1 and error bars representing one standard deviation of the average concentration per group. See Example 11.

[0036] Figure 30 shows tumor growth inhibition in an established Jeko- 1 luciferase xenograft tumor model through the kinetics of quantified luciferase signals over time shown as a logar ithm of Total Flux (p / sec) of hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B, C and positive controls C90x38E4vl and Lunsumio® dosed at either 0.15 mg / kg or 0.14 mg / kg or 1.5 mg / kg on Days 6, 13 and 20 in a Jeko-1 luciferase -expressing xenograft tumor model as indicated by the arrows. Data represent mean ± SEM for all groups (n=5). See Example 12.

[0037] Figure 31 shows the in vivo tumor growth inhibition in an established humanized Z-138 xenograft model using hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE4 and TCE5 along with negative controls Control A, B, C and positive controls C90x38E4vl and Lunsumio® in a Z-138 xenograft tumor model. Tumor cells and PBMCs were co- implanted on Day 0, and dosing was once weekly as indicated by arrows starting on Day 6. Tumor volumes are shown as geometric mean + SEM, n = 6 per group. See Example 13.

[0038] Figure 32 shows the in vivo anti-tumor efficacy of in an immunocompetent syngeneic BAFFR+ tumor model using hBAFFR x hCD3 bispecific TCE1 at two doses along with negative Control A. Data represent mean ± SEM for all groups (n=4). See Example 14.

[0039] Figure 33 shows a dose-dependent in vivo tumor growth inhibition in a patient-derived xenograft (PDX) model of B-ALL using hBAFFR x hCD3 bispecific TCE1 along with negative controls (vehicle and Control A) and positive control mosunetuzumab. Data represent mean + SEM for all groups (n=6). See Example 15.SUMMARY OF THE INVENTION

[0040] The present invention describes bispecific T cell engagers (TCE) antibodies for the treatment of various B-cell cancers. One aim of the TCE specifically binds a human immune effector cell, human CD3, while the other arm specifically binds to human BAFFR.

[0041] Compared with monoclonal antibodies, bispecific antibodies offer some advantages such as superior cytotoxic effects on cancers as there is a lower rate of resistance due to the ability to target two different antigens. Bispecific antibodies that are immune-engaging such as those that target the general marker of T cells cluster of differentiation 3 (CD3) on one arm and a tumor-specific antigen on the other arm are known as T cell engagers (TCE). When both T cell and tumor cell are bound by a TCE a cytolytic synapse is formed whereby the T cell is activated and releases the pore-forming perforin and cytotoxic granzyme-B, leading to killing of the targeted tumor cell.

[0042] TCEs can be divided into two categories: the immunoglobulin G (IgG)-based antibodies, such as Lunsumio® - mosunetuzumab, and the variable fragment (Fv)-based bispecifics such as Blincyto® - blinatumomab. Bispecifics based on the IgG structure display a similar structure to native antibodies. In general, compared with Fv-based bispecifics, IgG-based bispecifics have longer half-lives in vivo because they arc larger in size so clearance by the kidney is more difficult. The solubility and stability of IgG-based bispecifics are also improved for the presence of the fragment crystallizable (Fc) domains over Fv-based bispecifics. As defined herein, recitation of the term TCEs will refer to IgG-based TCEs unless otherwise indicated.

[0043] Early methods of producing IgG-based TCEs involved combining half-molecules from heterogenous parental antibodies. However, such techniques were fraught with homo-dimer mispairings, for example co-expressing two heavy chains and two light chains to generate an IgG TCE can result in some niis-assembly and unwanted byproducts (Lewis SM et al., Nature Biotechnology 2014; 32: 191-202; Leaver-Fay A, et al., Structure 2016; 24: 641-651). Subsequent techniques of recombining functional halfmolecules to produce IgG-based TCEs include, but are not limited to orthogonal Fab interface (Lewis, S. et al., Nature Biotech, 2014;32: 191-198), DuoBody®- Genmab, XmAb® - Xencor, CrossMab (Schaefer, W. et al., PNAS 2011;108: 11187-92), knobs-into-holes (KiH)(Ridgway, J. et al., Protein Eng. 1996;9:617-21 and Atwell, S. et al., J Mol Biol 1997;270:26-35), and Biclonics® (De Nardis, C. et aL, JBC 2017; 292(35): 14706- 14717), all of which increase the likelihood of proper heterodimerization.

[0044] Another challenge is that TCEs require the correct pairing of two distinct light chains. Random light chain association would otherwise lead to a mixture of species with correctly assembled antibodies occurring only 25% of the time. Since the specific binding of antibodies to an antigen is mainly provided by the heavy chain, such specific antigen binding can be preserved when such an antibody has a noncognate light chain. Use of a common light chain (cLC) combined with two different heavy chains avoidsFab mispairings. Thus, only three peptide chains need to be expressed, rather than four, which is a clear advantage in terms of manufacturability as well as simplifying the purification process for typical biologies production. Common light chain antibodies have been isolated from phage scFv display libraries with a restricted light chain diversity (Merchant et al., Nature Biotech, 1998, 16:677-681) or phage Fab libraries with a unique light chain (Jackman et al., J Biol Chem 2010 Jul 2;285(27)). In an effort to skip the engineering process for identifying a cLC, McWhirter et al (WO2011 / 097603) created transgenic mice with a fixed cLC using a human germline VK1-39JK5 or VK3-20JK light chain.

[0045] Thus, the present disclosure provides human BAFFR / human CD3 bispecific TCEs that facilitates proper heterodimerization assembly and exhibits in vivo efficacy while minimizing CRS in at least one pre- clinical model of a B-cell cancer.

[0046] Cluster of differentiation 3 (CD3) is a protein complex and a T cell co-receptor that is involved in activating both the cytotoxic T cell (CD8+ naive T cells) and T helper cells (CD4+ naive T cells). It is composed of four distinct chains. In mammals, the complex contains a CD3y chain (SwissProt P09693), a CD35 chain (SwissProt P04234), and two CD3s chains (SwissProt P07766). These chains associate with the T-cell receptor (TCR) and the CD3-zeta (^-chain) to generate an activation signal in T lymphocytes. The TCR, CD3-zeta, and the other CD3 molecules together constitute the TCR complex.

[0047] B cell activating factor receptor (BAFF-R, also known as TNFRSF13C or CD268) is a TNF receptor superfamily (TNFRSF) member that is involved in B cell development and survival. BAFF-R expression is limited to B cells and found to be expressed at various stages of their maturation and differentiation, except during early B cell development.

[0048] The NCBI reference amino acid sequence of the human BAFFR is NP 443177.1. BAFF-R has an extracellular' domain (ECD) consisting of 78 amino acids containing a single cysteine-rich domain (CRD) harboring four cysteine residues. Two disulfide bridges formed by these four cysteine residues are necessary for the proper conformation of the CRD and therefore ligand binding (Kim et al. Nat Structural Bio, 2003).

[0049] BAFF-R expression has been documented on various human B-cell lymphomas, including pre-B ALL, CLL, and NHL, although information on expression levels is limited (Rodig et al. Human Pathol 2005, Parameswaran et al. Cancer Res 2010). Mechanistically, BAFF-R-signaling activates NF-KB pathways to promote tumor survival and proliferation and increased BAFF-R expression correlates with disease progression in patients with B-cell lymphoma and pre-B ALL (Qin, H. et al., Sci Trans Med 2019 v.ll, no.511). Furthermore, mouse strains expressing a mutant BAFF-R exhibit decreased B-cell life spans associated with a substantially reduced peripheral B-cell compartment, and BAFF-R-null mice exhibit greatly reduced B-cell numbers and are essentially devoid of marginal zone B cells (Hildebrand, J. et al., J Exp Med 2010, 207:2569-2579). Collectively, these reports suggest that BAFF-R signaling is a driver of B-cell growth and survival. This feature may also limit the ability of B-cell tumors to escape BAFFRdirected therapies by down-regulation of BAFF-R expression (Novak, A. et aL, Blood 2004 104:2247- 2253). BAFF-R expression is independent of CD 19 expression on malignant B cells such that observed downregulation of CD 19 antigen on malignant B cells were still able to be targeted by BAFFR CAR-T cell therapies (Qin, H. et al., Sci Transl Med. 2019: Sep 25; 11(511)).EMBODIMENTS

[0050] Embodiments of the present invention are contemplated to include, but are not limited to the following:

[0051] Embodiment 1. A bispecific antibody that specifically binds human B cell- activating factor receptor (hBAFFR) and human CD3 (hCD3), wherein the bispecific antibody comprises (a) a first antigen binding domain that specifically binds hBAFFR comprising a first heavy chain variable region (VH1) and a light chain variable region (VL1), wherein the VH1 comprises heavy chain complementarity determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the VL1 comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein:(a) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO:2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6; or(b) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO:30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6. and a second antigen binding domain that specifically binds human CD3.

[0052] Embodiment 2. The bispecific antibody of Embodiment 1, wherein the second antigen binding domain that specifically binds hCD3 comprises a second heavy chain variable region (VH2) and a light chain variable region (VL2), wherein the VH2 comprises heavy chain complementarity determining regions (HCDR) HCDR4, HCDR5, and HCDR6, and the VL2 comprises light chain complementarity determining regions (LCDR) LCDR4, LCDR5, and LCDR6.

[0053] Embodiment 3. A bispecific antibody that specifically binds hBAFFR and hCD3, wherein the bispecific antibody comprises (a) a first antigen binding domain that specifically binds hBAFFR and (b) a second antigen binding domain that specifically binds hCD3 comprising a heavy chain variable region (VH2) and a light chain variable region (VL2), wherein the VH2 comprises heavy chain complementarity determining regions (HCDR) HCDR4, HCDR5, and HCDR6, and the VL2 comprises light chain complementarity determining regions (LCDR) LCDR4, LCDR5, and LCDR6, wherein:a) HCDR4 comprises SEQ ID NO:7, HCDR5 comprises SEQ ID NO:8, HCDR6 comprises SEQ ID NO:9, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6; b) HCDR4 comprises SEQ ID NO: 19, HCDR5 comprises SEQ ID NO:20, HCDR6 comprises SEQ ID NO:21, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO: 6; or c) HCDR4 comprises SEQ ID NO:24, HCDR5 comprises SEQ ID NO:25, HCDR6 comprises SEQ ID NO:26, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6.

[0054] Embodiment 4. The bispecific antibody of any one of Embodiments 1-3, wherein the first antigen binding domain has about a 5-fold to about a 50-fold greater binding affinity (KD) for hB AFFR relative to the binding affinity the second antigen binding domain has for hCD3, as measured by surface plasmon resonance (SPR). In another embodiment, the hBAFFR x hCD3 bispecific of any one of Embodiments 1- 3. where the first antigen binding domain that binds hBAFFR has about a 1.5-fold to about a 2-fold greater binding affinity (KD) or a 2-fold to about a 5-fold greater binding affinity (KD) or about 5-fold to about a 10-fold greater binding affinity (KD) or about a 5-fold to about a 20-fold greater binding affinity (KD) or about a 5-fold to about a 30-fold greater binding affinity (KD) or about a 5-fold to about a 40-fold greater binding affinity (KD) or about a 5-fold to about a 50-fold greater binding affinity (KD) or about a 10-fold to about a 200-fold greater binding affinity (KD) or about a 20-fold to about a 200-fold greater binding affinity (KD) or about a 30-fold to about a 200-fold greater binding affinity (KD) or about a 40-fold to about a 200-fold greater binding affinity (KD) or about a 50-fold to about a 200-fold greater binding affinity (KD) or about a 10-fold to about a 100- fold greater binding affinity (KD) or about a 10-fold to about a 50- fold greater binding affinity (KD) or about a 10-fold to about a 20- fold greater binding affinity (KD) for hBAFFR relative to the binding affinity the second antigen binding domain has for human CD3, as measured by surface plasmon resonance (SPR).

[0055] Embodiment 5. The bispecific antibody of any one of Embodiments 1-4, wherein the bispecific antibody demonstrates an in vivo tumor growth inhibition of at least 10% or greater. In another embodiment the hBAFFR x hCD3 bispecific antibody of any one of Embodiments 1-4, demonstrates an in vivo tumor growth inhibition of at least 10% or greater, at least 20% or greater, at least 30% or greater, at least 40% or greater, at least 50% or greater, at least 60% or greater, at least 70% or greater, at least 80% or greater. In yet another embodiment, the hBAFFR x hCD3 bispecific described herein demonstrates an in vivo tumor growth inhibition of between 2% to 10%, of between 10% to 20%, of between 20% to 30%, of between30% to 40%, of between 40% to 50%, of between 50% to 60%, of between 60% to 70%, of between 70% to 80%, of between 80% to 90%, or of between 90% to 100%.

[0056] Embodiment 6. The bispecific antibody of any one of Embodiments 1-5, wherein the bispecific antibody induces an in vivo IFNg concentration of 6000 fg / ml or less. In another embodiment, the hB AFFR x hCD3 bispecific antibody of any one of Embodiments 1-5, induces an in vivo IFNg concentration of 6000 fg / ml or less, or of 5000 fg / ml or less, or of 4000 fg / ml or less, or of 3000 fg / ml or less, or of 2000 fg / ml or less, or of 1000 fg / ml or less, or of 900 fg / ml or less or of 800 fg / ml or less, or of 700 fg / ml or less, or of 600 fg / ml or less, or of 500 fg / ml or less, or of 400 fg / ml or less, or of 300 fg / ml or less, or of 200 fg / ml or less, or of 100 fg / ml or less, or of 50 fg / ml or less. In another embodiment, the hBAFFR x hCD3 bispecific described herein induces an in vivo IFNg concentration of between 50-100 fg / ml, of between 100-200 fg / ml, of between 200-300 fg / ml, of between 300-400 fg / ml, of between 400-500 fg / ml, of between 500- 600 fg / ml, of between 600-700 fg / ml, of between 700-800 fg / ml, of between 800-900 fg / ml, of between 900-1000 fg / ml, of between 1000-2000 fg / ml, of between 2000-3000 fg / ml, of between 3000-4000 fg / ml, of between 4000-5000 fg / ml, of between 5000-6000 fg / ml.

[0057] Embodiment 7. The bispecific antibody of any one of Embodiments 1-6, wherein the bispecific antibody inhibits binding of hBAFFR to hBAFF.

[0058] Embodiment 8. The bispecific antibody of any one of Embodiments 1-7, wherein the bispecific antibody inhibits antibody-induced shedding of the hBAFFR extracellular domain.

[0059] Embodiment 9. The bispecific antibody of Embodiment 2, wherein:(a) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ IDNO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ IDNO:6, HCDR4 comprises SEQ ID NO:7, HCDR5 comprises SEQ ID NO:8, HCDR6 comprises SEQ IDNO:9, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ IDNO:6:(b) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO: 19, HCDR5 comprises SEQ ID NO:20, HCDR6 comprises SEQ ID NO:21, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6;(c) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO:24, HCDR5 comprises SEQ ID NO:25, HCDR6 comprisesSEQ ID NO:26, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6;(d) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO: 30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO:7, HCDR5 comprises SEQ ID NO:8, HCDR6 comprises SEQ ID NO:9, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6; or(e) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO: 30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO: 19, HCDR5 comprises SEQ ID NO:20, HCDR6 comprises SEQ ID NO:21, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6.

[0060] Embodiment 10. The bispecific antibody of any one of Embodiments 1-9, wherein:(a) the VH1 comprises SEQ ID NO: 10 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO: 11 and tire VL2 comprises SEQ ID NO: 12;(b) the VH1 comprises SEQ ID NO: 10 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO:22 and the VL2 comprises SEQ ID NO: 12;(c) the VH1 comprises SEQ ID NO: 10 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO: 27 and the VL2 comprises SEQ ID NO: 12;(d) the VH1 comprises SEQ ID NO:32 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO: 11 and the VL2 comprises SEQ ID NO: 12; or(e) the VH1 comprises SEQ ID NO:32 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO:22 and the VL2 comprises SEQ ID NO: 12.

[0061] Embodiment 11. The bispecific antibody of any one of Embodiments 1-10, further comprising an Fc region comprising (a) a BAFFR heavy chain constant region comprising a first CH2 and a first CH3 domains and (b) a CD3 heavy chain constant region comprising a second CH2 and a second CH3 domains, wherein the first CH3 domain has amino acid substitutions L351D and L368E and the second CH3 domain has amino acid substitutions L351K and T366K. In another embodiment, the bispecific antibody of any one of Embodiments 1-10, further comprising an Fc region comprising (a) a BAFFR heavy chain constant region comprising a first CH2 and a first CH3 domains and (b) a CD3 heavy chain constantregion comprising a second CH2 and a second CH3 domains, wherein the first CH3 domain has amino acid substitutions L351K and T366K and the second CH3 domain has amino acid substitutions L351D and L368E where the mutation numbering is according to Kabat.

[0062] Embodiment 12. The bispecific antibody of any one of Embodiments 1-10, further comprising an Fc region comprising (a) a BAFFR heavy chain constant region comprising a first CH2 and a first CH3 domains and (b) a CD3 heavy chain constant region comprising a second CH2 and a second CH3 domains, wherein the first CH3 domain has amino acid substitutions T366S / L368A / Y407V and the second CH3 domain has amino acid substitution T366W. In another embodiment, the bispecific antibody of any one of Embodiments 1-10, further comprising an Fc region comprising (a) a BAFFR heavy chain constant region comprising a first CH2 and a first CH3 domains and (b) a CD3 heavy chain constant region comprising a second CH2 and a second CH3 domains, wherein the first CH3 domain has amino acid substitution T366W and the second CH3 domain has amino acid substitutions T366S / L368A / Y407V where the mutation numbering is according to Kabat.

[0063] Embodiment 13. The bispecific antibody of any one of Embodiment 11 or 12, wherein the Fc region comprises Fc silencing mutations.

[0064] Embodiment 14. The bispecific antibody of Embodiment 13, wherein the Fc silencing mutations are (a) L235G and G236R or (b) L234A, L235A or (c) L234A, L235A and D265A or (d) L234A, L235A and P329G or (e) N297A or (f) N297A and K322A or (g) L234A, L235A and D265S where the mutation numbering is according to Kabat.

[0065] Embodiment 15. The bispecific antibody of any one of Embodiments 1-14, wherein the antibody comprises a first heavy chain (HC1) and a common light chain (cLC) that specifically binds hB AFFR and a second heavy chain (HC2) and said common light chain (cLC) that specifically binds human CD3 wherein:(a) HC1 comprises SEQ ID NO: 16. HC2 comprises SEQ ID NO: 17, cLC comprises SEQ ID NO: 18;(b) HC1 comprises SEQ ID NO: 16, HC2 comprises SEQ ID NO:23, cLC comprises SEQ ID NO: 18;(c) HC1 comprises SEQ ID NO: 16, HC2 comprises SEQ ID NO:28, cLC comprises SEQ ID NO: 18;(d) HC1 comprises SEQ ID NO:33, HC2 comprises SEQ ID NO: 17, cLC comprises SEQ ID NO: 18; or(e) HC1 comprises SEQ ID NO:33, HC2 comprises SEQ ID NO:23, cLC comprises SEQ ID NO: 18.

[0066] Embodiment 16. The bispecific antibody of any one of Embodiments 1-15, wherein the antibody is a human IgGl or IgG4 isotype.

[0067] Embodiment 17. The bispecific antibody of Embodiment 16, wherein the antibody is a human IgGl isotype.

[0068] Embodiment 18. A nucleic acid encoding the amino acid sequences of Embodiment 15.

[0069] Embodiment 19. A host cell transfected with: a) a first vector comprising the nucleic acids encoding SEQ ID NO: 16, and a second vector comprising the nucleic acids encoding SEQ ID NO: 17; b) a first vector comprising the nucleic acids encoding SEQ ID NO: 16, and a second vector comprising the nucleic acids encoding SEQ ID NO:23; c) a first vector comprising the nucleic acids encoding SEQ ID NO: 16, and a second vector comprising the nucleic acids encoding SEQ ID NO:28; d) a first vector comprising the nucleic acids encoding SEQ ID NO: 33, and a second vector comprising the nucleic acids encoding SEQ ID NO: 17; or e) a first vector comprising the nucleic acids encoding SEQ ID NO: 33, and (j) a second vector comprising the nucleic acids encoding SEQ ID NO:23.

[0070] Embodiment 20. The host cell of Embodiment 19, further transfected with a third vector comprising the nucleic acids encoding SEQ ID NO: 18.

[0071] Embodiment 21. The host cell of Embodiment 19, wherein the host cell is a mammalian host cell.

[0072] Embodiment 22. A process of producing a bispecific antibody comprising culturing the cell of Embodiment 20 or 21 in a cultur e medium under conditions such that the bispecific antibody is expressed and then recovered from the culture medium.

[0073] Embodiment 23. A pharmaceutical composition comprising the hB AFFR x hCD3 bispecific antibody of any one of Embodiments 1-17 and 22, and a pharmaceutically acceptable excipient, diluent or carrier.

[0074] Embodiment 24. An isolated antibody that specifically binds hB AFFR, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementar ity determining regions (HCDR): HCDR1, HCDR2, and HCDR3, and the VL comprises light chain complementarity determining regions (LCDR): LCDR1, LCDR2, and LCDR3, wherein:(a) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO:2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6; or(b) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO:30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6.

[0075] Embodiment 25. The antibody of Embodiment 24, wherein: a) the VH comprises SEQ ID NO: 10 and the VL comprises SEQ ID NO: 12; or b) the VH comprises SEQ ID NO: 32 and the VL comprises SEQ ID NO: 12.

[0076] Embodiment 26. The antibody of Embodiment 24 or 25, wherein the antibody comprises a heavy chain (HC) and a light chain (LC), wherein: a) the HC comprises SEQ ID NO:34 and the LC comprises SEQ ID NO: 18; or b) the HC comprises SEQ ID NO:35 and the LC comprises SEQ ID NO: 18.

[0077] Embodiment 27. The antibody of any one of Embodiments 24-26, wherein the antibody is a human IgGl or IgG4 isotype.

[0078] Embodiment 28. The antibody of Embodiment 27, wherein the antibody is a human IgGl isotype.

[0079] Embodiment 29. The antibody of any one of Embodiments 24-28, wherein the antibody is an antibody fragment or antigen-binding fragment.

[0080] Embodiment 30. The antibody of Embodiment 29, wherein the antibody fragment or antigen-binding fragment is a Fab, a Fab’, an F(ab’)2, a single-chain variable fragment (scFv), an Fv, a disulfide-linked Fv (sdFv), an Fd fragment, or a single-chain Fab (scFab).

[0081] Embodiment 31. The antibody of any one of Embodiments 24-30, wherein the antibody is a multispecific antibody.

[0082] Embodiment 32. The antibody of Embodiment 31, wherein the multispecific antibody is a bispecific antibody, or a trispecific antibody, or a tetraspecific antibody, or a diabody, or a tandem scFv, or a tandem VHH, or a tandem scFab.

[0083] Embodiment 33. An antibody-drug conjugate (ADC) comprising the antibody of any one ofEmbodiments 24-32 and a drug moiety.

[0084] Embodiment 34. The ADC of Embodiment 33, wherein the drug moiety is selected from the group consisting of auristatin, N-acetyl-y calicheamicin, maytansinoid, pyrrolobenzodiazepine, exatecan and SN-38.

[0085] Embodiment 35. An immunocytokine comprising the antibody of any one of Embodiments24-32 and a cytokine.

[0086] Embodiment 36. The immunocytokine of Embodiment 35, wherein the cytokine is selected from the group consisting of IL-2, IL-4, IL-10, IL-12, IL-15, TNF, and IFNa.

[0087] Embodiment 37. A chimeric antigen receptor (CAR) comprising the antibody of any one of Embodiments 24-32, a transmembrane domain, and an intracellular signaling domain.

[0088] Embodiment 38. A pharmaceutical composition comprising the hBAFFR antibody of any one of Embodiments 24-32 or the ADC of any one of Embodiments 33-34 or the immunocytokine of any of Embodiments 35-36 or the CAR of Embodiment 37 and a pharmaceutically acceptable excipient, diluent or carrier.

[0089] Embodiment 39. A method of treating B-cell cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the bispecific antibody of any one of Embodiments 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37.

[0090] Embodiment 40. The method of Embodiment 39, wherein the B-cell cancer is relapsed or refractory.

[0091] Embodiment 41. The method of Embodiment 39 or 40, wherein the B-cell cancer is B-cell acute lymphoblastic leukemia (B-ALL); Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL): chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa-associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); high-grade B-cell lymphoma (HGBCL); Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B-cell prolymphocytic leukemia (B-PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary central nervous system (CNS) lymphoma; and primary intraocular lymphoma.

[0092] Embodiment 42. A method of treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the bispecific antibody of any one of Embodiments 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37.

[0093] Embodiment 43. The method of claim 45, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (IBD), and psoriasis.

[0094] Embodiment 44. The bispecific antibody of any one of Embodiments 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37 for use in the treatment of a B-cell cancer.

[0095] Embodiment 45. The use of Embodiment 44, wherein the B-cell cancer is relapsed or refractory.

[0096] Embodiment 46. The use of Embodiment 44 or 45, wherein the B-cell cancer is B-cell acute lymphoblastic leukemia (B-ALL); Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL); chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa-associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); high-grade B-cell lymphoma (HGBCL); Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B-cell prolymphocytic leukemia (B-PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary central nervous system (CNS) lymphoma; and primary intraocular lymphoma.

[0097] Embodiment 47. The bispecific antibody of any one of Embodiment 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37 for use in the treatment of an autoimmune disorder.

[0098] Embodiment 48. The use of Embodiment 47, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (IBD), and psoriasis.

[0099] Embodiment 49. A pharmaceutical composition comprising the bispecific antibody of any one of Embodiments 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37 for use in treating B-cell cancer.[000100] Embodiment 50. The pharmaceutical composition of Embodiment 49, wherein theB-cell cancer is relapsed or refractory.[000101] Embodiment 51. The pharmaceutical composition of Embodiment 49 or 50, wherein the B-cell cancer is B-cell acute lymphoblastic leukemia (B-ALL); Hodgkin lymphoma (HL); nonHodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL); chronic lymphocytic leukemia (CLL); 1small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa-associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); highgrade B-cell lymphoma (HGBCL): Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B-cell prolymphocytic leukemia (B- PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary central nervous system (CNS) lymphoma; and primary intraocular lymphoma.[000102] Embodiment 52. A pharmaceutical composition comprising the bispecific antibody of any one of Embodiments 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37, for use in the treatment of an autoimmune disorder.[000103] Embodiment 53. The pharmaceutical composition of Embodiment 52, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (IBD), and psoriasis.[000104] Embodiment 54. Use of the bispecific antibody of any one of Embodiments 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37, in the manufacture of a medicament for the treatment of a B-cell cancer.[000105] Embodiment 55. The use of Embodiment 54, wherein the B-cell cancer is relapsed or refractory.[000106] Embodiment 56. The use of Embodiments 54 or 55, wherein the B-cell cancer is B- cell acute lymphoblastic leukemia (B-ALL); Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL); chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa-associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); high-grade B-cell lymphoma (HGBCL); Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B-cell prolymphocytic leukemia (B-PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary’ central nervous system (CNS) lymphoma; and primary intraocular' lymphoma.[000107] Embodiment 57. Use of the bispecific antibody of any one of Embodiments 1-17 and 23 or the antibody of any one of Embodiments 24-32 or the ADC of Embodiments 33-34 or the immunocytokine of Embodiments 35-36 or the CAR of Embodiment 37, in the manufacture of a medicament for the treatment of an autoimmune disorder.[000108] Embodiment 58. The use of Embodiments 57, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (IBD), and psoriasis.DEFINITIONS[000109] The term “antibody,” as used herein, refers to an isolated immunoglobulin molecule that specifically binds an antigen, such as, for example, a tumor antigen. Embodiments of an antibody include a monoclonal antibody, polyclonal antibody, human antibody, humanized antibody, chimeric antibody, bispecific or multispecific antibody, or conjugated antibody. The antibodies can be of any class (e.g., IgG, IgE, IgM, IgD, IgA), and any subclass (e.g., IgGl, IgG2, IgG3, IgG4), unless otherwise specified.[000110] An exemplary bispecific antibody or T-cell engager (TCE) of the present disclosure is an immunoglobulin G (IgG) type antibody comprised of four' polypeptide chains: two heavy chains (HC) and two light chains that are common (cLC) that are cross-linked via inter-chain disulfide bonds. The aminoterminal portion of each of the four polypeptide chains includes a variable region of about 100-125 or more amino acids primarily responsible for antigen recognition. The carboxyl-terminal portion of each of the four polypeptide chains contains a constant region primarily responsible for effector function. Each heavy chain (HC) is comprised of a heavy chain variable region (VH), a heavy chain constant region (Cnl), a hinge region, a heavy chain constant region 2 (CH2) and a heavy chain constant region 3 (CH3). Each common light chain is comprised of a light chain variable region (VL) and a light chain constant region (LC). The IgG isotype may be further divided into subclasses (e.g., IgGl, IgG2, IgG3, and IgG4).[000111] The VH and VL regions can be further subdivided into regions of hyper- variability, termed complementarity determining regions (CDRs), interspersed with regions that are more conserved, termed framework regions (FR). The CDRs are exposed on the surface of the protein and are important regions of the antibody for antigen binding specificity. Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxyl-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. Herein, the three CDRs of the heavy chain are referred to as “HCDR1, HCDR2, and HCDR3” and the three CDRs of the light chain are referred to as “LCDR1, LCDR2 and LCDR3”. The CDRs contain most of the residues that form specific interactions with the antigen. Assignment of amino acid residues to the CDRs may be done according to schemes well known to those of skill in the art, including thosedescribed in Kabat (Kabat et al., “Sequences of Proteins of Immunological Interest,” National Institutes of Health, Bethesda, Md. (1991)), Chothia (Chothia et al., “Canonical structures for the hypervariable regions of immunoglobulins”, Journal of Molecular- Biology, 196, 901-917 (1987); Al-Lazikani et al., “Standard conformations for the canonical structures of immunoglobulins”, Journal of Molecular Biology, 273, 927- 948 (1997)), North (North et aL, “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)), or IMGT (the international ImMunoGeneTics database available on at www.imgt.org; see Lefranc et aL, Nucleic Acids Res. 1999; 27:209-212). Unless otherwise specified, the present disclosed CDR sequences herein use the North numbering convention.[000112] Also contemplated are antibody fragments or antigen-binding fragments that, as used herein, comprise at least a portion of an antibody retaining the ability to specifically interact with an antigen or an epitope of the antigen, such as Fab, Fab’, F(ab’)2, Fv fragments, scFv antibody fragments, scFab, disulfide-linked Fvs (sdFv), a Fd fragment.[000113] The term “antigen binding domain”, as used herein, refers to a portion of an antibody, antibody fragment, bispecific antibody, multispecific binding protein, antibody-drug conjugate, immunocytokine, chimeric antigen receptor (CAR) that specifically binds an antigen or an epitope of the antigen.[000114] The term “bispecific”, as used herein, refers to a molecule that comprises two distinct antigen-binding domains. A bispecific binding molecule can bind two different antigens or two different epitopes of the same antigen. Exemplary embodiments of bispecific molecules include the TCEs disclosed herein.[000115] The term “multispecific”, as used herein, refers to a molecule that comprises two or more distinct antigen-binding domains. A multispecific binding molecule can bind two or more different antigens, or two or more different epitopes of the same antigen. Exemplary embodiments of multispecific binding molecules include bispecific, trispecific or tetraspecific binding molecules known in the field, as well as single-chain multispecific binding molecules such as diabodies, tandem scFvs, tandem VHHs, or tandem scFabs.[000116] The term “antibody drug conjugate” (ADC) as used herein refers to a class of compounds comprising (a) an antibody or antibody fragment, (2) a payload, such as a cytotoxic agent, an immunological modulator or therapeutic peptide, and (3) a linker that conjugates the antibody to the payload.[000117] The term “chimeric antigen receptor” (CAR) refers to a recombinant polypeptide construct comprising at least an extracellular antigen binding domain, a transmembrane domain and an intracellular signaling domain.[000118] The term “Fc silencing mutation(s)” as used herein involves mutations in the amino acid sequence of the Fc regions of an antibody where human Fc gamma receptors of effector cells bind to anantibody. These mutations reduce or eliminate effector function while retaining binding to the neonatal Fc receptor, important for normal antibody pharmacokinetics.[000119] The term “immunocytokine” as used herein is a molecule that comprises an antigenbinding domain connected to a cytokine by chemical conjugation. In some embodiments, the antigenbinding domain is connected to the cytokine by fusion to the cytokine. The immunocytokine can further comprise an Fc domain connected to the antigen-binding domain.[000120] The terms “nucleic acid” or “polynucleotide”, as used interchangeably herein, refer to polymers of nucleotides, including single-stranded and / or double-stranded nucleotide-containing molecules, such as DNA, cDNA and RNA molecules, incorporating native, modified, and / or analogs of, nucleotides. Polynucleotides of the present disclosure may also include substrates incorporated therein, for example, by DNA or RNA polymerase or a synthetic reaction.[000121] Polynucleotides of the present disclosure may be expressed in a host cell, for example after the polynucleotides have been operably linked to an expression control sequence. Expression control sequences capable of expression of polynucleotides to which they are operably linked are well known in the art. For example, an expression vector may include a sequence that encodes one or more signal peptides that facilitate secretion of the polypeptide(s) from a host cell. The signal peptide may be an immunoglobulin signal peptide or a heterologous signal peptide, for example. Expression vectors containing a polynucleotide of interest (e.g., a polynucleotide encoding a polypeptide of an antibody) may be transferred into a host cell by well-known methods. Additionally, expression vectors may contain one or more selection markers, e.g., tetracycline, neomycin, and dihydrofolate reductase, to aide in detection of host cells transformed with the desired polynucleotide sequences.[000122] A host cell includes cells stably or transiently transfected, transformed, transduced or infected with one or more expression vectors expressing all or a portion of an antibody of the present disclosure. According to some embodiments, a host cell may be stably or transiently transfected, transformed, transduced or infected with expression vector(s) expressing HC polypeptides and an expression vector expressing LC polypeptides of an antibody of the present disclosure. In some embodiments, a host cell may be stably or transiently transfected, transformed, transduced or infected with an expression vector expressing HC and LC polypeptides of an antibody of the present disclosure. The antibody of the present invention may be produced in mammalian cells such as CHO, NS0, HEK293 or COS cells according to techniques well known in the art.[000123] Medium, into which an antibody of the present invention has been secreted, may be purified by conventional techniques, such as mixed-mode methods of ion-exchange and hydrophobic interaction chromatography. For example, the medium may be applied to and eluted from a Protein A or G column using conventional methods; mixed-mode methods of ion-exchange and hydrophobic interactionchromatography may also be used. Soluble aggregate and multimers may be effectively removed by common techniques, including size exclusion, hydrophobic interaction, ion exchange, or hydroxyapatite chromatography. The product may be immediately frozen, for example at -70°C, refrigerated, or may be lyophilized. Various methods of protein purification may be employed, and such methods are known in the art and described, for example, in Deutscher, Methods in Enzymology 182: 83-89 (1990) and Scopes, Protein Purification: Principles and Practice, 3rd Edition, Springer, NY (1994).[000124] The term “relapse” or “relapsed” as used herein is when a disease, such as a cancer, returns following a successful treatment. A synonymous term to relapse is “recurrence”.[000125] The term “refractory” as used herein is when a disease, such as a cancer, fails to respond to a medical treatment from the start of treatment. A synonymous term to refractory is “resistance”. A refractory disease, such as a refractory cancer is different from a relapsed disease, such as a relapsed cancer, defined above.[000126] The terms “specifically bind” and “specifically binds” as used herein are intended to mean, unless indicated otherwise, the ability of an antibody or molecule to form a chemical bond or attractive interaction with another protein or molecule, which results in proximity of the antibody and other protein or molecule as determined by common methods known in the ait.[000127] The term “T-cell engager(s)” (TCEs) as used herein refers to a particula- type of bispecific antibody where one of the antibody arms specifically binds to a tumor-associated antigen (TAA) and the other antibody arm specifically binds to CD3 such that the TCE engages a cytotoxic T cell through the CD3 arm and redirects the T cell towards a tumor cell expressing the TAA in order for the TCE to form a cytolytic synapse into which the engaged T cell releases pore-forming perforin and cytotoxic granzyme-B, leading to killing of the targeted tumor cell. In one embodiment, TCEs disclosed herein are the human BAFFR x human CD3 bispecific antibodies of the invention. As used herein the terms “BAFFR TCE” and “BAFFR x CD3 bispecific” or “BAFFR x CD3 bispecific antibody” are synonymous.[000128] The term “treating” or “treat” in the context of disease as used herein refer to reducing the severity and / or frequency of one or more symptoms, eliminating one or more symptoms and / or the underlying cause of said symptoms, reducing the frequency or likelihood of one or more symptoms and / or their underlying cause, delaying, preventing and / or slowing the progression of diseases and / or disorders and improving or remediating damage caused, directly or indirectly, by the diseases and / or disorders. For clarity, treating a disease does not include and is separate from preventing a disease.[000129] The sequences of the BAFFR antibodies and BAFFR x CD3 bispecific antibodies of the invention are numbered according to the sequence identifier numbers listed in Tables 1 and 2, respectively. The sequences in both Tables 1 and 2 arc amino acid sequences and the CDR sequences use the Northnumbering convention, unless otherwise indicated (see North, B. et al., J Mol Biol. 2011 Feb 18; 406(2):228-256).TABLE 1: hBAFFR Antibodies of the InventionTABLE 2: hBAFFR x hCD3 Bispecific Antibodies of the InventionEXAMPLES[000130] Example 1 : Generation of BAFFR x CD3 Bispecific Antibodies[000131] Immunization of MeMo® mice[000132] A diverse panel of cLC-based B AFF-R-targeting monoclonal antibodies were generated by selecting and characterizing antigen-specific molecules from MeMo® mice, which generate a single light chain or common light chain (cLC) fully human antibodies in combination with diversified heavy chains (see WO2009 / 157771). MeMo® mice were immunized with BAFF-R antigenic moieties, including the use of different forms of DNA, protein and cell-based delivery, as appropriate.[000133] A diverse panel of cLC-based human CD3 monoclonal antibodies was obtained using MeMo® mice (sec for instance W02020 / 204708). MeMo® mice were immunized with BAFF-R antigenic moieties, including the use of different forms of DNA, protein and cell-based delivery, as appropriate.[000134] The BAFF-R and CD3 binding domain sequences herein, once characterized and sequenced through the techniques provided herein, can be subsequently obtained by any method known in the art.[000135] Production and Screening of hBAFFR x hCD3 Bispecifics[000136] 15 hBAFFR arms were selected and paired with 23 hCD3 arms. The hBAFFR arms were cloned into an expression vector that creates specific mutations L351D and L368E in the CH3 region of the hBAFFR antibody, while the hCD3 arms were cloned into an expression vector that creates specific mutations L351K and T366K in the CH3 region of the hCD3 antibody, thereby allowing the two arms to appropriately heterodimerize.[000137] The resulting 363 hBAFFR x hCD3 bispecifics were screened for T cell activation using a Jeko-1 and Jurkat-NFAT-RE reporter assay (Promega) according to manufacturer’s instructions and 64 hBAFFR x hCD3 bispecifics were selected. Subsequent screening in a Jeko-1 and donor T cell co-culture assay for cytotoxicity and cytokine release was performed on the 64 bispecifics, resulting in 12 selected based on cytotoxicity, affinity, and cytokine release. These 12 bispecifics were then screened in a cell binding and Jeko-1 or Z-138 cell lines and donor PBMCs co-culture assay for cytotoxicity and cytokine release, resulting in 6 bispecifics selected.[000138] Reformatting of hBAFFR x hCD3 Bispecifics[000139] The 6 hBAFFR x hCD3 bispecifics were reformatted from a DEKK backbone to a knob- in-hole backbone comprising the T366W substitution in the hCD3 arm (the “knob”) and the T366S / L368A / Y407V in the hBAFFR arm (the “hole”). Fc silencing mutations LALADS: L234A / L235A / D265S were also introduced by conventional cloning techniques.[000140] For many of the examples, the following TCEs and controls were used:TABLE 3: Test Molecules and Controls[000141] Example 2: In Vitro Characterization of Cell Binding Activity to BAFFR and CD3[000142] This study was performed to test the cell binding activity of huBAFFR x huCD3 bispecifics(TCE1; TCE2; TCE3; TCE4; and TCE5) in a human BAFFR+ cell line Jeko-1 (ATCC CRL-3006) and in a human CD3+ cell line Jurkat clone E6-1 (ATCC CRL-TIB-152). Controls used: Control A, B, C, C90x38E4vl, TTx38E4vl, and Lunsumio®.[000143] Jcko-1 and Jurkat cells were counted and resuspended in cold staining buffer with 20 pg human Fc block. Cells were seeded 5xl04cells / well (25 pl / well volume) in 96-well plates and incubated on ice for 30 minutes. Titrated antibodies were added to the cells at 1:1 volume and incubated on ice for 2hours; all antibodies were diluted to a starting final concentration of 15 |ig / ml or 100 nM, except for TCE4 which was diluted to a starting final concentration of 13.7 pg / ml or 91.8 nM. Plates were centrifuged at 2000 rpm for 2 minutes at 4°C to pellet the cells. Cells were washed 3X with 100 pl staining buffer by centrifugation. PE-conjugated mouse anti-human IgG secondary antibody was prepared in staining buffer at 1:25 dilution. Cells were incubated with 50 pl / well of diluted secondary antibody on ice for 30 minutes. Zombie Violet™ viability dye was prepared in PBS at 1 : 1000 dilution. Cells were resuspended in 50 pl / well viability dye and incubated on ice for 20 minutes. Cells were washed IX and resuspended in 100 pl staining buffer for analysis on the Attune NxT flow cytometer.[000144] Plates were run on the Attune NxT flow cytometer (ThermoScientific) and analysis was performed using FlowJo (vl0.9). Doublets and dead cells were excluded in the gating strategy on FlowJo. The PE-MFI (geometric mean) was obtained for each sample based on singlets and live cells. The following gating strategy was used: cells (FSC-A vs. SSC-A) single cells (SSC-A vs. SSC-H) live cells (SSC- A vs. Zombie Violet™) gated on Zombie Violet™ negative — > PE-MFI (geometric mean). The MFIs were transferred to Microsoft Excel for further analysis. Background (buffer only wells) MFI was subtracted from all wells. Normalization across all plates was done using plate control wells, in which “max activity” wells included 15 pg / ml C90x38E4vl and “min activity” wells included 15 pg / ml LSN3985061. Percent activity was calculated as % = ((sample MFI- min MFI) / (max MFI-min MFI))*100. Generation of graphs and relative EC50 calculations were performed using GraphPad Prism. Antibody concentrations (nM) were transformed to logarithmlO of concentrations. Curves were fitted by the non-linear regression log(agonist) vs. response - variable slope (four parameters) model in GraphPad Prism.[000145] Summary: All hBAFFR x hCD3 bispecifics tested bind to human BAFF-R-expressing Jeko-1 cells, see Figure 1 A. Bispecifics with the same BAFF-R arm (Clone A or Clone B) had compar able relative EC50s (<3X difference) on Jeko-1 cells, however, different maximum binding values were observed, see Figure IB. CD3 binding on the surface of Jurkat cells was observed with all bispecifics, see Figure 2A. TCEs and Controls A, B and C with the same CD3 arm had comparable relative EC50s on Jurkat cells, see Figure 2B.[000146] Example 3: Evaluate hBAFFR and hCD3 Binding by ELISA[000147] This study was performed to test the protein binding activity of hBAFFR x hCD3 bispecifics: TCE1, TCE2, TCE3, TCE4, and TCE5 with human BAFF-R recombinant protein, human CD3 heterodimer epsilon delta recombinant protein, and human CD3 heterodimer epsilon gamma recombinant protein in ELISA. Controls used: Control A, B, C, C90x38E4vl, TTx38E4vl, and Lunsumio®.[000148] Immulon 4HBX 96-wcll plates were coated with a volume of 100 pl / well of 1 pg / ml recombinant protein (in PBS). Plates were sealed and incubated overnight in 4°C on a plate shaker. Nextday, plates were washed 3X with IX PBS-Tween (contains 0.05% Tween) using a plate washer (ELx-405 wash program IMM_300_3). Plates were then blocked with 300 pl / well of blocking buffer (3% BSA in PBS) for 2 hours at room temperature with orbital shaking. Antibody dilutions in assay buffer (1% BSA in PBS) were prepared manually, 10-point 3-fold dilution with a starting concentration of 15 pg / ml orlOO nM (with the exception of TCE4, starting concentration of 13.7 pg / ml or 91.8 nM . Antibodies used for plate normalizations were also prepared at 15 pg / ml. Blocking buffer was decanted and antibody dilutions (including plate controls or assay buffer wells) were added to the plates at 100 pl / well and incubated for 1 hour at room temperature with orbital shaking. Peroxidase-conjugated anti-human IgG F(ab’)2 secondary was prepared in assay buffer at 1 : 10,000 dilution. Plates were washed 3X. Anti-human secondar y was added to the plates at 100 pl / well and incubated for 1 hour at room temperature with orbital shaking. Plates were then washed 3X. TMB substrate was added to the plates at 100 pl / well for 5 minutes. Then 100 pl / well of stop solution was added and plates were read at 450 nm on the SpectraMax M5e plate reader using the SoftMax Pro program. Background (value of assay buffer-only wells) was subtracted from all values. Normalization across all plates were performed using plate control wells, in which “max activity” wells included 15 pg / ml C90x38E4vl and “min activity” wells included 15 pg / ml LSN3985061. Percent activity was calculated as % — ((sample value - min) / (max-min))*100. Generation of graphs and EC50 calculations were performed using GraphPad Prism. Titrated antibody concentrations (nM) were transformed to logarithm of concentrations. Curves were fitted by the non-linear regression log( agonist) vs. response - variable slope (four parameters) model in Graphpad Prism.[000149] Summary: All hBAFFR x hCD3 bispecifics tested displayed binding to human BAFFR recombinant protein, see Figure 3A. TCEs with the same BAFFR aim had very similar EC50s, see Figure 3B. CD3 binding activity of all bispecifics was observed with both human CD3 heterodimer epsilon delta and heterodimer epsilon gamma recombinant proteins, see Figures 4A and 5A. TCEs with the same CD3 arm had comparable EC50s, see Figures 4B and 5B.[000150] Example 4: In Vitro Characterization of Bispecific Internalization[000151] This study was performed to evaluate internalization of hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE3, TCE4, and TCE5 and negative controls Control A, B, and C in Jeko-1 cell line expressing BAFFR and Jurkat cell line expressing CD3. TCEs and negative controls were conjugated with Alexa Fluor 488 (AF488) by combining 0.5mg of antibody in amine-free buffer with 1.25-2pL of lOrnM AF488 NHS Ester dissolved in DMSO and sodium bicarbonate (10% v / v) for one hour at room temperature, protected from light. Labeled TCEs were subsequently transferred to 30K MW protein concentrators. Excess dye was removed with the addition of PBS and repeated centrifugation at 14,000 RPM for 10 minutes at room temperature until flow-through was colorless. The protein and label concentration of eachAF488-conjugated TCE was assessed using the NanoDrop spectrophotometer. Degree-of-labeling (DOL) was calculated by dividing molar concentration of AF488 by molar concentration of protein.[000152] Jeko-1 cells incubated with azide-free purified Fc Block according to manufacturer’s instructions or CD3-expressing Jurkat cells were added to 96-well polypropylene plates at 50-100,000 cells per well in 50pL of assay buffer. AF488-conjugated TCEs were serially titrated to generate a 10-point 4- fold dilution series with a starting concentration of 32 pg / mL in assay buffer: 50pL were added to cells in duplicate. Plates were covered with breathable seals and incubated at 37°C for 24 hours. To terminate the assay, plates were centrifuged at 800xg for 2 minutes at 4°C and cell pellets were resuspended in cold FACs buffer. After washing twice, cells were resuspended in 1:1000 Zombie Violet™ Live / Dead dye in IX PBS and incubated on ice for 20 minutes. Plates were washed again and cells were resuspended in 1:50 anti- AF488 antibody in FACs buffer to quench signal from surface bound AF488- TCEs. Samples were acquired on the Attune NxT flow cytometer along with Quantum AF488 MESF beads from Bangs Laboratories, according to manufacturer’s instructions.[000153] Single, live cells were identified using the FlowJo V10 software, following sequential gating of FSC-A vs SSC- A, FSC-H vs FSC-A, and Zombie Violet™ Live / Dead dye exclusion. Geometric mean fluorescent intensity (gMFI) of AF488 in single, live cells was then evaluated. Run-specific gMFI values of beads and manufacturer provided MESF values were used to generate a log-log plot and linear fit model in Graphpad Prism 10; this was used to interpolate MESF values of samples which were converted to Intracellular Antibody Accumulated (IAA) by dividing by DOL for each TCE.[000154] Summary: Intracellular antibody accumulation (IAA) of hBAFFR x hCD3 bispecifics in BAFFR-expressing Jeko-1 cells at 24 hours aligns with affinity of the BAFFR arm with BAFFR clone A bispecifics having higher IAA than BAFFR clone B bispecifics (Figure 6). Little to no IAA was observed in Jeko-1 cells treated with the CD3 negative controls at 24 hours, see Figure 6. Additionally, IAA of hBAFFR x hCD3 bispecifics in CD3-expressing Jurkat cells at 24 hours was observed with the highest concentrations at 27nM and 107 nM (Figure 7). In addition, IAA of the bispecifics tested corresponded to potency observed in cytotoxicity assays (data not shown). Though some internalization is observed, TCE- mediated cytotoxic activity occurs at much lower concentrations than doses with substantial IAA. IAA of hBAFFR x hCD3 bispecifics in BAFFR-expressing Jeko-1 and CD3-expressing Jurkat aligns with affinity of the BAFFR arm and CD3 arm, demonstrating the target-specific internalization of these bispecifics.[000155] Example 5: In Vitro Cytokine Release Characterization[000156] This study was performed to evaluate levels of pro-inflammatory cytokines induced by TCEs 1-5 and negative controls Control A, B and C in healthy donor PBMCs co-culturcd with human malignant B cell lines. Z-138 (CRL-3001) and Jeko-1 (CRL-3006) were originally sourced from ATCC.Nalm-6 (ACC 128) was originally sourced from DSMZ. DiscoverX KILR Retroparticles were purchased from Eurofins and used to transduce reporter cells to be utilized in cytotoxicity assays, according to manufacturer’s instructions. BAFFR was deleted from the genome of Nalm-6 cells prior to KILR reporter cell line generation by introducing single guide RNA via lentivirus and using the CRISPR / Cas9 system (TNFRSF13C CRISPR guide RNA_pLentiCRISPR v2 from Genscript).[000157] Supernatant was removed from cytotoxicity assays at 48 hours, see Example 9. lOpL from quadruplicate wells were combined into a single well per sample. Samples were stored at -80°C and thawed at room temperature at the start of the assay. The BD Cytometric Bead Array lyophilized standard was reconstituted in assay diluent and titrated according to manufacturer’s instructions. Duplicate standard curves and samples were transferred to assay plates at lOpL per well. Capture beads were vortexed and 2pL of each capture bead per test were combined with 12pL of PE detection reagent per test. The capture bead / PE detection reagent solution was added to all wells at 20pL per well. The assay plate was incubated for 2 hours at room temperature in the dark with agitation (500 RPM).[000158] Assay plates were washed twice with the addition of 200pL wash buffer per well and centrifugation at 400xg for 5 minutes. Standards and samples were resuspended in lOOpL wash buffer and acquired on the Attune NxT flow cytometer. Analyte-specific bead populations were identified using the FlowJo V10 software, following sequential gating of FSC-H vs SSC-H and APC vs FSC-H. Geometric mean fluorescent intensity (gMFl) of PE in each bead population was then evaluated. Standard curve and blank gMFI values were used to generate a log-log plot and nonlinear fit model for sigmoidal dose-response (variable slope) in Graphpad Prism 10; this was used to interpolate analyte concentrations of samples.[000159] Summary: Levels of pro-inflammatory cytokines induced by the hBAFFR x hCD3 bispecifics tested in high BAFF-R-expressing cell lines, Jeko-1 (Fig. 8A-B) and Z-138 (Fig. 9A-B), were relatively low and overall correspond to affinity of the BAFFR arm, with TCEs using the BAFFR clone A arm having greater cytokine release than those using BAFFR clone B. This trend is also observed in the Nalm-6 cell line which has lower surface expression of BAFF-R and concordantly lower cytokine levels (Fig. 10A-B). In Nalm-6 BAFF-R-KO target cells lacking BAFF-R expression, cytokine release is only observed at the highest TCE concentrations confirming the target- specific cytokine release by hBAFFR x hCD3 leads (Fig. 11A-B).[000160] Example 6: Evaluating Endogenous B Cell Depletion in Healthy Donor PBMCs[000161] This study was performed to evaluate T cell-mediated endogenous B cell depletion induced by the hBAFFR x hCD3 bispecifics: TCEs 1-5 in healthy donor PBMCs. Controls used were negative controls Control A, B C, and TTx38E4vl along with positive controls of Lunsumio® and C90x38E4vl.[000162] Healthy PBMCs were thawed in culture media and kept in a 37°C incubator for 2 hours before use. Antibody dilutions in PBS were prepared manually, 8-point 4-fold dilution within plate starting at lOOx final concentration. PBMCs were plated in 96-well plates at a density of IxlO5cells / well in 160 pl / well using the Thermo MultiDrop Combi Reagent Dispenser. The antibody dilution series was diluted in assay media to 5X final concentration and transferred to the cells at 40 pl / well for a final volume of 200 pl / well starting concentration 1600 ng / ml, except for TCE4 starting at 1469 ng / ml. After incubating with antibodies for 48 hours at 37°C in 5% CO:, cells were harvested into 96-well conical polypropylene plates and pelleted by centrifugation. Human Fc block was diluted in staining buffer at 1:100 and added to the cells (20 pl / well) on ice for 10 mins. Diluted APC-CD 19 (1:10) and Zombie Violet™ viability dye (1:500) were added simultaneously (20 pl) to the cells and incubated on ice for 20 mins. Cells were washed by centrifugation once with PBS and resuspended in 100 pl / well of staining buffer for flow cytometer analysis. [000163] Plates were run on the Attune NxT flow cytometer (ThermoScientific) and analysis was performed using FlowJo (vl0.9). Doublets and dead cells were excluded in the gating strategy on FlowJo. The following gating strategy was used: cells (FSC-A vs. SSC-A) — > single cells (SSC-A vs. SSC-H) — > live cells (SSC-A vs. Zombie Violet™) gating on Zombie Violet™ negative cells — APC-Count. The APC counts (number of CD19+ cells) were obtained for each sample based on singlets and live cells. The counts were transferred to Microsoft Excel for further analysis. Percent % cytotoxicity (Activity) was calculated by: lOO-lOOx (# of live CD 19+ cells in treated sample / average # of live CD 19+ cells in untreated samples), where untreated samples= PBS only.[000164] Normalization across all plates were performed using plate control wells, in which “max activity” wells included 1.6 pg / ml C90x38E4vl and “min activity” wells included 1.6 pg / ml LSN3985061 control. Cytotoxicity percentages were then normalized and calculated as: Normalized % cytotoxicity = 100*((sample % cytotoxicity - avg % LSN3985061 cytotoxicity) I (avg C90x38E4vl % cytotoxicity - avg % LSN3985061 cytotoxicity)).[000165] Generation of graphs and relative EC50 calculations were performed using GraphPad Prism. Antibody concentrations (nM) were transformed to logarithmlO of concentrations. Curves were fitted by the non-linear regression log(agonist) vs. response - variable slope (four parameters) model in Graphpad Prism.[000166] Summary: All hBAFF-RxhCD3 bispecifics tested elicited T cell killing of autologous B- cells in all three healthy donor PBMCs (Fig. 12A-C, F; Fig. 13A-C, F; Fig. 14A-C, F). Across all three PBMC donors, TCEs with the BAFFR arm clone A had more potent killing than those with the BAFFR arm clone B (Fig. 12A, C, F; Fig. 13A, C, F; Fig. 14A, C, F).[000167] Example 7: In Vitro T-Cell Activation[000168] The study was performed to evaluate T cell activation induced by the hBAFFR x hCD3 bispecifics tested: TCEs 1-5. Controls used: Control A, B, C, C90x38E4vl, TTx38E4vl, and Lunsumio®. [000169] Jurkat NFAT-RE luciferase reporter cells were plated in a 384- well plate at a density of 5xl03cells / well in assay media using the Thermo MultiDrop Combi Reagent Dispenser. For co-culture assays, target cells were added to the Jurkat-NFAT effector cells at a density of 5xl03cells / well in assay media for a 1:1 target:effector cell ratio. Antibody dilutions in PBS were prepared manually, 10-point 4- fold dilution within plate starting at 50x final concentration. The antibody dilution series was diluted in assay media to 5x final concentration and transferred to cells. After incubating with antibodies for 24 hours at 37°C in 5%CO2, cells were processed using the Bio-Gio Luciferase Assay System and Thermo MultiDrop Combi Reagent Dispenser. Luminescence signal was measured using a Molecular Devices Spectramax M5e. Raw luminescence values were plotted in GraphPad Prism. Curves were fitted by the non-linear regression log( agonist) vs. response - variable slope (four parameters) model in Graphpad Prism.[000170] Luminescence (0.5 ms) values were measured on the SpectraMax M5e plate reader using the SoftMax Pro program. Raw luminescence values were plotted in GraphPad Prism for generation of graphs and relative EC50 calculations.[000171] Summary: T-cell activation was observed with all hBAFFR x hCD3 bispecifics tested in the presence of hBAFF-R-expressing B-cell tumor cell lines. The highest T cell activation activity was observed in the highest hBAFFR expressing Jeko-1 cells (Fig. 15A-C) while lower T cell activation activities were observed with Z-138 cells (Fig. 16A-C) and Nalm-6 cells (Fig. 17A-C), with the latter two expressing less hBAFFR levels than Jeko-1. No T-cell activation was observed with Nalm-6 BAFF-R KO cells or in the absence of target cells (data not shown), indicating BAFFR needs to be present for hBAFFR x hCD3 leads to activate T-cells.[000172] Example 8: In Vitro T-Cell Activation, Proliferation and Tumor Cell Cytotoxicity[000173] This study was performed to evaluate the ability of: hBAFFR x hCD3 bispecifics: TCEs 1-5, negative controls Control A, B, C, and positive controls of Lunsumio® and C90x38E4vl, to induce T cell activation and proliferation and T-cell mediated tumor cell cytotoxicity utilizing human healthy donor PBMCs co-cultured with Jeko-1 cells. PBMCs were thawed in 37°C water bath and transferred into 15 mL centrifuge tube containing 7 mL of complete media (RPMI+10% HI FBS+ lx Glutamax) and washed once at 300xg for 5 min. Cells were resuspended in 5 mL RoboSep buffer and counted using the Cellometer cell viability counter. Cells were transferred to 14 mL polystyrene tube, washed, and resuspended in 1 mL RoboSep buffer for T cell isolation. T cell isolation was manually performed using human T cell isolation kit by Stemcell and the “Big Easy” EasySepTM magnet. The T cells were washed and resuspended inRoboSep buffer and counted for CFSE labeling. Isolated T cells (effector cells) were washed once with 10 mL of lx PBS and resuspended with 10 mL of lx PBS containing 10 pl of diluted CFSE and incubated in 37°C, 5% for 20 min. Added 30 mL of complete media and let sit at RT for 5 min, then washed. The cells were resuspended with 10 mL complete media and rested for 10 min at RT before counting. The cell concentration was adjusted with complete media to 0.625 x 106cells / mL and 80 pl (50,000 cells / well) of CFSE labeled T cells were plated into 96-well TC treated U bottom plate. Washed 30 million Jeko-1 cells (target cells) in 10 mL lx PBS twice and resuspended with 1 mL Diluent C from PKH26 kit. Prepared 2x of dye solution and added 1 mL of cells into 1 mL of 2x dye solution and mixed by pipetting. Cells were incubated for 1-5 min with periodic mixing. Added 5 mL of complete media and washed at 300xg for 10 min and carefully removed the supernatant. Cells were resuspended with 10 mL complete media and transferred to new tube and washed for 5 min three times. Cells were counted after final wash and cell concentration was adjusted with complete media te 0.125 x 106cells / mL and 80pL (10,000 target cells / well) were plated into 96-well containing CFSE labeled T cells. Antibody dilutions were prepared in PBS, 10- point 4-fold dilution in 96-well deep plate starting at 50x final concentration. The antibody dilution series was then diluted in complete media to 5x final concentration and transferred to cells. Cells were incubated in 37°C, 5% CO2 for 48 or 96 hours. On day of harvest, cells were washed once and resuspended with 25 pl of stain buffer containing 1:100 of human Fc block and incubated on ice for 30 min. Staining antibody mix (CD4, CD8, CD25, and CD69 at 1:50 per antibody) was prepared at 2x in brilliant staining buffer and 25 pl of mix was added and incubated for 1 hr on ice, protected from light. Cells were washed 3x at 700xg for 3 min and resuspended with 80 pl stain buffer containing helix blue (1:1000 dilution) and 40 pl was collected on the Attune flow cytometer.[000174] Data was analyzed using FlowJo version 10.10.0 and the following gating strategy was used:• T cell activation: cells (FSC-A vs SSC-A) a single cells (FSC-A vs FSC-H) a live cells (FSC-A vs BV421 -Helix Blue) a CD4 or CD8+ (FSC-A vs BV650-CD4 or FSC-A vs BV605-CD8) a %CD25 or %CD69 (histogram of APC-CD25 or PerCpCy5.5-CD69).• T cell proliferation: cells (FSC-A vs SSC-A) a single cells (FSC-A vs FSC-H) a live cells (FSC-A vs BV421-Helix Blue) a CD4 or CD8+ (FSC-A vs BV650-CD4 or FSC-A vs BV605-CD8) a % CFSE (Histogram of FITC-CFSE)• PKH-26+: cells (FSC-A vs SSC-A) a single cells (FSC-A vs FSC-H) a live cells (FSC-A vs BV421- Helix Blue) a PKH-26+ (FSC-A vs PE-PKH-26) a # of cells[000175] Percent % cytotoxicity (Activity) was calculated by: 100-lOOx (# of live PKH26+ cells in treated sample / average # live PKH26+ cells in untreated samples), where untreated samples= T cells +Jeko-1, PBS only. Tested antibody concentrations were transformed to loglO (common), and data was plotted as non-linear regression curve fit (sigmoidal, 4PL, X is log (concentration)) on GraphPad Prism version 10.1.2.[000176] Summary: In both Donor 1 and 2, by 48 hours, hBAFFR x hCD3 TCEs tested induced low levels of cytotoxicity (Fig. 18 A, C) and induced T cell activation based on an early T cell activation marker CD69+ (Fig. 20A, C, E, G). By 96 hours the TCEs tested induced higher levels of cytotoxicity (Fig. 18B, D) and induced T cell activation through a late T cell activation marker CD25+ (Fig. 21B, D, F, H) in both donors. The majority of the CD4+ and CD8+ T cells treated with the TCEs tested reached maximum levels of CD25 activation (Fig. 21B, D, F, H) and proliferation (Fig. 19B, D, F, H) by 96 hours for both donors. T cell activation (Fig. 20A-H and Fig. 21A-H), T cell proliferation (Fig. 19A-H), and T cell cytotoxicity (Fig. 18A-D) were not observed with the negative CD3 controls suggesting that the cytotoxicity, proliferation, and activation observed with the hBAFFR x hCD3-treated groups were due to the specific engagement of the anti-BAFFR arm to BAFFR+ cells.[000177] Example 9: In Vitro T-Cell Cytotoxicity in Malignant B Cell Lines[000178] This study was performed to evaluate T cell cytotoxicity of hBAFFR x hCD3 TCEs 1-5 on malignant B cell lines. KILR target lines of high-expressing hBAFFR Z-138 and JeKo-1, and low- expressing hBAFFR cell line Nalm-6 or Nalm-6 BAFF-R knock out (KO) cells were added to 384-well assay plates at 2,500 cells per well in 20uL of assay buffer. Normal, healthy donor PBMC were added as effector cells in two effector-to-target cell (E:T) ratios; 25,000 PBMC in 20uL of assay buffer were added to 10:1 E:T wells and 12,500 PBMC in 20uL of assay buffer were added to 5:1 E:T wells. TCEs tested: hBAFFR x hCD3 bispecifics TCE1, TCE2, TCE3, TCE4 and TCE5 and negative controls Control A, B and C were serially titrated to generate a 10-point 4- fold dilution series with a starting concentration of 80pg / mL in assay buffer; lOpL were added to cells in quadruplicate. PBS or lysis buffer were added to minimum or maximum signal control wells, respectively. Plates were covered with breathable seals and incubated at 37°C for 48 hours. At the time of assay termination, DiscoverX Detection Kit reagents 1, 2 and 3 were combined in a 4:1:1 ratio, according to manufacturer’s instructions. Assay plates were removed from the 37°C incubator and lOpL of supernatant taken from each well for downstream cytokine analysis, see Example 5. Detection reagents were added at 30pL per well and plates were incubated at room temperature for 45 minutes. Luminescence was detected using the SpectraMax M5e plate reader with standard settings. [000179] Luminescence values were converted to percent activity using a two-point normalization where average values from lysis buffer control wells determined the maximum signal and average values from PBS control wells determined the minimum signal. Maximum activity and relative EC50 values ofdose-response curves were calculated in Graphpad Prism 10. Curves were fitted by the non-linear regression log(agonist) vs. response - variable slope model in Graphpad Prism.[000180] Cytotoxic activity of hBAFFR x hCD3 bispecifics tested in high BAFF-R expressing cell lines, Jeko-l(Fig. 22A-B) and Z-138 (Fig. 23A-B), appeared to correspond to the affinity of the hBAFFR arm with the hBAFFR clone A having a higher maximum activity and potency than those with the hBAFFR clone B (Figures 23A-B, 24A-B, 25A-B and 26). Affinity of the hCD3 arm additionally differentiates the activity of the hBAFFR x hCD3 bispecifics with TCE1 having the highest maximum activity and potency. This trend was observed at both effector-to-target cell ratios tested 5:1 and 10:1. Despite lower surface expression of hBAFFR on the Nalm-6 cell line, hBAFFR x hCD3 bispecifics tested maintain cytotoxic activity at both E:T ratios (Figures 24A-B and 26). Reduced cytotoxic activity in Nalm-6 BAFF-R-KO cells confirms the target-specificity of hBAFFR x hCD3 tested (Figure 25A-B).[000181] Summary: As summarized in Figure 26, cytotoxic activity of hBAFFR x hCD3 TCEs is observed in high BAFFR expressing cell lines, Jeko-1 and Z-138, which corresponds to affinity of the BAFFR arm and CD3 arm. The TCEs tested maintain cytotoxic activity in the Nalm-6 cell line, despite lower surface expression of BAFFR. This activity is target-specific, as evidenced by reduced cytotoxic activity in Nalm-6 BAFF-R-KO target cells.[000182] Example 10: Ex Vivo Analysis of Serum Cytokine Levels in a Jeko-1 Luciferase Model[000183] Serum cytokine levels produced by humanized mice treated with hBAFFR x hCD3 bispecifics and controls were evaluated in a Jeko-1 luciferase tumor model. 50 pl of serum per mice was collected from mice treated as described in Example 12 and stored in -80°C until cytokine detection was performed. Serum was used once without any freeze-thaw cycles. Two assays, a IL2 single-plex and a corplex cytokine 10-plex, were used for each time point of this study, thus two sets of assays were used. The two sets of assays were performed on separate days. Assays were conducted per manufacturer’s instruction. Briefly, samples were prepared by adding 22 pl of serum to 33 pl of diluent. Each assay plate was washed 5x with 300 pl of lx washing buffer before loading of calibrators and samples. 50 pl of either calibrators or samples was added to the assay plate and shaken on benchtop shaker at -525 rpm for 2 hours. Each assay plate was washed for 5x with 300 pl of lx washing buffer before adding 50 pl of biotinylated detection reagent and shaken for 30 minutes. Each plate was washed for another 5x with 300 pl of lx washing buffer before adding 50 pl of streptavidin-HRP and shaken for 30 minutes. Each assay plate was washed lOx with 300 pl of lx washing buffer before addition of the SuperSignal reagents and immediately scanned on the SP-X Imager in the Ultrasensitive setting.[000184] Assay was read on the SP-X Imager and data was analysis using the SP-X Analysis software, version 2.2.8789. Assay product information and sample plate layout with calibrator and sampledilution factors were loaded onto software prior to data analysis. Standard curve for each analyte was manually and minimally adjusted to ensure a curve fit close to 1. After confirming the standard curve for each analyte, quantification of each sample was calculated by the software. Sample concentration was exported to Excel and graphed on Spotfire with the lower limit of quantification (LLoQ), limit of detection (LoD), and error bars representing one standard deviation of the average concentration per group.[000185] Summary: Levels of induced IL2 and IFNg were highest by TCE1, followed by TCE2, TCE4 and TCE5 (Fig. 27A and C). TCE1 induced a minor increase in IL-8 levels (Fig. 27 A). Levels of other 10-plex analytes (IL4, IL5, IL6, TNFa, ILlb, IL10, IL12p70, IL22) induced by the hBAFFR x hCD3 bispecifics were low and below the LLoQ (Fig. 27A, B, C). For nearly all cytokines measured, Lunsumio® induced higher levels than the TCEs tested (Fig. 27A, B, C).[000186] Example 11: Ex Vivo Analysis of Serum Cytokine Levels in a Z-138 Xenograft Model [000187] Serum cytokine levels produced by humanized mice treated with the hBAFFR x hCD3 bispecifics and controls in a Z-138 xenograft tumor model performed as described in Example 13 were evaluated. 50 pl of serum per mice was collected at 2 hours and 24 hours post treatment and stored in - 80°C until cytokine detection was performed. Serum was used once without any freeze-thaw cycles. Two assays, a IL2 single-plex and a corplex cytokine 10-plex, were used for each time point of this study, thus two sets of assays were used. The two sets of assays were performed on separate days. Assays were conducted per manufacturer’s instruction. Briefly, samples were prepared by adding 22 pl of serum to 33 pl of diluent. Each assay plate was washed 5x with 300 pl of lx washing buffer before loading of calibrators and samples. 50 pl of either calibrators or samples was added to the assay plate and shaken on benchtop shaker at -525 rpm for 2 hours. Each assay plate was washed for 5x with 300 pl of lx washing buffer before adding 50 pl of biotinylated detection reagent and shaken for 30 minutes. Each plate was washed for another 5x with 300 pl of lx washing buffer before adding 50 pl of streptavidin-HRP and shaken for 30 minutes. Each assay plate was washed l Ox with 300 pl of lx washing buffer before addition of the SuperSignal reagents and immediately scanned on the SP-X Imager in the Ultrasensitive setting.[000188] Assay was read on the SP-X Imager and data was analysis using the SP-X Analysis software, version 2.2.8789. Assay product information and sample plate layout with calibrator and sample dilution factors were loaded onto software prior to data analysis. Standard curve for each analyte was manually and minimally adjusted to ensure a curve fit close to 1. After confirming the standard curve for each analyte, quantification of each sample was calculated by the software. Sample concentration was exported to Excel and graphed on Spotfire with the lower limit of quantification (LLoQ), limit of detection (LoD), and error bar's representing one standard deviation of the average concentration per group.[000189] Summary: Serum cytokine levels induced by treatment of hBAFF-RxhCD3 bispecifics tested in a humanized mantle cell lymphoma Z-138 xenograft established tumor model were evaluated at 2 hours and 24 hours post 1st treatment.[000190] In the 2-hour samples, IL-2 was induced by TCE1, followed by TCE2 (Fig. 28C). TCE2 induced a minor increase in IL-8, IL- 10 and IL-22 levels (Fig. 28A and B). For many cytokines measured, Lunsumio® induced higher cytokine release as compared to the TCEs tested, see Figure 28A, B and C. Overall, higher induction of IFNg and IL-8 than other cytokines was observed across multiple samples (Fig. 28A).[000191] In the 24-hour samples, IL-2 was induced by TCE2, followed by TCE1 (Fig. 29C). IFNg was induced by TCE1, followed by TCE2 (Fig. 29 A). IL-6 was induced by TCE1, followed by TCE2 and TCE5 (Fig. 29C). TCE1 and TCE2 induced a minor increase in IFNg, IL-5, IL-8, IL-10 and IL- 22 levels, see Figure 29A, B and C. As with the 2 hour timepoint, for many cytokines measured, Lunsumio® induced higher cytokine release as compared to the TCEs tested at 24 hours, see Figure 29A, B and C. Overall, induction of IFNg, IL-5, IL-8, IL-10 and IL-22 was higher than other cytokines across multiple samples (Fig. 29A and B). Levels of other 10-plex analytes (IL-lb, IL-4, IL-12p70, TNFa) by the hBAFFR x hCD3 bispecifics tested were low and below the LLoQ (Fig. 29A, B and C).[000192] Example 12: In Vivo Analysis in Jeko-1 Xenograft Model[000193] This study was performed to evaluate anti-tumor activity of hBAFFR x hCD3 bispecifics TCE1-5 along with negative controls Control A, B, C and positive controls C90x38E4vl, and Lunsumio® in a humanized systemic mantle cell lymphoma Jeko-1 -luciferase xenograft mouse model. Jeko-1 Luciferase-expressing (Jekol-luc) single clone 2B5 cells (Jekol-luc-cl2B5) are derived from the human mantle cell lymphoma Jeko-1 cell line by stably integration of a constitutive Firefly luciferase expression construct (Systembio, Cat#LL250PA-l ). Parental Jeko-1 was obtained from the American Type Culture Collection, CRL-3006™. Jekol -luc-cl2B5 cells were maintained in ATCC-formulated RPMI-1640 Medium, Catalog No. 30-2001, supplemented 20% fetal bovine serum (Cat#SH300070.03 from CYTIVA) and 1 pg / ml puromycin (Cat#A1113803 from ThermoFisher). All cultures were maintained in a humidified incubator at 37°C under 5% COi / 95% air. Following recovery from frozen stocks, low cell passages (up to 4) were used in the experiment. Human PBMCs were isolated from whole blood (Donor#8068, AllCell, Lot# 3029827) using Ficoll-Hypaque density-gradient centrifugation and then frozen at -196°C until use.[000194] All the test articles were diluted freshly for each dosing to a final concentration of 0.015 mg / ml or 0.15 mg / ml in PBS, and animals were dosed by body weight (10 JJ l / g) intravenously.[000195] Female NOD SCID gamma (NSG) mice (Strain No. 005557) were obtained from Jackson Laboratory. Jeko-1 luciferase-expressing cells were prepared at 2.5 xl06 / ml in PBS (single-cell suspensionsof over 90% viability), i.v. (tail vein) injected 200ul into each mouse (0.5 xl06 / mouse). Tumor growth was identified by bioluminescent imaging at Day 5 after the inoculation, the mice were randomized into different groups and started the treatments once weekly for three weeks.[000196] 6-7-week female NSG mice were inoculated with 0.5 xlO6luciferase-expressing Jeko-1 cells via tail vein on Day 0. They were randomized into 12 groups based on luciferase signal intensities on Day 5. The mice were injected i.v. (tail vein) with 4xl06human PBMCs (donor#8068) on Day 6. 2 hours after PBMC injection, 0.15mg / kg or 1.5 mg / kg of the indicated test articles or vehicle were administered i.v. by body weight (10 pl / g) once a week for three weeks. Bioluminescence images were taken before treatment on Day 5, Day 12, Day 19 and Day 26 to monitor the tumor growth (data not shown).• Group 01: Jeko-l-luc only, vehicle, QWx3 doses• Group 02: Jeko-l-i- PBMCs, vehicle, QWx3 doses• Group 03: 0.15 mg / kg TCElQWx3 doses• Group 04: 0.15 mg / kg TCE3, QWx3 doses• Group 05: 0.15 mg / kg TCE2, QWx3 doses• Group 06: 0.14 mg / kg TCE4, QWx3 doses• Group 07: 1.5 mg / kg TCE5, QWx3 doses• Group 08: 0.15 mg / kg Control A, QWx3 doses• Group 09: 0.15 mg / kg Control C, QWx3 doses• Group 10: 0.15 mg / kg Control B, QWx3 doses• Group 11: 0.15 mg / kg C90x38E4vl, QWx3 doses• Group 12: 0.15 mg / kg Lunsumio®, QWx3 doses[000197] Bioluminescence imaging (BLI) is based on the sensitive detection of visible light produced during enzyme (luciferase)-mediated oxidation of a molecular' substrate when the enzyme is expressed in vivo as a molecular reporter. The BLI in this study was performed by IVIS 200 System (Xenogen). Prior to each imaging, the animals were injected by an intraperitoneal route with a luciferin solution (VivoGlo™ Luciferin, In Vivo Grade, cat# P1043), prepared 15 mg / ml stock in PBS and dosed at 150 mg / kg by body weight (10 pl / g). Allowing luciferin to be distributed in awake animals for 10 minutes. Under luminescent image model, mice were imaged dorsally under 2% isoflurane gas anesthesia. The image acquisition time was between 5 seconds to 1 minute to obtain unsaturated images in a small binning model. BLI signal is quantified in regions of interest (ROIs) drawn on whole body and the signal is expressed as photons per second, representing the flux radiating omni-directionally from the user-defined region. Images are analyzed using Living Image 4.7.4 (PerkinElmer, Waltham, MA) software. Data were analyzed using the GraphPad Prism 9.3.1 software (Graph-Pad Software, USA). Statistical differences were assessed asindicated by using an unpaired t-test and two-way ANOVA test. Differences were considered significant at p < 0.05. Body weights were measured twice weekly. The % change in body weight was calculated by the formula (body weight on observation day - body weight on initial day) / body weight on initial day x 100%. [000198] Summary: Six days after the first dose on Day 12, Jeko-1 tumor regression was observed in mice treated with TCE1 and TCE2, anti- tumor activities of which were comparable to Lunsumio® (p<0.001), see Figure 30. In all 3 treatment groups (TCE1, TCE2, and Lunsumio®), tumors started to regrow after Day 19. TCE3, TCE4 and TCE5 significantly inhibited tumor growth until Dayl9. The 3rd dose did not retain tumor growth inhibition in all the groups. The three mock aim controls did not show any in vivo activities compared to the vehicle group. No significant body weight loss was observed in any group (data not shown).[000199] Example 13: In Vivo Analysis in Established Z-138 Xenograft Model[000200] This study was performed to evaluate anti-tumor activity of hBAFFR x hCD3 bispecifics TCE1-5 and negative controls Control A, B, C, and positive controls C90x38E4vl, and Lunsumio® in an established humanized mantle cell lymphoma Z-138 xenograft model in NSG mice. The Z-138 human lymphoma cell line was obtained from the American Type Culture Collection (ATCC, CRL-3001™, Lot#57634322). Z-138 cells were maintained in ATCC-formulated Iscove's Modified Dulbecco's Medium (1MEM), Catalog No. 30-2005, supplemented 10% fetal bovine serum (Cat#SH300070.03). All cultures were maintained in a humidified incubator at 37°C under 5% CCL / 95% air. Following recovery from frozen stocks, low cell passages (up to 4) were used in the experiment. Human PBMCs were isolated from whole blood (Donor B001000834, Miltenyi, Lot# 031908290118999) using Ficoll-Hypaque density-gradient centrifugation and then frozen at -196°C until use.[000201] All the test articles were diluted freshly for each dosing to a final concentration of 0.05 mg / ml in phosphate-buffered saline (PBS). *Note: concentration for TCE4 was mistaken for 7.7 mg / ml when prepared dosing to mice. Thus, final concentration of TCE4 is 0.046 mg / ml.[000202] Female NOD SCID gamma (NSG) mice (Strain No. 005557) were obtained from Jackson Laboratory and acclimated for 1 week before initiating the experiment. Mice were housed in a 12-hour light / dark cycle facility under pathogen-free conditions in microisolator cages with standard laboratory chow and water ad libitum. Prepared Z-138 cells [10x10® with 6 xlO5PBMCs in 100 pL, single-cell suspensions of over 90% viability in Hank’s Balanced Saline Solution, mixed with an equal volume of Matrigel (100 pL)] were subcutaneously injected into the right hind flank of each mouse.[000203] On day 0, 5xl06Z-138 human lymphoma cells were mixed with 0.3xl06healthy human PBMCs and injected subcutaneously into right flank of mice (200pl / mousc, in Hank's Balanced Salt Solution with an equal volume of Matrigel). When tumors reached approximately 200 mm3at day 6 postthe cell implantation, mice were randomized into eight groups (6 mice / group). Treatment groups were all dosed at 0.5mg / kg by intravenous injection (IV) once a week for three weeks. Tumor volume (TV) and body weight were measured twice per week. TV was calculated as TV (mm3) = TT / 6 * length * width2. Animals were sacrificed due to progressive disease if tumor burden was greater than 2000 mm3, or growth would surpass 2000 mm3before the next measurement.• Group 1: Z-138+PBMCs, Vehicle• Group 2: Z-138+PBMCs, 0.5 mg / kg TCE1, QW x 3 doses• Group 3: Z-138+PBMCs, 0.5 mg / kg TCE3, QW x 3 doses• Group 4: Z-138+PBMCs, 0.5 mg / kg TCE2, QW x 3 doses• Group 5: Z-138+PBMCs, 0.5 mg / kg TCE4, QW x 3 doses• Group 6: Z-138+PBMCs, 0.5 mg / kg TCE5, QW x 3 doses• Group 7: Z-138+PBMCs, 0.5 mg / kg Control A, QW x 3 doses• Group 8: Z-138+PBMCs, 0.5 mg / kg Control C, QW x 3 doses• Group 9: Z-138+PBMCs, 0.5 mg / kg Control B, QW x 3 doses• Group 10: Z-138+PBMCs, 0.5 mg / kg C90x38E4vl, QW x 3 doses• Group 11: Z-138+PBMCs, 0.5 mg / kg Lunsumio®, QW x 3 doses[000204] Blood samples were collected retro-orbitally at 2 hrs and 24 hrs post the first dose (3 mice / group at each time points) to measure cytokine levels (included in a separate study report) in serum separator tube (BD sku#365967). Adequate time was allowed for blood to clot (~20 minutes) at room temperature, then blood was centrifuge at 10,000xg for 10 mins in a refrigerated centrifuge. Serum was collected, aliquoted and stored in -80°C until cytokine detection experiment.[000205] Tumor volumes were transformed to a loglO scale to equalize variance across time and treatment. LoglO volume and body weight were separately analyzed using a two-way repeated measures analysis of variance model (RM ANOVA) consisting of time, treatment, and the interaction between time and treatment using the MIXED procedure of the SAS software package (Version 9.4). Spatial Power covariance structure was used to model the correlation of observations across time for the same subject. Kenward and Roger (1997) denominator degrees of freedom (DDFM) calculations were used for tests of fixed effects. Post-hoc pairwise t-tests were used to compare tumor volumes and body weights of treated groups to the control group on the summarized day, p- values < 0.05 were considered statistically significant. The MIXED procedure was also used separately for each treatment group to calculate least squares means (LS Means) and standard errors for each time point for the purpose of plotting and inclusion.[000206] Efficacy Calculations: Efficacy was calculated at the end of the treatment if number of remaining control group subjects was at least half the baseline sample size or greater than 4. Otherwise,efficacy was calculated on the most recent observation day prior to the end of treatment where these conditions were met.• Percent treatment / control (% T / C) values was calculated using the following formula:• % T / C = 100 x AT / AC if AT > 0• % Regression = 100 x AT / Tinitiai if AT < 0 where:• T = mean tumor volume of the drug-treated group on the final day of the study;• AT = mean tumor volume of the drug-treated group on the final day of the study - mean tumor volume of the drug-treated group on initial day of dosing;• Tinitiai = mean minor volume of the drug-treated group on initial day of dosing;• C = mean tumor volume of the control group on the final day of the study: and• AC = mean tumor volume of the control group on the final day of the study - mean tumor volume of the control group on initial day of dosing.• The % change in body weight was calculated as:• (BW current - BW initial) / (BW initial) x 100[000207] Data was calculated as percent body weight change from the day of treatment initiation.[000208] Summary: hBAFFR x hCD3 bispccifics tested demonstrated anti-tumor efficacy in established human mantle cell lymphoma Z- 138 xenograft mouse model co- implanted with human PBMCs. TCEsl-5 significantly inhibited Z-138 tumor growth (P < 0.001) on Day 32 compared with hPBMCs Vehicle (Group 1). See Figure 31. Among the five hBAFFR x hCD3 bispecifics tested, TCE2 showed the lowest T / C rate. Tumors in all the three mock arm control groups had very similar growth rate with the vehicle group. No significant body weight loss was observed in any group (data not shown).[000209] Example 14: In Vivo Antitumor Activity in Immunocompetent Syngeneic BAFFR+ Tumor Model[000210] Murine tumor cells EO771 expressing human B AFFR were implanted subcutaneously in humanized CD3EDG mice. TCE1 at two doses: 0.5 mg / kg and 0.05 mg / kg along with isotype Control A were injected intravenously three times at Day 1, 9 and 15 post EO771 cell implantation.[000211] Data are mean ± SEM where N — 4.[000212] Summary: TCE1 shows potent anti-tumor activity against human BAFFR expressing mouse tumor model in humanized CD3EDG mice with competent immune system, at a dose as low as 0.05 mg / kg, demonstrating potency of this TCE. See Figure 32.[000213] Example 15: In Vivo Antitumor Activity in Patient-Derived B-ALL Xenograft Model [000214] Patient derived B-ALL model BP2101 is homogenously double positive for human CD19 and human BAFFR. About 30% of BP2101 cells are human CD20 positive and concomitantly positive for human CD19 and human BAFFR. BP2101 cells were implanted intravenously into NSG mice. After 20 days, 3xl06human donor PBMC per mouse were engrafted, followed by treatment with TCE1 24hr later at different dosages: 2.0mg / kg, 0.5mg / kg, or 0.15mg / kg. An isotype negative control (Control A) was tested at 2.0mg / kg as well as a positive control (mosunetuzumab) at 0.5mg / kg. All test articles and controls were administered IV, once weekly. Peripheral blood of all mice was subjected to flow analysis for hCD19+ cells and hCD3+ T cells at 24hr after each dosing.[000215] One-way ANOVA was used for statistical analysis. All data were compared to Vehicle *P<0.0001; **P=0.0003. Data are mean ± SEM.[000216] Summary: TCE1 reduces B cells in patient derived B-ALL model humanized with PBMCs in a dose-dependent fashion 24hr after 3rd TCE dosing. Further, TCE1 demonstrated a complete depletion of patient-derived B-ALL B cells at 2 mg / kg. See Figure 33.

Claims

CLAIMS1 . A bispecific antibody that specifically binds human B cell-activating factor receptor (hB AFFR) and human CD3 (hCD3), wherein the bispecific antibody comprises (a) a first antigen binding domain that specifically binds hBAFFR comprising a first heavy chain variable region (VH1) and a light chain variable region (VL1), wherein the VH1 comprises heavy chain complementarity determining regions (HCDR) HCDR1, HCDR2, and HCDR3, and the VL1 comprises light chain complementarity determining regions (LCDR) LCDR1, LCDR2, and LCDR3, wherein:(a) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO:2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6; or(b) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO:30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:

6. and a second antigen binding domain that specifically binds human CD3.

2. The bispecific antibody of claim 1, wherein the second antigen binding domain that specifically binds hCD3 comprises a second heavy chain variable region (VH2) and a light chain variable region (VL2), wherein the VH2 comprises heavy chain complementarity determining regions (HCDR) HCDR4, HCDR5, and HCDR6, and the VL2 comprises light chain complementarity determining regions (LCDR) LCDR4, LCDR5, and LCDR6.

3. A bispecific antibody that specifically binds hBAFFR and hCD3, wherein the bispecific antibody comprises (a) a first antigen binding domain that specifically binds hBAFFR and (b) a second antigen binding domain that specifically binds hCD3 comprising a heavy chain variable region (VH2) and a light chain variable region (VL2), wherein the VH2 comprises heavy chain complementarity determining regions (HCDR) HCDR4, HCDR5, and HCDR6, and the VL2 comprises light chain complementarity determining regions (LCDR) LCDR4, LCDR5, and LCDR6, wherein: a) HCDR4 comprises SEQ ID NO:7, HCDR5 comprises SEQ ID NO:8, HCDR6 comprises SEQ ID NO:9, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6: b) HCDR4 comprises SEQ ID NO: 19, HCDR5 comprises SEQ ID NO:20, HCDR6 comprises SEQ ID NO:21, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO: 6; orc) HCDR4 comprises SEQ ID NO:24, HCDR5 comprises SEQ ID NO:25, HCDR6 comprises SEQ ID NO:26, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6.

4. The bispecific antibody of any one of claim 1-3, wherein the first antigen binding domain has about a 5-fold to about a 50-fold greater binding affinity (KD) for hBAFFR relative to the binding affinity the second antigen binding domain has for hCD3, as measured by surface plasmon resonance (SPR).

5. The bispecific antibody of any one of claims 1-4, wherein the bispecific antibody demonstrates an in vivo tumor growth inhibition of at least 10% or greater.

6. The bispecific antibody of any one of claims 1-5, wherein the bispecific antibody induces an in vivo IFNg concentration of 6000 fg / ml or less.

7. The bispecific antibody of any one of claims 1-6, wherein the bispecific antibody inhibits binding of hBAFFR to hBAFF.

8. The bispecific antibody of any one of claims 1-7, wherein the bispecific antibody inhibits antibody- induced shedding of the hBAFFR extracellular domain.

9. The bispecific antibody of claim 2, wherein:(a) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ IDNO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ IDNO:6, HCDR4 comprises SEQ ID NO:7, HCDR5 comprises SEQ ID NO:8, HCDR6 comprises SEQ IDNO:9, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ IDNO:6;(b) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO: 19, HCDR5 comprises SEQ ID NO:20, HCDR6 comprises SEQ ID NO:21, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6;(c) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO: 2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO:24, HCDR5 comprises SEQ ID NO:25, HCDR6 comprises SEQ ID NO:26, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6;(d) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO: 30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO:7, HCDR5 comprises SEQ ID NO:8, HCDR6 comprises SEQ ID NO:9, LCDR4 comprises SEQ ID NO:4, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6; or(e) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO: 30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6, HCDR4 comprises SEQ ID NO: 19, HCDR5 comprises SEQ ID NO:20, HCDR6 comprises SEQ ID NO:21, LCDR4 comprises SEQ ID NON, LCDR5 comprises SEQ ID NO:5, LCDR6 comprises SEQ ID NO:6.

10. The bispecific antibody of any one of claims 1-9, wherein:(a) the VH1 comprises SEQ ID NO: 10 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO: 11 and the VL2 comprises SEQ ID NO: 12;(b) the VH1 comprises SEQ ID NO: 10 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO:22 and the VL2 comprises SEQ ID NO: 12;(c) the VH1 comprises SEQ ID NO: 10 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO: 27 and the VL2 comprises SEQ ID NO: 12:(d) the VH1 comprises SEQ ID NO:32 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO: 11 and the VL2 comprises SEQ ID NO: 12; or(e) the VH1 comprises SEQ ID NO:32 and the VL1 comprises SEQ ID NO: 12 and the VH2 comprises SEQ ID NO:22 and the VL2 comprises SEQ ID NO: 12.

11. The bispecific antibody of any one of claims 1-10, further comprising an Fc region comprising (a) a B AFFR heavy chain constant region comprising a first CH2 and a first CH3 domains and (b) a CD3 heavy chain constant region comprising a second CH2 and a second CH3 domains, wherein the first CH3 domain has amino acid substitutions L351D and L368E and the second CH3 domain has amino acid substitutions L351K and T366K.

12. The bispecific antibody of any one of claims 1-10, further comprising an Fc region comprising (a) a BAFFR heavy chain constant region comprising a first CH2 and a first CH3 domains and (b) a CD3 heavy chain constant region comprising a second CH2 and a second CH3 domains, wherein the first CH3 domainhas amino acid substitutions T366S / L368A / Y407V and the second CH3 domain has amino acid substitutionT366W.

13. The bispecific antibody of any one of claims 11 or 12, wherein the Fc region comprises Fc silencing mutations.

14. The bispecific antibody of claim 13, wherein the Fc silencing mutations are (a) L235G and G236R or (b) L234A, L235A or (c) L234A, L235A and D265A or (d) L234A, L235A and P329G or (e) N297A or (f) N297A and K322A or (g) L234A, L235A and D265S.

15. The bispecific antibody of any one of claims 1-14, wherein the antibody comprises a first heavy chain (HC1) and a common light chain (cLC) that specifically binds hBAFFR and a second heavy chain (HC2) and said common light chain (cLC) that specifically binds human CD3 wherein:(a) HC1 comprises SEQ ID NO:16, HC2 comprises SEQ ID NO:17, cLC comprises SEQ ID NO:18;(b) HC1 comprises SEQ ID NO:16, HC2 comprises SEQ ID NO:23, cLC comprises SEQ ID NO:18;(c) HC1 comprises SEQ ID NO:16, HC2 comprises SEQ ID NO:28, cLC comprises SEQ ID NO:18;(d) HC1 comprises SEQ ID NO:33, HC2 comprises SEQ ID NO:17, cLC comprises SEQ ID NO:18; or(e) HC1 comprises SEQ ID NO:33, HC2 comprises SEQ ID NO:23, cLC comprises SEQ ID NO:18.

16. The bispecific antibody of any one of claims 1-15, wherein the antibody is a human IgGl or IgG4 isotype.

17. The bispecific antibody of claim 16, wherein the antibody is a human IgGl isotype.

18. A nucleic acid encoding the amino acid sequences of claim 15.

19. A host cell transfected with: a) a first vector comprising the nucleic acids encoding SEQ ID NO: 16, and a second vector comprising the nucleic acids encoding SEQ ID NO:17; b) a first vector comprising the nucleic acids encoding SEQ ID NO: 16, and a second vector comprising the nucleic acids encoding SEQ ID NO:23; c) a first vector comprising the nucleic acids encoding SEQ ID NO: 16, and a second vector comprising the nucleic acids encoding SEQ ID NO:28; d) a first vector comprising the nucleic acids encoding SEQ ID NO: 33, and a second vector comprising the nucleic acids encoding SEQ ID NO: 17; ore) a first vector comprising the nucleic acids encoding SEQ ID NO: 33, and (j) a second vector comprising the nucleic acids encoding SEQ ID NO:23.

20. The host cell of claim 19, further transfected with a third vector comprising the nucleic acids encoding SEQ ID NO: 18.

21. The host cell of claim 19, wherein the host cell is a mammalian host cell.

22. A process of producing a bispecific antibody comprising culturing the cell of claim 20 or 21 in a culture medium under conditions such that the bispecific antibody is expressed and then recovered from the culture medium.

23. A pharmaceutical composition comprising the hBAFFR x hCD3 bispecific antibody of any one of claims 1-17 and 22, and a pharmaceutically acceptable excipient, diluent or carrier.

24. An isolated antibody that specifically binds hBAFFR, wherein the antibody comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises heavy chain complementarity determining regions (HCDR) : HCDR 1 , HCDR2, and HCDR3 , and the VL comprises light chain complementarity determining regions (LCDR): LCDR1, LCDR2, and LCDR3, wherein:(a) HCDR1 comprises SEQ ID NO:1, HCDR2 comprises SEQ ID NO:2, HCDR3 comprises SEQ ID NO:3, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6; or(b) HCDR1 comprises SEQ ID NO:29, HCDR2 comprises SEQ ID NO:30, HCDR3 comprises SEQ ID NO:31, LCDR1 comprises SEQ ID NO:4, LCDR2 comprises SEQ ID NO:5, LCDR3 comprises SEQ ID NO:6.

25. The antibody of claim 24, wherein: a) the VH comprises SEQ ID NO: 10 and the VL comprises SEQ ID NO: 12; or b) the VH comprises SEQ ID NO: 32 and the VL comprises SEQ ID NO: 1226. The antibody of claim 24 or 25, wherein the antibody comprises a heavy chain (HC) and a light chain (LC), wherein: a) the HC comprises SEQ ID NO:34 and the LC comprises SEQ ID NO: 18; or b) the HC comprises SEQ ID NO:35 and the LC comprises SEQ ID NO: 18.

27. The antibody of any one of claims 24-26, wherein the antibody is a human IgGl or IgG4 isotype.

28. The antibody of claim 27, wherein the antibody is a human IgGl isotype.

29. The antibody of any one of claims 24-28, wherein the antibody is an antibody fragment or antigenbinding fragment.

30. The antibody of claim 29, wherein the antibody fragment or antigen-binding fragment is a Fab, a Fab’, an F(ab’)2, a single-chain variable fragment (scFv), an Fv, a disulfide-linked Fv (sdFv), an Fd fragment, or a single-chain Fab (scFab).

31. The antibody of any one of claims 24-30, wherein the antibody is a multispecific antibody.

32. The antibody of claim 31, wherein the multispecific antibody is a bispecific antibody, or a trispecific antibody, or a tetraspecific antibody, or a diabody, or a tandem scFv, or a tandem VHH, or a tandem scFab.

33. An antibody-drug conjugate (ADC) comprising the antibody of any one of claims 24-32 and a drug moiety.

34. The ADC of claim 33, wherein the drug moiety is selected from the group consisting of auristatin, N-acetyl-y calicheamicin, maytansinoid, pyrrolobenzodiazepine, exatecan and SN-38.

35. An immunocytokine comprising the antibody of any one of claims 24-32 and a cytokine.

36. The immunocytokine of claim 35, wherein the cytokine is selected from the group consisting of IL-2, IL-4, IL- 10, IL- 12, IL- 15, TNF, and IFNa.

37. A chimeric antigen receptor (CAR) comprising the antibody of any one of claims 24-32, a transmembrane domain, and an intracellular signaling domain.

38. A pharmaceutical composition comprising the hB AFFR antibody of any one of claims 24-32 or the ADC of any one of claims 33-34 or the immunocytokinc of any of claims 35-36 or the CAR of claim 37 and a pharmaceutically acceptable excipient, diluent or carrier.

39. A method of treating B-cell cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the bispecific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24-32 or the ADC of claims 33-34 or the immunocytokine of claims 35- 36 or the CAR of claim 37.

40. The method of claim 39, wherein the B-cell cancer is relapsed or refractory.

41. The method of claim 39 or 40, wherein the B-cell cancer is B-cell acute lymphoblastic leukemia (B-ALL); Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL);chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa- associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); high-grade B-cell lymphoma (HGBCL); Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B- cell prolymphocytic leukemia (B-PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary central nervous system (CNS) lymphoma; and primary intraocular lymphoma.

42. A method of treating an autoimmune disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the bispccific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24-32 or the ADC of claims 33-34 or the immunocytokine of claims 35-36 or the CAR of claim 37.

43. The method of claim 45, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (IBD), and psoriasis.

44. The bispecific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24- 32 or the ADC of claims 33-34 or the immunocytokine of claims 35-36 or the CAR of claim 37 for use in the treatment of a B-cell cancer.

45. The use of claim 44, wherein the B-cell cancer is relapsed or refractory.

46. The use of claim 44 or 45, wherein the B-cell cancer is B-cell acute lymphoblastic leukemia (B- ALL); Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL); chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa- associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); high-grade B-cell lymphoma (HGBCL); Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B- cell prolymphocytic leukemia (B-PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary central nervous system (CNS) lymphoma; and primary intraocular lymphoma.

47. The bispecific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24- 32 or the ADC of claims 33-34 or the immunocytokine of claims 35-36 or the CAR of claim 37 for use in the treatment of an autoimmune disorder.

48. The use of claim 47, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (IBD), and psoriasis.

49. A pharmaceutical composition comprising the bispecific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24-32 or the ADC of claims 33-34 or the immunocytokine of claims 35-36 or the CAR of claim 37 for use in treating B-cell cancer.

50. The pharmaceutical composition of claim 49, wherein the B-cell cancer is relapsed or refractory.

51. The pharmaceutical composition of claim 49 or 50, wherein the B-cell cancer is B-cell acute lymphoblastic leukemia (B-ALL); Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL); chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa-associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); high-grade B-cell lymphoma (HGBCL); Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B-cell prolymphocytic leukemia (B-PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary central nervous system (CNS) lymphoma; and primary intraocular' lymphoma.

52. A pharmaceutical composition comprising the bispecific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24-32 or the ADC of claims 33-34 or the immunocytokine of claims 35-36 or the CAR of claim 37, for use in the treatment of an autoimmune disorder.

53. The pharmaceutical composition of claim 52, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (TBD), and psoriasis.

54. Use of the bispecific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24-32 or the ADC of claims 33-34 or the immunocytokine of claims 35-36 or the CAR of claim 37, in the manufacture of a medicament for the treatment of a B-cell cancer.

55. The use of claim 54, wherein the B-cell cancer is relapsed or refractory.

56. The use of claim 54 or 55, wherein the B-cell cancer is B-cell acute lymphoblastic leukemia (B- ALL); Hodgkin lymphoma (HL); non-Hodgkin lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma which is a subtype of DLBCL; follicular lymphoma (FL); chronic lymphocytic leukemia (CLL); small lymphocytic lymphoma (SLL); mantle cell lymphoma (MCL); marginal zone lymphomas and extranodal marginal zone B-cell lymphoma (also known as mucosa- associated lymphoid tissue (MALT) lymphoma); mediastinal gray zone lymphoma (MGZL); nodal marginal zone B-cell lymphoma; splenic marginal zone B-cell lymphoma (SMZL); splenic diffuse red pulp small B-cell lymphoma (SDRPL); high-grade B-cell lymphoma (HGBCL); Burkitt lymphoma (BL) and Burkitt-like lymphoma (BLL); lymphoplasmacytic lymphoma (or Waldenstrom macroglobulinemia); B- cell prolymphocytic leukemia (B-PLL); hairy cell leukemia (HCL); multiple myeloma (MM): plasma cell neoplasms; primary central nervous system (CNS) lymphoma; and primary intraocular lymphoma.

57. Use of the bispecific antibody of any one of claims 1-17 and 23 or the antibody of any one of claims 24-32 or the ADC of claims 33-34 or the immunocytokine of claims 35-36 or the CAR of claim 37, in the manufacture of a medicament for the treatment of an autoimmune disorder.

58. The use of claim 57, wherein the autoimmune disorder is rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), multiple sclerosis (MS), celiac disease (CD), type I diabetes, primary Sjogren’s syndrome (pSS), Guillain-Barre syndrome, inflammatory bowel disease (IBD), and psoriasis.

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