A CD19 / CD20 bispecific antibody with dual FC domains

Abstract

Provided herein are methods for: (1) rapidly depleting circulating B cells and remodeling one or more B cell compartments, (2) treating B cell-related autoimmune diseases, and (3) B cell malignancies, using B cell depleting antibodies that are directed to CD19 or CD20 and one or more target antigens. Further provided herein is a CD19 / CD20 bispecific antibody with dual Fc domains that mediate enhanced effector functions and B cell depletion. HB2198 demonstrated enhanced binding to Fcγ receptors, potent effector functions, and efficient depletion of B cells in vitro and in vivo.

Description

Attorney Docket: 53080.4002 / WOA CD19 / CD20 BISPECIFIC ANTIBODY WITH DUAL FC DOMAINS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 721,259, filed November 15, 2024, which is hereby incorporated by reference in its entirety.SEQUENCE LISTING

[0002] The instant application contains a Sequence Listing which has been submitted electronically in ST.26 XML format and is hereby incorporated by reference in its entirety. Said ST.26 XML format file was created on November 12, 2025, is named 53080_4002-WO_SL.xml and is 336,338 bytes in size.BACKGROUND

[0003] B cells have been shown to be not merely bystanders but rather play an important role in the development and progression of multiple autoimmune diseases and lymphoproliferative disorders. In autoimmune diseases characterized by B cell pathogenesis, B cells contribute to disease pathology through several mechanisms, including the production of autoantibodies that target self-antigens, the activation of T cells via antigen presentation, and the secretion of pro-inflammatory cytokines that amplify immune responses. Autoantibodies can directly damage tissue, activate complement pathways, and perpetuate chronic inflammation, as exhibited in, for example, systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjogren’s disease (SjD), and multiple sclerosis (MS). Similarly, B cells play a central role in B cell malignancies because these disorders involve the uncontrolled proliferation of B cells. Dysregulation of B cell proliferation leads to an accumulation of pathological B cells at any number of different stages of maturity depending on the specific B cell malignancy. These pathological B cells will accumulate in one or more regions throughout the body, or persist in circulation, replacing healthy B cells capable of fighting an infection with abnormal B cells.

[0004] There has been some clinical success in treating patients suffering from B cell malignancies or autoimmune diseases characterized by B cell pathogenesis using B cell depleting therapies for protracted periods of time. Despite the success exhibited in select patientAttorney Docket: 53080.4002 / WOpopulations, there remains a diverse range of outcomes depending on numerous factors, such as, for example, the disease state, the patient population, the B cell depleting therapy utilized, and the period of time for which a patient is treated. As such, there remains an unmet need for additional B cell depleting therapies capable of treating autoimmune diseases characterized by B cell pathogenesis and / or treating B cell malignancies.SUMMARY

[0005] In one aspect, the present disclosure provides a method for rapidly depleting circulating B cells in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein: (a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD) selected from a group including: (i) an anti-CD19 ABD, and (ii) an anti-CD20 ABD; (b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; and (c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject.

[0006] In a further embodiment and in accordance with the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered for 4 or fewer consecutive days.

[0007] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

[0008] In a further embodiment, and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours. In some further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 7 days. In some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 2-3 days. In still some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 24 hours.Attorney Docket: 53080.4002 / WO

[0009] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0010] In a further embodiment and in accordance with any of the above, the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

[0011] In a further embodiment and in accordance with any of the above, a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, characterized by an increased ratio of circulating CD27' B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration. In some further embodiments, the B cell niche comprises B cells resident to the circulatory system. In still some further embodiments, depletion of the circulating B cells occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

[0012] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration. In some further embodiments, the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof. In still some further embodiments, (i) at least one of the one or more B cell compartments comprises one or more lymph nodes; and (ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the spleen; and (ii) the tissue-resident B cells comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof. In a separate further embodiment, (i) atAttorney Docket: 53080.4002 / WOleast one of the one or more B cell compartments comprises bone marrow; and (ii) the tissueresident B cells comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises mucosa-associated lymphoid tissue (MALT); and (ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the thymus; and (ii) the tissue-resident B cells comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the skin; and (ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the liver; and (ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

[0013] In a further embodiment and in accordance with the above, at least one of the one or more B cell compartments exhibits remodeling of a B cell niche, characterized by an increased ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells as compared to a baseline ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells. In some further embodiments, the remodeling of the B cell niche occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

[0014] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route. In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered as a bolus injection, as an IV infusion, or as a continuous infusion.

[0015] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest. In some further embodiments, individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof. In still some further embodiments, at least one of theAttorney Docket: 53080.4002 / WOone or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD103. In yet still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD 138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD 103.

[0016] In a further embodiment and in accordance with any of the above, (i) the at least one antigen binding domain (ABD) is an anti-CD19 ABD; and (ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement. In some further embodiments, the antiCD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD19 ABD is in a Fab format. In some other further embodiments, the anti-CD19 ABD is in a scFv format. In still some other further embodiments, the anti-CD19 ABD is in a VHH format.

[0017] Alternatively, or in addition to, in a further embodiment and in accordance with any of the above, (i) the at least one antigen binding domain (ABD) is an anti-CD20 ABD; and (ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the.1 Horney Docket: 53080.4002 / WOcharacteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement. In some further embodiments, the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD20 ABD is in a Fab format. In some other further embodiments, the anti-CD20 ABD is in a scFv format. In still some other further embodiments, the anti-CD20 ABD is in a VHH format.

[0018] In a further embodiment and in accordance with any of the above, the method comprises administering an anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof). In some further embodiments, (i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and / or (ii) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0019] Alternatively, or in addition to, in a further embodiment and in accordance with any of the above, (i) the method comprises administering a multispecific antibody (or antigen binding fragment thereof); and (ii) the multispecific antibody (or antigen binding fragment thereof) comprises: (A) an anti-CD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest. In some further embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-Attorney Docket: 53080.4002 / WOP, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD 103. In still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF- , (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD103. In yet still some further embodiments, (i) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and / or (ii) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0020] In a further embodiment and in accordance with any of the aspects and / or embodiments described herein comprising the use of a B cell depleting antibody (or antigen binding fragment thereof) comprising an anti-CD19 ABD, the anti-CD19 ABD specifically binds human CD 19 (i.e., the anti-CD19 ABD comprises an anti-human CD19 ABD). In some further embodiments, the anti-human CD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD19 ABD is in a Fab format. In some other further embodiments, the anti-human CD 19 ABD is in a scFv format. In some other further embodiments, the anti-human CD19 ABD is in a VHH format. In some other furtherAttorney Docket: 53080.4002 / WOembodiments wherein a B cell depleting antibody comprises two or more ABDs that specifically bind human CD 19, individual instances of the two or more ABDs may be in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format. Depending on the valence for human CD 19, a B cell depleting antibody can utilize the same format or distinct formats (or a combination where a first subset of the ABDs are present in a first format and one or more other subsets of the ABDs are present in one or more other formats for instances where valence for human CD 19 is > 3).

[0021] In a further embodiment and in accordance with the above, the anti-human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In some other further embodiments, the anti-human CD 19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), or (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In still some other further embodiments, (i) the anti -human CD19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair); (ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iv) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. Alternatively, or in addition to, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl -3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), andAttorney Docket: 53080.4002 / WO94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0022] In a further embodiment and in accordance with any of the aspects and / or embodiments described herein comprising the use of a B cell depleting antibody (or antigen binding fragment thereof) comprising an anti-CD20 ABD, the anti-CD20 ABD specifically binds human CD20 (i.e., the anti-CD20 ABD comprises an anti-human CD20 ABD). In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD20 ABD is in a Fab format. In some other further embodiments, the anti-human CD20 ABD is in a scFv format. In some other further embodiments, the anti-human CD20 ABD is in a VHH format. In some other further embodiments wherein a B cell depleting antibody comprises two or more ABDs that specifically bind human CD20, individual instances of the two or more ABDs may be in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format. Depending on the valence for human CD20, a B cell depleting antibody can utilize the same format or distinct formats (or a combination where a first subset of the ABDs are present in a first format and one or more other subsets of the ABDs are present in one or more other formats for instances where valence for human CD20 is > 3).

[0023] In a further embodiment and in accordance with the above, the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, or (E) SEQ ID NOs: 249 and 253, respectively. In some other further embodiments, the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ IDAttorney Docket: 53080.4002 / WONOs: 242-244 (vhCDRl -3) and SEQ ID NOs: 246-248 (vlCDRl-3), or (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In still some other further embodiments, (i) the anti -human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair); (ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iv) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. Alternatively, or in addition to, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0024] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains. In some further embodiments, the one or more Fc domains comprise one or more variant Fc domains. In still some further embodiments, the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity. Conversely, in some other further embodiments, the one or more Fc domains comprises one or more amino acid substitutions that ablate FcyR binding activity. With respect to the embodiments wherein the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity, in yet still some further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity comprises one or more amino acid substitution mutations selected from aAttorney Docket: 53080.4002 / WOgroup including: 236A, S239D, S239E, I332E, I332D, S239D / T332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243A, 243L, 264A, 264V, and 299T. In yet some even further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity are S239D / I332E. Conversely, with respect to the embodiments wherein the one or more variant Fc domains comprise one or more amino acid substitutions that ablate FcyR binding activity, in yet still some further embodiments, the one or more amino acid substitutions that ablate FcyR binding activity are selected from a group including: (i) P329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv) L234F / L235E / P331S (LFLEPS), and (v) L234F / L235E / P329G (LFLEPG).

[0025] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that enhance FcRn activity and / or serum half-life. In some further embodiments, the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life comprises one or more amino acid substitution mutations selected from a group including: (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), and (iii) M428L / N434S (LS).

[0026] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that ablate a Protein A binding site of at least one of the one or more Fc domains. In some further embodiments, the one or more amino acid substitutions that ablate a Protein A binding site comprise H435R / Y436F (RF).

[0027] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that promote heterodimerization of a first Fc domain with a second Fc domain.

[0028] In a further embodiment and in accordance with any of the above, the B cell depleting antibody is a GEM-DIMER-formatted antibody. In some further embodiments, the GEM-DIMER-formatted antibody comprises: (i) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81; (ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36; (iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125; and (iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116 (i.e., the GEM-DIMER-formatted antibody comprises protein ID [21-98], as shown in Fig. 21 and Fig. 29). In some other further embodiments, the GEM-DIMER-formatted antibody comprises anyAttorney Docket: 53080.4002 / WOone of protein IDs [21 -01 ]-[21 -130], as shown in Fig. 21.

[0029] In a further embodiment and in accordance with any of the above, the subject is a human subject.

[0030] In another aspect, the present disclosure provides a method for treating an autoimmune disease characterized by B cell pathogenesis in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein: (a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD) selected from a group including: (i) an anti-CD19 ABD, and (ii) an anti-CD20 ABD; (b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; and (c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject, thereby treating the autoimmune disease characterized by B cell pathogenesis in the subject.

[0031] In a further embodiment and in accordance with the above, the autoimmune disease characterized by B cell pathogenesis is selected from a group including: (i) acquired hemophilia, (ii) alopecia areata, (iii) amyloidosis, (iv) anti-NMDA receptor encephalitis, (v) antiphospholipid syndrome, (vi) autoimmune Addison’s disease, (vii) autoimmune angioedema, (viii) autoimmune autonomic ganglionopathy, (ix) autoimmune encephalitis, (x) autoimmune gastritis, (xi) autoimmune hemolytic anemia, (xii) autoimmune hepatitis, (xiii) autoimmune hyperlipidemia, (xiv) autoimmune hypophysitis, (xv) autoimmune inner ear disease, (xvi) autoimmune Interstitial Lung Disease, (xvii) autoimmune lymphoproliferative syndrome, (xviii) autoimmune myelofibrosis, (xix) autoimmune myocarditis, (xx) autoimmune oophoritis, (xxi) autoimmune pancreatitis, (xxii) autoimmune polyglandular syndromes, (xxiii) autoimmune progesterone dermatitis, (xxiv) autoimmune retinopathy, (xxv) Balo disease, (xxvi) bullous pemphigoid, (xxvii) Castleman disease, (xxviii) celiac disease, (xxix) chronic autoimmune urticaria, (xxx) chronic inflammatory demyelinating polyneuropathy, (xxxi) Churg-Strauss syndrome, (xxxii) Cogan’s syndrome, (xxxiii) cold agglutinin disease, (xxxiv) CREST syndrome, (xxxv) Cronkhite-Canada syndrome, (xxxvi) cryptogenic organizing pneumonia, (xxxvii) dermatitisAttorney Docket: 53080.4002 / WOherpetiformis, (xxxviii) dermatomyositis, (xxxix) discoid lupus, (xl) Dressier’s syndrome, (xli) eczema, (xlii) essential mixed cryoglobulinemia, (xliii) Evans syndrome, (xliv) giant cell arteritis, (xlv) glomerulonephritis, (xlvi) Goodpasture’s syndrome, (xlvii) granulomatosis with polyangiitis, (xlviii) Graves’ disease, (xlix) Guillain-Barre syndrome, (1) Hashimoto’s thyroiditis, (li) Henoch-Schdnlein purpura, (lii) Hurst’s disease, (liii) IgA nephropathy, (liv) IgG4-related sclerosing disease, (Iv) immune thrombocytopenia, (Ivi) immune-mediated necrotizing myopathy, (Ivii) inclusion body myositis, (Iviii) juvenile idiopathic arthritis, (lix) Kawasaki disease, (lx) Lambert-Eaton myasthenic syndrome, (Ixi) leukocytoclastic vasculitis, (Ixii) lichen planus, (Ixiii) lichen sclerosus, (Ixiv) linear IgA disease, (Ixv) lupus nephritis, (Ixvi) Meniere’s disease, (Ixvii) microscopic polyangiitis, (Ixviii) mixed connective tissue disease, (Ixix) mucous membrane pemphigoid, (Ixx) multiple sclerosis, (Ixxi) myasthenia gravis, (Ixxii) neuromyelitis optica, (Ixxiii) optic neuritis, (Ixxiv) palindromic rheumatism, (Ixxv) paraneoplastic cerebellar degeneration, (Ixxvi) paraneoplastic pemphigus, (Ixxvii) pemphigoid gestationis, (Ixxviii) pemphigus foliaceus, (Ixxix) pemphigus vulgaris, (Ixxx) pernicious anemia, (Ixxxi) Pityriasis lichenoides et varioliformis acuta, (Ixxxii) POEMS syndrome, (Ixxxiii) polyarteritis nodosa, (Ixxxiv) polymyositis, (Ixxxv) primary biliary cholangitis, (Ixxxvi) primary sclerosing cholangitis, (Ixxxvii) pure red cell aplasia, (Ixxxviii) relapsing polychondritis, (Ixxxix) rheumatoid arthritis, (xc) scleritis, (xci) scleroderma, (xcii) Sjogren’s syndrome, and (xciii) systemic lupus erythematosus. In some further embodiments, the autoimmune disease characterized by B cell pathogenesis is systemic lupus erythematosus (SLE).

[0032] In a further embodiment and in accordance with the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered for 4 or fewer consecutive days.

[0033] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

[0034] In a further embodiment, and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours. In some further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 7 days. In some other further embodiments, the B cell depleting antibody (orAttorney Docket: 53080.4002 / WOantigen binding fragment thereof) has a serum half-life that is less than about 2-3 days. In still some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 24 hours.

[0035] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0036] In a further embodiment and in accordance with any of the above, the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

[0037] In a further embodiment and in accordance with any of the above, a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, characterized by an increased ratio of circulating CD27’ B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration. In some further embodiments, the B cell niche comprises B cells resident to the circulatory system. In still some further embodiments, depletion of the circulating B cells occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

[0038] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration. In some further embodiments, the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof. In still some further embodiments, (i) at least one of the one or more B cell compartments comprises one or more lymph nodes; and (ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof. In aAttorney Docket: 53080.4002 / WOseparate further embodiment, (i) at least one of the one or more B cell compartments comprises the spleen; and (ii) the tissue-resident B cells comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises bone marrow; and (ii) the tissueresident B cells comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises mucosa-associated lymphoid tissue (MALT); and (ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the thymus; and (ii) the tissue-resident B cells comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the skin; and (ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the liver; and (ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

[0039] In a further embodiment and in accordance with the above, at least one of the one or more B cell compartments exhibits remodeling of a B cell niche, characterized by an increased ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells as compared to a baseline ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells. In some further embodiments, the remodeling of the B cell niche occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

[0040] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route. In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered as a bolus injection, as an IV infusion, or as a continuous infusion.

[0041] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs thatAttorney Docket: 53080.4002 / WOspecifically bind one or more target antigens of interest. In some further embodiments, individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof. In still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-0, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD103. In yet still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-0, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD 138, (xxviii) human lL-4Ra, (xxix) human IL-13, (xxx) human LL-13Ral, (xxxi) human lL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD 103.

[0042] In a further embodiment and in accordance with any of the above, (i) the at least one antigen binding domain (ABD) is an anti-CD19 ABD; and (ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement. In some further embodiments, the antiCD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD19 ABD is in a Fab format. In some other further embodiments, the anti-CD19 ABD is in a scFv format. In still some other further embodiments, the anti-CD19 ABD is in a VHH format.Attorney Docket: 53080.4002 / WO

[0043] Alternatively, or in addition to, in a further embodiment and in accordance with any of the above, (i) the at least one antigen binding domain (ABD) is an anti-CD20 ABD; and (ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement. In some further embodiments, the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD20 ABD is in a Fab format. In some other further embodiments, the anti-CD20 ABD is in a scFv format. In still some other further embodiments, the anti-CD20 ABD is in a VHH format.

[0044] In a further embodiment and in accordance with any of the above, the method comprises administering an anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof). In some further embodiments, (i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and / or (ii) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0045] Alternatively, or in addition to, in a further embodiment and in accordance with any of the above, (i) the method comprises administering a multispecific antibody (or antigen binding fragment thereof); and (ii) the multispecific antibody (or antigen binding fragment thereof) comprises: (A) an anti-CD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest. In some furtherAttorney Docket: 53080.4002 / WOembodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD 103. In still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-p, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD103. In yet still some further embodiments, (i) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and / or (ii) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0046] In a further embodiment and in accordance with any of the aspects and / or embodiments described herein comprising the use of a B cell depleting antibody (or antigen binding fragment thereof) comprising an anti-CD19 ABD, the anti-CD19 ABD specifically binds human CD19 (i.e., the anti-CD19 ABD comprises an anti-human CD19 ABD). In some further embodiments, the anti-human CD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. InAttorney Docket: 53080.4002 / WOstill some further embodiments, the anti-human CD19 ABD is in a Fab format. Tn some other further embodiments, the anti-human CD19 ABD is in a scFv format. In some other further embodiments, the anti-human CD 19 ABD is in a VHH format. In some other further embodiments wherein a B cell depleting antibody comprises two or more ABDs that specifically bind human CD 19, individual instances of the two or more ABDs may be in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format. Depending on the valence for human CD 19, a B cell depleting antibody can utilize the same format or distinct formats (or a combination where a first subset of the ABDs are present in a first format and one or more other subsets of the ABDs are present in one or more other formats for instances where valence for human CD 19 is > 3).

[0047] In a further embodiment and in accordance with the above, the anti -human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In some other further embodiments, the anti-human CD 19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), or (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In still some other further embodiments, (i) the anti -human CD19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair); (ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iv) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. Alternatively, or in addition to, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl -3) are selected from a group including: (i) amino acid residues 110 (vhCDR3) of SEQ ID NO: 257 andAttorney Docket: 53080.4002 / WOamino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0048] In a further embodiment and in accordance with any of the aspects and / or embodiments described herein comprising the use of a B cell depleting antibody (or antigen binding fragment thereof) comprising an anti-CD20 ABD, the anti-CD20 ABD specifically binds human CD20 (i.e., the anti-CD20 ABD comprises an anti-human CD20 ABD). In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD20 ABD is in a Fab format. In some other further embodiments, the anti-human CD20 ABD is in a scFv format. In some other further embodiments, the anti-human CD20 ABD is in a VHH format. In some other further embodiments wherein a B cell depleting antibody comprises two or more ABDs that specifically bind human CD20, individual instances of the two or more ABDs may be in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format. Depending on the valence for human CD20, a B cell depleting antibody can utilize the same format or distinct formats (or a combination where a first subset of the ABDs are present in a first format and one or more other subsets of the ABDs are present in one or more other formats for instances where valence for human CD20 is > 3).

[0049] In a further embodiment and in accordance with the above, the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, or (E) SEQ ID NOs: 249 and 253, respectively. In some other further embodiments, the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprisingAttorney Docket: 53080.4002 / WOthe amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), or (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In still some other further embodiments, (i) the anti -human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair); (ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iv) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. Alternatively, or in addition to, the set of variable heavy chain complementarity determining regions (vhCDRl-3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0050] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains. In some further embodiments, the one or more Fc domains comprise one or more variant Fc domains. In still some further embodiments, the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity. Conversely, in some other further embodiments, the one or more Fc domains comprises one or more amino acid substitutions that ablate FcyR binding activity. With respect to the embodiments wherein the one or more variantAttorney Docket: 53080.4002 / WOFc domains comprise one or more amino acid substitutions that enhance FcyR binding activity, in yet still some further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity comprises one or more amino acid substitution mutations selected from a group including: 236A, S239D, S239E, I332E, I332D, S239D / I332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243A, 243L, 264A, 264V, and 299T. In yet some even further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity are S239D / I332E. Conversely, with respect to the embodiments wherein the one or more variant Fc domains comprise one or more amino acid substitutions that ablate FcyR binding activity, in yet still some further embodiments, the one or more amino acid substitutions that ablate FcyR binding activity are selected from a group including: (i) P329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv) L234F / L235E / P331S (LFLEPS), and (v) L234F / L235E / P329G (LFLEPG).

[0051] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that enhance FcRn activity and / or serum half-life. In some further embodiments, the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life comprises one or more amino acid substitution mutations selected from a group including: (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), and (iii) M428L / N434S (LS).

[0052] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that ablate a Protein A binding site of at least one of the one or more Fc domains. In some further embodiments, the one or more amino acid substitutions that ablate a Protein A binding site comprise H435R / Y436F (RF).

[0053] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that promote heterodimerization of a first Fc domain with a second Fc domain.

[0054] In a further embodiment and in accordance with any of the above, the B cell depleting antibody is a GEM-DIMER-formatted antibody. In some further embodiments, the GEM-DIMER-formatted antibody comprises: (i) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81; (ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36; (iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125;Attorney Docket: 53080.4002 / WOand (iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116 (i.e., the GEM-DIMER-formatted antibody comprises protein ID [21-98], as shown in Fig. 21 and Fig.29). In some other further embodiments, the GEM-DIMER-formatted antibody comprises any one of protein IDs [21 -01 ]-[21 -130], as shown in Fig. 21.

[0055] In a further embodiment and in accordance with any of the above, the subject is a human subject.

[0056] In another aspect, the present disclosure provides a method for treating a B cell malignancy in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein: (a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD) selected from a group including: (i) an anti-CD19 ABD, and (ii) an anti-CD20 ABD; (b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; and (c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject, thereby treating the B cell malignancy in the subject.

[0057] In a further embodiment and in accordance with the above, the B cell malignancy is selected from a group including: (i) diffuse large B-cell lymphoma (DLBCL), (ii) chronic lymphocytic leukemia (CLL), (iii) follicular lymphoma, (iv) mantle cell lymphoma, (v) marginal zone lymphoma, (vi) Burkitt lymphoma, (vii) Hodgkin lymphoma, (viii) Waldenstrom macroglobulinemia, (ix) multiple myeloma, (x) hairy cell leukemia, (xi) acute lymphoblastic leukemia (B-ALL), (xii) primary central nervous system lymphoma (PCNSL), (xiii) small lymphocytic lymphoma (SLL), (xiv) lymphoplasmacytic lymphoma, and (xv) primary mediastinal B-cell lymphoma. In one further embodiment, the B cell malignancy comprises diffuse large B-cell lymphoma (DLBCL). In another further embodiment, the B cell malignancy comprises chronic lymphocytic leukemia (CLL). In another further embodiment, the B cell malignancy comprises follicular lymphoma. In another further embodiment, the B cell malignancy comprises mantle cell lymphoma. In another further embodiment, the B cell malignancy comprises marginal zone lymphoma. In another further embodiment, the B cellAttorney Docket: 53080.4002 / WOmalignancy comprises Burkitt lymphoma. Tn another further embodiment, the B cell malignancy comprises Hodgkin lymphoma. In another further embodiment, the B cell malignancy comprises Waldenstrom macroglobulinemia. In another further embodiment, the B cell malignancy comprises multiple myeloma. In another further embodiment, the B cell malignancy comprises hairy cell leukemia. In another further embodiment, the B cell malignancy comprises acute lymphoblastic leukemia (B-ALL). In another further embodiment, the B cell malignancy comprises primary central nervous system lymphoma (PCNSL). In another further embodiment, the B cell malignancy comprises small lymphocytic lymphoma (SLL). In another further embodiment, the B cell malignancy comprises lymphoplasmacytic lymphoma. In another further embodiment, the B cell malignancy comprises primary mediastinal B-cell lymphoma.

[0058] In a further embodiment and in accordance with the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered for 4 or fewer consecutive days.

[0059] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

[0060] In a further embodiment, and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours. In some further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 7 days. In some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 2-3 days. In still some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 24 hours.

[0061] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0062] In a further embodiment and in accordance with any of the above, the circulating B cellsAttorney Docket: 53080.4002 / WOcomprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

[0063] In a further embodiment and in accordance with any of the above, a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, characterized by an increased ratio of circulating CD27' B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration. In some further embodiments, the B cell niche comprises B cells resident to the circulatory system. In still some further embodiments, depletion of the circulating B cells occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

[0064] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration. In some further embodiments, the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof. In still some further embodiments, (i) at least one of the one or more B cell compartments comprises one or more lymph nodes; and (ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the spleen; and (ii) the tissue-resident B cells comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises bone marrow; and (ii) the tissueresident B cells comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises mucosa-associated lymphoid tissue (MALT); and (ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof. In a separate further embodiment, (i) at least oneAttorney Docket: 53080.4002 / WOof the one or more B cell compartments comprises the thymus; and (ii) the tissue-resident B cells comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the skin; and (ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof. In a separate further embodiment, (i) at least one of the one or more B cell compartments comprises the liver; and (ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

[0065] In a further embodiment and in accordance with the above, at least one of the one or more B cell compartments exhibits remodeling of a B cell niche, characterized by an increased ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells as compared to a baseline ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells. In some further embodiments, the remodeling of the B cell niche occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

[0066] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route. In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered as a bolus injection, as an IV infusion, or as a continuous infusion.

[0067] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest. In some further embodiments, individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof. In still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD103.Attorney Docket: 53080.4002 / WOIn yet still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-0, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD 138, (xxviii) human IL-4Ru, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD 103.

[0068] In a further embodiment and in accordance with any of the above, (i) the at least one antigen binding domain (ABD) is an anti-CD19 ABD; and (ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement. In some further embodiments, the anti-CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD19 ABD is in a Fab format. In some other further embodiments, the anti-CD19 ABD is in a scFv format. In still some other further embodiments, the anti-CD19 ABD is in a VHH format.

[0069] Alternatively, or in addition to, in a further embodiment and in accordance with any of the above, (i) the at least one antigen binding domain (ABD) is an anti-CD20 ABD; and (ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement. In some further embodiments, the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD20 ABD is inAttorney Docket: 53080.4002 / WOa Fab format. In some other further embodiments, the anti-CD20 ABD is in a scFv format. In still some other further embodiments, the anti-CD20 ABD is in a VHH format.

[0070] In a further embodiment and in accordance with any of the above, the method comprises administering an anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof). In some further embodiments, (i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD19 in the presence of complement; and / or (ii) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0071] Alternatively, or in addition to, in a further embodiment and in accordance with any of the above, (i) the method comprises administering a multispecific antibody (or antigen binding fragment thereof); and (ii) the multispecific antibody (or antigen binding fragment thereof) comprises: (A) an anti-CD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest. In some further embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD 103. In still some further embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) humanAttorney Docket: 53080.4002 / WOTSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD103. In yet still some further embodiments, (i) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and / or (ii) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0072] In a further embodiment and in accordance with any of the aspects and / or embodiments described herein comprising the use of a B cell depleting antibody (or antigen binding fragment thereof) comprising an anti-CD19 ABD, the anti-CD19 ABD specifically binds human CD 19 (i.e., the anti-CD19 ABD comprises an anti-human CD19 ABD). In some further embodiments, the anti-human CD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD19 ABD is in a Fab format. In some other further embodiments, the anti-human CD 19 ABD is in a scFv format. In some other further embodiments, the anti-human CD19 ABD is in a VHH format. In some other further embodiments wherein a B cell depleting antibody comprises two or more ABDs that specifically bind human CD 19, individual instances of the two or more ABDs may be in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format. Depending on the valence for human CD 19, a B cell depleting antibody can utilize the same format or distinct formats (or a combination where a first subset of the ABDs are present in a first format and one or more other subsets of the ABDs are present in one or more other formats for instances where valence for human CD 19 is > 3).Attorney Docket: 53080.4002 / WO

[0073] In a further embodiment and in accordance with the above, the anti -human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In some other further embodiments, the anti-human CD 19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), or (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In still some other further embodiments, (i) the anti -human CD19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair); (ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iv) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. Alternatively, or in addition to, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl -3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.Attorney Docket: 53080.4002 / WO

[0074] In a further embodiment and in accordance with any of the aspects and / or embodiments described herein comprising the use of a B cell depleting antibody (or antigen binding fragment thereof) comprising an anti-CD20 ABD, the anti-CD20 ABD specifically binds human CD20 (i.e., the anti-CD20 ABD comprises an anti-human CD20 ABD). In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD20 ABD is in a Fab format. In some other further embodiments, the anti-human CD20 ABD is in a scFv format. In some other further embodiments, the anti-human CD20 ABD is in a VHH format. In some other further embodiments wherein a B cell depleting antibody comprises two or more ABDs that specifically bind human CD20, individual instances of the two or more ABDs may be in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format. Depending on the valence for human CD20, a B cell depleting antibody can utilize the same format or distinct formats (or a combination where a first subset of the ABDs are present in a first format and one or more other subsets of the ABDs are present in one or more other formats for instances where valence for human CD20 is > 3).

[0075] In a further embodiment and in accordance with the above, the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, or (E) SEQ ID NOs: 249 and 253, respectively. In some other further embodiments, the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), or (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In still some other further embodiments, (i) the anti -human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair); (ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (iii) vhCDRl-3 consist of amino acid residues -110 (vhCDR3) of SEQ ID NO: 186; andAttorney Docket: 53080.4002 / WO(iv) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. Alternatively, or in addition to, the set of variable heavy chain complementarity determining regions (vhCDRl-3) and the set of variable light chain complementarity determining regions (vlCDRl -3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0076] In a further embodiment and in accordance with any of the above, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains. In some further embodiments, the one or more Fc domains comprise one or more variant Fc domains. In still some further embodiments, the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity. Conversely, in some other further embodiments, the one or more Fc domains comprises one or more amino acid substitutions that ablate FcyR binding activity. With respect to the embodiments wherein the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity, in yet still some further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity comprises one or more amino acid substitution mutations selected from a group including: 236A, S239D, S239E, I332E, I332D, S239D / I332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243A, 243L, 264A, 264V, and 299T. In yet some even further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity are S239D / I332E. Conversely, with respect to the embodiments wherein the one or more variant Fc domains comprise one or more amino acid substitutions that ablate FcyR binding activity, in yet still some further embodiments, the one or more amino acid substitutions that ablate FcyR binding activity are selected from a group including: (i)Attorney Docket: 53080.4002 / WOP329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv) L234F / L235E / P331S (LFLEPS), and (v) L234F / L235E / P329G (LFLEPG).

[0077] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that enhance FcRn activity and / or serum half-life. In some further embodiments, the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life comprises one or more amino acid substitution mutations selected from a group including: (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), and (iii) M428L / N434S (LS).

[0078] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that ablate a Protein A binding site of at least one of the one or more Fc domains. In some further embodiments, the one or more amino acid substitutions that ablate a Protein A binding site comprise H435R / Y436F (RF).

[0079] In a further embodiment and in accordance with any of the above, the one or more Fc domains comprises one or more amino acid substitutions that promote heterodimerization of a first Fc domain with a second Fc domain.

[0080] In a further embodiment and in accordance with any of the above, the B cell depleting antibody is a GEM-DIMER-formatted antibody. In some further embodiments, the GEM-DIMER-formatted antibody comprises: (i) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81; (ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36; (iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125; and (iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116 (i.e., the GEM-DIMER-formatted antibody comprises protein ID [21-98], as shown in Fig. 21 and Fig. 29). In some other further embodiments, the GEM-DIMER-formatted antibody comprises any one of protein IDs [21-01]-[21-130], as shown in Fig. 21.

[0081] In a further embodiment and in accordance with any of the above, the subject is a human subject.

[0082] In another aspect, the present disclosure provides a method for rapidly depleting circulating B cells in a human subject in need thereof, wherein the method comprises intravenously or subcutaneously administering a bispecific anti-human CD 19 x anti-humanAttorney Docket: 53080.4002 / WOCD20 GEM-DIMER-formatted antibody in an amount sufficient to deplete circulating B cells in the human subject, wherein: (i) the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody comprises: (A) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81, (B) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36, (C) a first light chain comprising the amino acid sequence of SEQ ID NO: 125, and (D) a second light chain comprising the amino acid sequence of SEQ ID NO: 116; (ii) the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; (iii) depletion of the circulating B cells occurs for a period of at least 5 or more days; and (iv) the bispecific anti -human CD 19 x anti -human CD20 GEM-DIMER-formatted antibody is administered for 4 or fewer consecutive days to the human subject.

[0083] In a further embodiment and in accordance with the above, the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0084] In a further embodiment and in accordance with any of the above, depletion of the circulating B cells occurs for a period of: (i) at least 5 or more weeks, or (ii) at least 5 or more months.

[0085] In a further embodiment and in accordance with any of the above, the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

[0086] In a further embodiment and in accordance with any of the above, (i) a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells; (ii) the B cell niche comprises B cells resident to the circulatory system; and (iii) the remodeling is characterized by an increased ratio of circulating CD27’ B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration.Attorney Docket: 53080.4002 / WO

[0087] In a further embodiment and in accordance with any of the above, (i) the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to a baseline level of tissue-resident B cells located in the one or more B cell compartments determined prior to the first administration; (ii) the one or more B cell compartments comprise: (A) one or more lymph nodes, (B) the spleen, (C) bone marrow, (D) mucosa-associated lymphoid tissue (MALT), (E) the thymus, (F) the skin, (G) the liver, or any combination thereof; and (iii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, (G) follicular B cells, (H) marginal zone B cells, (I) memory B cells, (J) pro-B cells, (K) immature B cells, or any combination thereof.

[0088] In a further embodiment and in accordance with any of the above, (i) the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and (ii) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antib ody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0089] In a further embodiment and in accordance with any of the above, the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours. In some further embodiments, serum half-life is less than about 7 days. In some other further embodiments, serum half-life is less than about 2-3 days. In yet some other further embodiments, serum half-life is less than about 24 hours.Attorney Docket: 53080.4002 / WO

[0090] In another aspect, the present disclosure provides a method for treating an autoimmune disease characterized by B cell pathogenesis in a human subject in need thereof, wherein the method comprises administering a bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody in an amount sufficient to deplete circulating B cells in the human subject, wherein: (i) the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody comprises: (A) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81, (B) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36, (C) a first light chain comprising the amino acid sequence of SEQ ID NO: 125, and (D) a second light chain comprising the amino acid sequence of SEQ ID NO: 116; (ii) the bispecific anti -human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; (iii) depletion of the circulating B cells occurs for a period of at least 5 or more days; and (iv) the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody is administered for 4 or fewer consecutive days to the human subject, thereby treating the autoimmune disease characterized by B cell pathogenesis in the human subject.

[0091] In a further embodiment and in accordance with the above, the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0092] In a further embodiment and in accordance with any of the above, depletion of the circulating B cells occurs for a period of: (i) at least 5 or more weeks, or (ii) at least 5 or more months.

[0093] In a further embodiment and in accordance with any of the above, the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

[0094] In a further embodiment and in accordance with any of the above, (i) a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells; (ii) the B cell niche comprises B cells resident to the circulatory system; and (iii) the remodeling is characterized byAttorney Docket: 53080.4002 / WOan increased ratio of circulating CD27’ B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration.

[0095] In a further embodiment and in accordance with any of the above, (i) the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to a baseline level of tissue-resident B cells located in the one or more B cell compartments determined prior to the first administration; (ii) the one or more B cell compartments comprise: (A) one or more lymph nodes, (B) the spleen, (C) bone marrow, (D) mucosa-associated lymphoid tissue (MALT), (E) the thymus, (F) the skin, (G) the liver, or any combination thereof; and (iii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, (G) follicular B cells, (H) marginal zone B cells, (I) memory B cells, (J) pro-B cells, (K) immature B cells, or any combination thereof.

[0096] In a further embodiment and in accordance with any of the above, (i) the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and (ii) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0097] In a further embodiment and in accordance with any of the above, the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours. InAttorney Docket: 53080.4002 / WOsome further embodiments, serum half-life is less than about 7 days. In some other further embodiments, serum half-life is less than about 2-3 days. In yet some other further embodiments, serum half-life is less than about 24 hours.

[0098] In a further embodiment and in accordance with any of the above, the autoimmune disease characterized by B cell pathogenesis comprises systemic lupus erythematosus (SLE).

[0099] In another aspect, the present disclosure provides a method for treating a B cell malignancy in a human subject in need thereof, wherein the method comprises administering a B cell depleting antibody (antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the human subject, wherein: (i) the bispecific anti-human CD 19 x antihuman CD20 GEM-DIMER-formatted antibody comprises: (A) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81, (B) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36, (C) a first light chain comprising the amino acid sequence of SEQ ID NO: 125, and (D) a second light chain comprising the amino acid sequence of SEQ ID NO: 116; (ii) the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; (iii) depletion of the circulating B cells occurs for a period of at least 5 or more days; and (iv) the bispecific anti -human CD 19 x anti -human CD20 GEM-DIMER-formatted antibody is administered for 4 or fewer consecutive days to the human subject, thereby treating the B cell malignancy in the human subject.

[0100] In a further embodiment and in accordance with the above, the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0101] In a further embodiment and in accordance with any of the above, depletion of the circulating B cells occurs for a period of: (i) at least 5 or more weeks, or (ii) at least 5 or more months.

[0102] In a further embodiment and in accordance with any of the above, the circulating B cellsAttorney Docket: 53080.4002 / WOcomprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

[0103] In a further embodiment and in accordance with any of the above, (i) a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells; (ii) the B cell niche comprises B cells resident to the circulatory system; and (iii) the remodeling is characterized by an increased ratio of circulating CD27’ B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration.

[0104] In a further embodiment and in accordance with any of the above, (i) the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to a baseline level of tissue-resident B cells located in the one or more B cell compartments determined prior to the first administration; (ii) the one or more B cell compartments comprise: (A) one or more lymph nodes, (B) the spleen, (C) bone marrow, (D) mucosa-associated lymphoid tissue (MALT), (E) the thymus, (F) the skin, (G) the liver, or any combination thereof; and (iii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, (G) follicular B cells, (H) marginal zone B cells, (I) memory B cells, (J) pro-B cells, (K) immature B cells, or any combination thereof.

[0105] In a further embodiment and in accordance with any of the above, (i) the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement; and (ii) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressingAttorney Docket: 53080.4002 / WOCD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0106] In a further embodiment and in accordance with any of the above, the bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours. In some further embodiments, serum half-life is less than about 7 days. In some other further embodiments, serum half-life is less than about 2-3 days. In yet some other further embodiments, serum half-life is less than about 24 hours.

[0107] In a further embodiment and in accordance with any of the above, the B cell malignancy is selected from a group including: (i) diffuse large B-cell lymphoma (DLBCL), (ii) chronic lymphocytic leukemia (CLL), (iii) follicular lymphoma, (iv) mantle cell lymphoma, (v) marginal zone lymphoma, (vi) Burkitt lymphoma, (vii) Hodgkin lymphoma, (viii) Waldenstrom macroglobulinemia, (ix) multiple myeloma, (x) hairy cell leukemia, (xi) acute lymphoblastic leukemia (B-ALL), (xii) primary central nervous system lymphoma (PCNSL), (xiii) small lymphocytic lymphoma (SLL), (xiv) lymphoplasmacytic lymphoma, and (xv) primary mediastinal B-cell lymphoma. In one further embodiment, the B cell malignancy comprises diffuse large B-cell lymphoma (DLBCL). In another further embodiment, the B cell malignancy comprises chronic lymphocytic leukemia (CLL). In another further embodiment, the B cell malignancy comprises follicular lymphoma. In another further embodiment, the B cell malignancy comprises mantle cell lymphoma. In another further embodiment, the B cell malignancy comprises marginal zone lymphoma. In another further embodiment, the B cell malignancy comprises Burkitt lymphoma. In another further embodiment, the B cell malignancy comprises Hodgkin lymphoma. In another further embodiment, the B cell malignancy comprises Waldenstrom macroglobulinemia. In another further embodiment, the B cell malignancy comprises multiple myeloma. In another further embodiment, the B cell malignancy comprises hairy cell leukemia. In another further embodiment, the B cell malignancy comprises acute lymphoblastic leukemia (B-ALL). In another further embodiment, the B cell malignancy comprises primary central nervous system lymphoma (PCNSL). In another further embodiment, the B cell malignancy comprises small lymphocytic lymphoma (SLL). In another further embodiment, the B cell malignancy comprises lymphoplasmacytic lymphoma. In another furtherAttorney Docket: 53080.4002 / WOembodiment, the B cell malignancy comprises primary mediastinal B-cell lymphoma.BRIEF DESCRIPTION OF THE DRAWINGS

[0108] A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings (also “Fig.”, “FIG”, “Figure”, “Figures”, “Figs.”, and “FIGs.” herein) of which:

[0109] Fig, 1: Structure and target binding of HB2198 in primary cells and CD19+ or CD20+ cell lines. Fig. 1A shows a schematic representation of HB2198 structure. Anti-CD19 and anti-CD20 Fab domains are shown in maroon and blue, respectively. FcyR binding enhancing mutation (SD / IE) are illustrated with green stars. White circles represent ACE2 domains mediating dimerization. Fig. IB shows binding to human B cells evaluated in PBMCs by incubating the cells in the presence of HB2198 or comparator antibodies as indicated for 30 minutes on ice. The cells were then stained with secondary anti-human Fcy-PE and B cell staining cocktail. B cells were identified as viable, CD3-, CD40+, CD21+ by flow cytometry. Triplicate mean ± SD of geometric mean fluorescence intensity (gMFl) of anti-human IgG, Fcy-specific-PE secondary antibody is shown with 4-parameter non-linear regression curve. Figs. 1C-1E show HB2198 and comparator antibody binding to Raji WT (Fig. 1C), Raji CD19KO (Fig. ID), and Raji CD20KO cells (Fig. IE) evaluated by flow cytometry. Figs. 1F-1H show HB2198 and comparator antibody binding to HEK293 (Fig. IF) and HEK293 transfected with human CD20 (Fig. 1G) or human CD19 cDNA (Fig. 1H). Geometric mean fluorescence intensity (MFI) of staining and 4 parameter logistic regression curve is shown. Representative plots are cumulative of 2-3 independent experiments.

[0110] Fig.2: HB2198 efficiently depletes B cells from human whole blood and PBMC from healthy and SLE patient donors. Figs. 2A-2F show the results from experiments where human fresh whole blood from 14 healthy donors (Figs. 2A-2C) or five SLE patients (Figs, 2D-2F) was incubated for 18-24 hours with HB2198 or comparator antibodies as indicated. Mean live CD3' CD21+CD40+B cells were measured by flow cytometry in duplicate or triplicate. As shown in Figs. 2A and 2D, composite dose-response curved from all experiments at 0.006 - 100 nM were graphed, with means from individual experiments plotted. Log EC50 values (see, e g., Fig. 2B and 2E) and maximal depletion values (see, e.g., Fig. 2C and 2F) for B cell depletion areAttorney Docket: 53080.4002 / WOillustrated for all concentration ranges used for healthy (see, e.g., Fig. 2B and 2C) and SLE patient cultures (see, e.g., Fig. 2D and 2E). Figs. 2G-2L show the results from experiments where donor peripheral blood mononuclear cells (PBMCs) from healthy humans (Figs. 2G-2I) or SLE patients (Figs. 2J-2L) were cultured in the presence of HB2198 or a comparator antibody. As shown in Figs. 2G and 2J, composite dose-response curves from all experiments at 0.00127 -100 nM were graphed, with means from individual experiments plotted. Log EC50 values (see, e.g., Fig. 2H and Fig. 2K) and maximal depletion values (see, e.g., Fig. 21 and Fig. 2L) for B cell depletion are illustrated for all concentration ranges used for healthy (see, e.g., Fig. 2H and Fig.21) and SLE patient cultures (see, e.g., Fig. 2K and Fig. 2L). Dashed lines connect data obtained within the same experiment with same donor cells. Human IgGl isotype was included as an assay control in Fig. 2D, Fig. 2G, and Fig. 2J. Donor matched values in the presence of HB2198 were compared to rituximab and tafasitamab by ANOVA using Holm-Sidak multiple comparison test (*#p < 0.05, **•##p < 0.01).

[0111] Fig. 3: HB2198 exhibits potent ADCC activity in vitro. Fig. 3 shows the results from an experiment where Raji cells (see, e.g., Fig. 3A, Fig. 3B, and Fig. 3C), Raji CD19 KO (-see, e.g., Fig. 3D, Fig. 3E, and Fig. 3F) and Raji CD20 KO cells (see, e.g., Fig. 3G, Fig. 3H, and Fig.31) were incubated with IL-2 -treated human PBMCs for 4 hours in 25: 1 ratio with HB2198 and comparator antibodies as indicated. Triplicate mean ± SD of percent dead (propidium iodide+) target cells by flow cytometry is graphed vs test article concentration (nM) for 3 independent PBMC donors, Donor 1 (see, e.g., Figs. 3A, 3D, and 3G), Donor 2 (see, e.g., Figs. 3B, 3E, and 3H) and Donor 3 (see, e.g., Figs. 3C, 3F, and 31) as indicated and 4-parameter non-linear regression curve is shown. In each of the three donors, four highest concentrations of HB2198 resulted in higher cytotoxicity than rituximab or tafasitamab in Raji WT and Raji CD19 KO cells (p <0.01). In Raji CD20KO cells, HB2198 resulted in higher cytotoxicity when compared rituximab (p <0.01) but not when compared to tafasitamab.

[0112] Fig. 4: HB2198 induces potent ADCP activity in vitro. Fig. 4 shows the results from an experiment where Raji WT cells (see, e.g., Fig. 4A and Fig. 4B), Raji CD19 KO cells (see, e.g., Fig. 4C and 4D), and Raji CD20 KO cells (see, e.g., Fig. 4E and Fig. 4F) were incubated with human M2 macrophages for 2 hours in 2: 1 ratio with HB2198 (blue circles), rituximab (orange squares), tafasitamab (purple triangles), isotype control hlgGl (black diamonds). In each graph, triplicate mean ± SD of percent of macrophages positive for target cells by flow cytometry isAttorney Docket: 53080.4002 / WOshown with full titration in a representative experiment combined with a summary of AUC values in 3 independent PBMC CD 14+ donors. Similar cultures were performed using the same PBMC donors in the absence (see, e.g., Figs. 4A, 4C, and 4E) and presence (see, e.g., Figs. 4B, 4D, and 4F) of 10 mg / mL human IgG. Values are compared by ANOVA using Dunnett’s multiple comparison test (*,# p < 0.05, **,## p < 0.01).

[0113] Fig. 5: HB2198 induces CDC and direct cytotoxicity in vitro. To evaluate CDC activity, SU-DHL-4 cells (see, e.g., Fig. 5A) or Raji WT cells (see, e.g., Fig. 5B) were incubated with 20% human serum as a source of complement and with HB2198 (blue circles), rituximab (orange squares), tafasitamab (purple triangles), isotype hlgGl (black diamonds). To evaluate effector cell-independent direct cytotoxic activity, SU-DHL-4 cells were cultured for 48-72 hours with test articles alone and cell number determined by ATP luminescence (see, e.g., Fig.5C) or stained for Annexin V and propidium iodide and analyzed by flow cytometry (see, e.g., Fig. 5D). Percentages of dead cells are shown across titration of antibody and 4-parameter nonlinear regression curve shown.

[0114] Fig. 6: HB2198 binds to cynomolgus monkey B cells and is highly active in depleting B cells in vivo. Fig. 6 shows HB2198 binding in cynomolgus monkey PBMCs (see, e.g., Fig. 6A) or HEK293 stably transfected with cynomolgus monkey CD 19 cDNA (see, e.g., Fig. 6B). As shown in Fig. 6C, HB2198 depletion of B cells (CD3-CD40+) in cynomolgus whole blood was assessed after overnight culture. Figs. 6D-6F show the pharmacodynamic effect of HB2198 on circulating B cells in cynomolgus monkeys in vivo. Cynomolgus monkeys were treated with a single HB2198 dose of 0.2, 1,5, 25 mg / kg or repeated dose of 25 mg / kg on Days 0 and 14. 100 pL fresh whole blood was collected for flow cytometry analysis pre and post infusion at indicated time points. B cells were defined as live, CD45+ lymphocytes that are CD3- CD14-CD56- CD 159a- CD40+. Average percent of baseline B cell number in cohorts of cynomolgus blood for single infusion (see, e.g., Fig. 6D and Fig. 6E) and repeated infusion, (25 mg / kg on Day 0 and Day 14) (see, e.g., Fig. 6F) is graphed over time. Figs. 6G-6I show the proportion of CD27-negative (naive) and CD27+ (Memory) expressing B cells before and after 3 months (Day 84) post infusion in individual animals following a single infusion (see, e.g., Fig. 6G) and repeated infusion (see, e.g., Fig. 6H). The percent reduction in B cells from baseline following single infusion or double infusion is graphed (see e.g., Fig 61). Time course of repeat doseAttorney Docket: 53080.4002 / WOanimals is shown in Fig. 6J. Values are compared by ANOVA using Dunnett’s multiple comparison test (* p < 0.05, ** p < 0.01).

[0115] Fig. 7: Binding of HB2198, rituximab, huFMC63 and Tafasitamab to Human and CD19 and CD20 using SPR on a Carterra LSA Instrument. For HB2198 and huFMC63, n = 11; rituximab n = 10; tafasitamab n = 4 determinations. Values are mean ± standard deviation rounded to two significant figures. NB = no binding.

[0116] Fig. 8: Binding of HB2198, Rituximab, huFMC63, Rituximab-SD / IE, huFMC63- SD / IE and Tafasitamab to Immobilized Human FcyR. Binding was measured by Biolayer Interferometry (BLI) using an Octet Red384 (Sartorius Stedim Biotech, France). * Fold represents the KD of rituximab divided by the KD of the comparator.

[0117] Fig. 9: Binding of HB2198, Rituximab, huFMC63, huFMC63-SD / IE and Tafasitamab to Immobilized Cynomolgus FcyR. Binding was measured by BLI using an Octet Red383 (Sartorius Stedim Biotech, Franch) with HEPES buffer at 26°C with orbital shaking speed of 1000 rpm. Cynomolgus FcyR were captured on anti-penta-histidine biosensors. * Fold represents the KD of rituximab divided by the KD of the comparator.

[0118] Fig. 10: Stability of HB2198 in buffer and serum at 37°C. HB2198 was incubated at 25 pg / mL in PBS containing 1% BSA (blue circles) or normal human serum (red squares). Aliquots were taken at time 0, 1.5, 3, 5 and 7 days, and analyzed by ELISA using CD19 capture and human Fc detection. Results are expressed as % of HB2198 remaining compared to time 0 (see, e g., Fig. 10A). Fig. 10B shows a schematic representation of samples being analyzed for HB2198 by capture on CD19-mouse Fc coated plates and detection with an HRP-conjugated anti-rituximab idiotype antibody followed by TMB colorimetric detection.

[0119] Fig. 11: Functional comparability of research grade biosimilar and pharmaceutical grade tafasitamab (Minjuvi®). Fig. 11 A shows that research grade tafasitamab has similar cell binding and ADCC activity to Minjuvi (Tafasitamab). Figs. 1 IB-1 ID show the results of experiments where RAJI cells (Fig. 1 IB), CD19KO RAJI cells (Fig. 11C) and CD20KO RAJI cells (Fig. 1 ID) were incubated with FcyRIIIa 158V reporter cells in a 1 :3 ratio for 5 hours with MabThera (orange squares), tafasitamab (purple triangles), Minjuvi (green circles), isotype hlgGl (black diamonds). Duplicate mean +- standard deviation of Relative Luciferase unit (RLU) is graphed vs test article concentration (nM).Attorney Docket: 53080.4002 / WO

[0120] Fig. 12: Binding of HB2198, rituximab, huFMC63 and tafasitamab to Human and Cynomolgus PBMC B Cells. Fig. 12 shows the results of experiments where IxlO5human (Fig.12A) or healthy cynomolgus monkey (Fig. 12B) PBMCs from 3 donors (Donor 1: left panel; Donor 2: middle panel; Donor 3: right panel) each were incubated with varying concentrations of HB2198 (blue circles), MabThera (orange squares), tafasitamab (purple triangles), huFMC63 (green triangles), or human IgGl isotype control (black diamonds) for 30 minutes on ice, washed and stained with phycoerythrin (PE) labeled anti -human Fey antibody and B cell staining cocktail, and analyzed by flow cytometry. B cells were identified as viable, CD3-, CD40+, CD21+ by flow cytometry. Geometric mean fluorescence intensity (gMFI) of PE is plotted vs test article concentration with 4-parameter logistic regression curve. Means of triplicate values ± SD of 3 individual donors from each species are shown.

[0121] Fig. 13: Binding of HB2198, rituximab, huFMC63 and Tafasitamab to Cynomolgus Monkey CD 19 and CD20. The binding of recombinant cynomolgus CD 19 and CD20 proteins to immobilized HB2198, MabThera, huFMC63, and tafasitamab was measured using SPR on a Carterra LSA Instrument. Data were analyzed using a 1 : 1 Langmuir binding model with the Carterra Kinetics Software. For HB2198 and huFMC63, n=l 1; MabThera n = 10; tafasitamab n = 4 determinations. Values are mean ± SD. NB = no binding.

[0122] Fig. 14: Summary of HB2198 and Comparators Binding to Human and Cynomolgus B Cells. EC50 and Emaxvalues were determined from experiments in Fig. 12.

[0123] Fig. 15: Binding of Cynomolgus Fey Receptors to Immobilized HB2198, MabThera, huFMC63, huFMC63S239D / I332E and Tafasitamab. Binding was measured using SPR according to the method outlined in Fig. 7, except that cynomolgus FcyR were captured on the Carterra chip. * Fold represents the KD of MabThera divided by the KD of the comparator.Dissociation of CD64 from all test articles could not be measured accurately in this assay.

[0124] Fig. 16 HB2198 serum concentrations were measured using ELISA. Mean ± SD HB2198 Serum Levels Following Single IV Infusion (Ih) of 0.2 mg / kg, 1 mg / kg, 5 mg / kg, or 25 mg / kg HB2198. For 25 mg / kg cohort, n=6. For all other cohorts, n=2. Dotted line represents LLOQ (0.0117 pg / mL). Symbols (X) denote time points that were BQL for indicated cohorts.

[0125] Fig. 17 Mean serum pharmacokinetic parameters of HB2198 following single or repeat administration by IV infusion in male and female cynomolgus monkeys. Values are mean ±Attorney Docket: 53080.4002 / WOstandard deviation (SD). Groups 3 and 4 were dosed with 25 mg / kg on Day 0. Group 4 received a repeat dose of 25 mg / kg on Day 14. Median (Range) is presented for Tmax.

[0126] Fig. 18: Mean ± SD HB2198 Serum Levels Following Repeat IV Infusion (Ih) of 25 mg / kg HB2198 on Day 0 and Day 14. HB2198 serum concentrations were measured using TP NC-0001. Dotted line represents LLOQ (0.0117 pg / mL). N = 4. Symbols (X) denote time points that were BQL.

[0127] Fig. 19: Binding of select antibodies for select FcyRs.

[0128] Fig. 20: Binding of select antibodies for select FcyRs.

[0129] Fig, 21 Listing of amino acid sequences for select antibody constructs.

[0130] Fig. 22: Binding of HB2198, rituximab, huFMC63 and Tafasitamab to Human and CD19 and CD20.

[0131] Fig. 23: Binding of HB2198, Rituximab, huFMC63, Rituximab-SD / IE, huFMC63- SD / IE and Tafasitamab to Immobilized Human FcyR.

[0132] Fig. 24: Bivalent binding affinities of tetrahedral antibodies to cell surface human Fc gamma receptor proteins determined by whole cell binding studies using Chinese Hamster Ovary (CHO) cell lines expressing individual recombinant human Fc gamma receptors, CHO-Kl / CD16a-158F (Catalog No. M00586), CHO-K 1 / CD 16a-l 58V (Catalog No. M00597), CHO-Kl / CD16b NA1 (Catalog No. M00602), CHO-Kl / CD32a-131H (Catalog No. M00598), CHO-Kl / CD32b-232Thr (Catalog No. M00600), CHO-K 1 / CD32C- 13 Gin (Catalog No. 601) and CHO-K1 / CD64 (Catalog. No. 588) (GenScript, Piscataway, New lersey). SDIE refers to presence of S239D and I332E mutations.

[0133] Fig. 25: Listing of amino acid sequences for exemplary constructs.

[0134] Fig. 26: Schematic of exemplary constructs.

[0135] Fig. 27: Listing of exemplary B cell-related autoimmune diseases and target antigens.

[0136] Fig. 28: Listing of exemplary B cell-related malignancies and target antigens.

[0137] Fig. 29: Listing of amino acid sequences for HB2198, an exemplary antibody that was generated using GEM-DIMER™ technology. HB2198 is a bispecific anti-human CD 19 x anti-CD20 antibody that incorporates Fab domains from rituximab and humanized FMC63 (huFMC63) and further comprises a set of amino acid substitution mutations (S239 / I332E) that enhance binding to Fey receptors (FcyR).Attorney Docket: 53080.4002 / WO

[0138] Fig. 30: Listing of amino acid sequences for exemplary anti-human CD20 antigen binding domains (Rituximab, ocrelizumab, obinutuzumab, ofatumumab, and ublituximab; VH domain, VL domain, vhCDRl-3, and vlCDRl-3 sequences).

[0139] Fig. 31 Listing of amino acid sequences for exemplary anti-human CD 19 antigen binding domains (huFMC63, tafasitamab, obexelimab, inebilizumab, and blinatumomab; VH domain, VL domain, vhCDRl-3, and vlCDRl-3 sequences).

[0140] Fig. 32: Listing of amino acid sequences for human CD 19.

[0141] Fig. 33: Listing of amino acid sequences for human CD20.

[0142] Fig, 34: Listing of amino acid sequences for exemplary peptide linkers.DETAILED DESCRIPTION OF THE INVENTION

[0143] The description is presented to enable one of ordinary skill in the art to make and use the invention and is provided in the context of a patent application and its requirements. The section headings used herein are for organization purposes only and are not to be construed as limiting the subject matter described. While various embodiments of the invention(s) of the present disclosure have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions may occur to those skilled in the art without departing from the invention(s). It should be understood that various alternatives to the embodiments of the invention(s) described herein may be employed in practicing any one of the inventions(s) set forth herein.

[0144] All patents, published patent applications, other publications, and sequences from GenBank, and other databases referred to herein are incorporated by reference in their entirety with respect to the related technology.

[0145] The contents of U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116 are incorporated by reference in their entirety, with particularity for descriptions of antibody formats, variable heavy / variable light / constant heavy / constant light domains, Fab domain, scFvs, and all other pertinent disclosure pertaining thereto described in the body of the specification, the drawings, and the sequence listing.Attorney Docket: 53080.4002 / WOT. DEFINITIONS

[0146] Unless defined otherwise, technical, and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present disclosure belongs. For purposes of the present disclosure, the following terms are defined below. The definitions provided are intended to apply to a given term, as well as other derivative linguistic re-phrasings and grammatical equivalents of the term.

[0147] As used herein, the terms “B cell, “B-cell,” “B lymphocyte,” and “B-lymphocyte,” which can be used interchangeably, are used generally to refer to a type of “leukocyte” (i.e., a white blood cell) that plays a central role in the adaptive immune systems by producing antibodies. They are primarily responsible for humoral immunity, a defense mechanism that targets pathogens and toxins outside of the body’s cells. Like all blood cells, B cells originate from hematopoietic stem cells (HSCs) in the bone marrow. Generally, immature B cells exit the bone marrow, undergo further maturation into naive follicular B cells or marginal zone B cells, and then will repeatedly circulate throughout the blood, lymph, and secondary lymphoid organs. Upon encountering a matching antigen (i.e., once aB cell “specifically binds” a “target antigen of interest”) the B cell is activated and will differentiate into short-lived plasmablasts or germinal center B cells, or they will differentiate into long-lived memory B cells. Following activation, plasma cells migrate to long-term survival “niches,” whereas memory B cells may re-enter circulation or one or more tissues to surveil for infection / disease.

[0148] As used herein, the term “compartment,” when used in reference to one or more cells of a subject, such as, for example, B cells, is generally meant to refer to an anatomic region, organ system, or specific organ of a subject where a given cell type is commonly found. Further, as used herein, the term “niche,” when used in reference to one or more cells of a subject, such as, for example, B cells, is generally meant to refer to a specific, localized microenvironment within a compartment. As used herein, the term “B cell compartment” refers to a broad physical location where B cells reside within one or more niches. Generally, B cells can be found circulating throughout blood or lymph fluid, or in one or more tissues of a subject. As such, the “B cell compartment” can comprise a “circulating compartment” or a “tissue-resident compartment.”Attorney Docket: 53080.4002 / WO

[0149] As used herein, the term “circulating B cell compartment” refers to B cells found within the “circulatory niche” (i.e., B cells resident to the circulatory system). B cells found within the circulatory niche may comprise one or more of the following: (i) naive B cells, (ii) memory B cells, and (iii) plasmablasts (also referred to as plasma cells).

[0150] As used herein, the term “tissue-resident B cell compartment” is meant B cells found within: (i) one or more lymph nodes, (ii) bone marrow of one or more bones, (iii) the spleen, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any niche thereof. Further included within the umbrella of “tissue-resident B cell compartment” are B cells contained within lymph vessels and lymph ducts, as well as B cells transported in lymph fluid to the extent that the lymph fluid flows through lymph vessels / ducts leading to and / or away from one of the other aforementioned tissue-resident B cell compartments.

[0151] With respect to lymph nodes, B cells can be found within one or more of the following niches: (a) follicular niche (also referred to as lymphoid follicles), (b) germinal centers, (c) medullary cords, and (d) subcapsular sinus niche (also referred to as the memory B cell recycling niche); and may comprise one or more of the following B cell types: (1) naive B cells, (2) activated B cells, (3) centroblasts, (4) centrocytes, (5) plasmablasts, (6) marginal zone-like B cells. For bone marrow, B cells can be found within one or more of the following niches: (a) lymphopoietic niche, (b) perisinusoidal niche, and (c) long-lived plasma cell niche; and may comprise one or more of the following B cell types: (1) pro-B cells, (2) immature B cells, (3) plasmablasts, and (4) memory B cells. For the spleen, B cells can be found within one or more of the following niches: (a) follicular B cell niche, (b) marginal zone B cell niche, and (c) memory B cell niche; and may comprise one or more of the following B cell types: (1) follicular B cells, (2) marginal zone B cells, and (3) memory B cells. For MALT, B cells can be found within one or more of the following niches: (a) inducible lymphoid aggregate, and (b) IgA-secreting niche; and may comprise one or more of the following B cell types: (1) naive B cells, (2) activated B cells, (3) memory B cells, and (4) plasmablasts. For the thymus, B cells can be found within one or more of the following niches: (a) medullary niche, and (b) perivascular space (PVS); and may comprise one or more of the following B cell types: (1) transitional B cells, and (2) mature B cells. For the skin, B cells can be found within one or more of the following niches: (a) homeostatic niche, and (b) inflammatory niche (also referred to as ectopic germinal centers); and may comprise one or more of the following B cell types: (1) memory B cells, and (2)Attorney Docket: 53080.4002 / WOplasmablasts. For the liver, B cells can be found within one or more of the following niches: (a) immune regulation and homeostasis niche, (b) inflammatory niche, and (c) memory B cell niche; and may comprise one or more of the following B cell types: (1) memory B cells, and (2) plasmablasts.

[0152] The present disclosure provides various aspects and embodiments directed to the “depletion” and / or “remodeling” of one or more B cell compartments (or niches thereof).Depletion and, in some instances, remodeling of one or more B cell compartments (or niches thereof) can effectuate treatment of a “B cell malignancy” and / or an “autoimmune disease associated with B cell pathogenesis,” or symptoms thereof.

[0153] As used herein, the term “depletion” of B cells (or a B cell compartment or niche thereof) is meant a reduction in one or more B cell compartments by at least about 30% or more in one or more B cell compartments following an administration of a “B cell depleting antibody” as compared to a baseline level of B cells within the one or more B cell compartments determined prior to a first administration of the B cell depleting antibody. In many instances, B cell depletion refers to a reduction (or, “depletion”) of at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more in circulating B cells within a period of time following an administration of a “B cell depleting antibody” as compared to a baseline level of circulating B cells determined prior to a first administration of the B cell depleting antibody. Alternatively, or in addition to, B cell depletion may refer to a reduction (or, “depletion”) of at least about 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more in tissue-resident B cells within one or more B cell compartments following an administration of a “B cell depleting antibody” as compared to a baseline level of tissueresident B cells determined prior to a first administration of the B cell depleting antibody.

[0154] As used herein, the term “remodeling” of B cells (or a B cell compartment (or niche thereof)) is meant a process by which the cellular makeup of a B cell compartment (or niche thereof) is dynamically changed in response to a signal, such as, for example, administration of a “B cell depleting antibody”, depletion of one or more B cells, etc. Generally, B cell remodeling is characterized by an altered ratio of the number of one or more specific B cell types compared to the number of all B cells following administration of a “B cell depleting antibody” as compared to a baseline ratio of CD27- to CD27+ B cells determined prior to a first administration of the B cell depleting antibody. In some embodiments, a B cell niche undergoingAttorney Docket: 53080.4002 / WOremodeling subsequent to depletion of B cell within the niche may be characterized by an increased ratio of CD27' B cells (i.e., naive B cells) to CD27+B cells (i.e., memory B cells). In some further embodiments, remodeling is characterized by an increased ratio of circulating CD27‘ B cells to circulating CD27+B cells. Alternatively, or in addition to, remodeling can be characterized by an increased ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells.

[0155] As used herein, the terms “treatment,” “treating,” and the like are used herein interchangeably to generally mean that a desired pharmacologic and / or physiologic effect is obtained in response to a B cell depleting antibody (or antigen binding fragment thereof), or a method employing a B cell depleting antibody (or antigen binding fragment thereof). The effect may be prophylactic, in terms of completely or partially preventing a disease, condition, or one or more symptom(s) thereof, and / or may be therapeutic in terms of a partial or complete cure for the disease or condition and / or an adverse effect, such as, for example, a symptom, attributable to the disease or condition. “Treatment” as used herein covers any treatment of a disease or condition of a subject and includes: (A) preventing the disease or condition from occurring in a subject which may be predisposed to the disease or condition but has not yet been diagnosed as having it; (b) inhibiting the disease or condition (e.g., arresting its development); or (c) relieving the disease or condition (e.g., causing regression of the disease or condition, providing improvement in one or more symptoms). Further contemplated herein are method for treating “B cell malignancies” and / or “autoimmune diseases characterized by B cell pathogenesis” using B cell depleting antibodies according to any of the methods of use described herein. As such, “treatment of a B cell malignancy” using a B cell depleting antibody includes: (a) preventing the B cell malignancy from occurring in a subject which may be predisposed to the B cell malignancy but has not yet been diagnosed as having it; (b) inhibiting the B cell malignancy; or (c) relieving the B cell malignancy. Similarly, “treatment of an autoimmune disease characterized by B cell pathogenesis” using a B cell depleting antibody includes: (A) preventing the autoimmune disease from occurring in a subject which may be predisposed to the autoimmune disease but has not yet been diagnosed as having it; (b) inhibiting the autoimmune disease; or (c) relieving the autoimmune disease.

[0156] As used herein, the term “B cell malignancy” refers to a broad group of various diseases characterized by the uncontrolled growth of abnormal B cells in the body. Nonlimiting examplesAttorney Docket: 53080.4002 / WOof B cell malignancies include: (i) diffuse large B-cell lymphoma (DLBCL), (ii) chronic lymphocytic leukemia (CLL), (iii) follicular lymphoma, (iv) mantle cell lymphoma, (v) marginal zone lymphoma, (vi) Burkitt lymphoma, (vii) Hodgkin lymphoma (some subtypes), (viii) Waldenstrom macroglobulinemia, (ix) multiple myeloma, (x) hairy cell leukemia, (xi) acute lymphoblastic leukemia (also referred to as B-ALL), (xii) primary central nervous system lymphoma (also referred to as PCNSL), (xiii) small lymphocytic lymphoma (also referred to as SLL), (xiv) lymphoplasmacytic lymphoma, and (xv) primary mediastinal B-cell lymphoma.

[0157] As used herein, the term “autoimmune disease characterized by B cell pathogenesis” refers to a broad group of diseases characterized by B cells within a subject that mistakenly target the subject’s own body (or cells, tissues, organs, organs systems, or anatomic regions thereof), contributing to disease through one or more of the following: (a) production of autoantibodies, (b) cytokine secretion, (c) antigen presentation, and (d) dysregulation of B cell tolerance. Nonlimiting examples of autoimmune diseases characterized by B cell pathogenesis include: (i) acquired hemophilia, (ii) alopecia areata, (iii) amyloidosis, (iv) anti-NMDA receptor encephalitis (also referred to as autoimmune encephalitis), (v) antiphospholipid syndrome, (vi) autoimmune Addison’s disease, (vii) autoimmune angioedema, (viii) autoimmune autonomic ganglionopathy, (ix) autoimmune encephalitis (also referred to as acute disseminated encephalomyelitis, ADEM), (x) autoimmune gastritis, (xi) autoimmune hemolytic anemia, (xii) autoimmune hepatitis, (xiii) autoimmune hyperlipidemia, (xiv) autoimmune hypophysitis (also referred to as lymphocytic hypophysitis), (xv) autoimmune inner ear disease (also referred to as autoimmune sudden sensorineural hearing loss, Meniere’s disease), (xvi) autoimmune Interstitial Lung Disease (also referred to as fibrosing alveolitis, idiopathic pulmonary fibrosis), (xvii) autoimmune lymphoproliferative syndrome, (xviii) autoimmune myelofibrosis, (xix) autoimmune myocarditis (also referred to as giant cell myocarditis), (xx) autoimmune oophoritis (also referred to as testicular autoimmunity, autoimmune orchitis), (xxi) autoimmune pancreatitis, (xxii) autoimmune polyglandular syndromes (also referred to as Schmidt syndrome), (xxiii) autoimmune progesterone dermatitis, (xxiv) autoimmune retinopathy (also referred to as birdshot chorioretinopathy), (xxv) Balo disease (also referred to as concentric sclerosis), (xxvi) bullous pemphigoid, (xxvii) Castleman disease, (xxviii) celiac disease, (xxix) chronic autoimmune urticaria, (xxx) chronic inflammatory demyelinating polyneuropathy, (xxxi) Churg-Strauss syndrome (also referred to as eosinophilic granulomatosis with polyangiitis,Attorney Docket: 53080.4002 / WOEGPA), (xxxii) Cogan’s syndrome, (xxxiii) cold agglutinin disease, (xxxiv) CREST syndrome (also referred to as limited scleroderma, systemic sclerosis), (xxxv) Cronkhite-Canada syndrome, (xxxvi) cryptogenic organizing pneumonia, (xxxvii) dermatitis herpetiformis, (xxxviii) dermatomyositis (also referred to as juvenile myositis), (xxxix) discoid lupus (also referred to as systemic lupus erythematosus, SLE), (xl) Dressier’s syndrome, (xli) eczema (also referred to as atopic dermatitis), (xlii) essential mixed cryoglobulinemia, (xliii) Evans syndrome, (xliv) giant cell arteritis (also referred to as temporal arteritis, Horton’s disease), (xlv) glomerulonephritis (also referred to as lupus nephritis), (xlvi) Goodpasture’s syndrome, (xlvii) granulomatosis with polyangiitis (also referred to as Wegener’s granulomatosis), (xlviii) Graves’ disease (also referred to as thyroid eye disease, Graves’ ophthalmopathy, thyroid-associated orbitopathy), (xlix) Guillain-Barre syndrome, (1) Hashimoto’s thyroiditis (also referred to as autoimmune thyroiditis), (li) Henoch-Schbnlein purpura, (lii) Hurst’s disease (also referred to as acute hemorrhagic leukoencephalitis), (liii) IgA nephropathy, (liv) IgG4-related sclerosing disease, (Iv) immune thrombocytopenia (also referred to as autoimmune thrombocytopenia purpura), (Ivi) immune-mediated necrotizing myopathy, (Ivii) inclusion body myositis, (Iviii) juvenile idiopathic arthritis (also referred to as adult-onset Still’s disease), (lix) Kawasaki disease, (lx) Lambert-Eaton myasthenic syndrome, (Ixi) leukocytoclastic vasculitis, (Ixii) lichen planus, (Ixiii) lichen sclerosus, (Ixiv) linear IgA disease, (Ixv) lupus nephritis (also referred to as systemic lupus erythematosus, SLE), (Ixvi) Meniere’s disease (also referred to as autoimmune inner ear disease), (Ixvii) microscopic polyangiitis (also referred to as ANCA-associated vasculitis), (Ixviii) mixed connective tissue disease (also referred to as undifferentiated connective tissue disease), (Ixix) mucous membrane pemphigoid (also referred to as ocular cicatricial pemphigoid), (Ixx) multiple sclerosis, (Ixxi) myasthenia gravis, (Ixxii) neuromyelitis optica (also referred to as Devic’s disease), (Ixxiii) optic neuritis, (Ixxiv) palindromic rheumatism, (Ixxv) paraneoplastic cerebellar degeneration, (Ixxvi) paraneoplastic pemphigus, (Ixxvii) pemphigoid gestationis (also referred to as herpes gestationis), (Ixxviii) pemphigus foliaceus, (Ixxix) pemphigus vulgaris, (Ixxx) pernicious anemia, (Ixxxi) Pityriasis Lichenoides et Varioliformis Acuta (also referred to as Mucha-Habermann disease), (Ixxxii) POEMS syndrome, (Ixxxiii) polyarteritis nodosa, (Ixxxiv) polymyositis, (Ixxxv) primary biliary cholangitis (also referred to as PBC), (Ixxxvi) primary sclerosing cholangitis, (Ixxxvii) pure red cell aplasia, (Ixxxviii) relapsing polychondritis, (Ixxxix) rheumatoid arthritis, (xc) scleritis, (xci) scleroderma (alsoAttorney Docket: 53080.4002 / WOreferred to as systemic sclerosis, CREST syndrome), (xcii) Sjogren’s syndrome (also referred to as Sjogren disease, SjD), and (xciii) systemic lupus erythematosus (also referred to as SLE, discoid lupus, lupus nephritis).

[0158] As used herein, the term “protein” refers to at least two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100 or more covalently attached amino acids, which includes proteins, polypeptides, oligopeptides, and peptides.

[0159] As used herein, the term “wild-type” refers to an amino acid sequence or a nucleotide sequence that is found in nature, including allelic variations. A wild-type protein has an amino acid sequence (or a nucleotide sequence encoding the amino acid sequence) that has not been intentionally modified.

[0160] As used herein, the term “residue” refers to a position in a protein and its associated amino acid identity. For example, Cysteine 252 (also referred to as Cys252 or C252) is a residue at position 252.

[0161] As used herein, the term “parent protein” refers to a “reference” protein, the amino acid sequence that encodes the reference protein, or the DNA sequence that encodes the amino acid sequence that encodes the reference protein. In some embodiments, the reference protein comprises a wild-type protein, the amino acid sequence encoding the wild-type protein, and / or the nucleic acid sequence encoding the amino acid sequence encoding the wild-type protein. In some embodiments, the reference protein comprises a human wild-type protein, the amino acid sequence encoding the human wild-type protein, and / or the nucleic acid sequence encoding the amino acid sequence encoding the human wild-type protein.

[0162] As used herein, the terms “variant protein,” “protein variant,” or “variant” refer to a protein that differs from that of a parent protein by virtue of at least one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100 or more modifications. The terms may refer to the protein itself, a composition comprising the protein, the amino acid sequence that encodes it, or the DNA sequence that encodes it. In some embodiments, the parent protein refers to a wild-type sequence. In some embodiments, the parent protein refers to a human wild-type sequence.

[0163] As used herein, the term “amino acid modification” refers to an amino acid substitution, insertion, and / or deletion in a polypeptide sequence. The position(s) where the amino acid(s) are modified and the number of amino acid(s) that may be modified in the amino acid sequence areAttorney Docket: 53080.4002 / WOnot particularly limited. In many preferred embodiments, amino acid modifications comprise amino acid substitutions.

[0164] As used herein, the terms “amino acid substitution” or “substitution” refer to the replacement of an amino acid at a particular position in a parent polypeptide sequence with a different amino acid. For example, Y40A designates a substitution of tyrosine at position 40 with an alanine at the same position. In some embodiments, the substitution is to an amino acid that is not naturally occurring at the particular position, either not naturally occurring within the organism or in any organism. For clarity, a protein that has been engineered to change the nucleic acid coding sequence but not to change the resulting amino acid (for example, exchanging CCU (encoding proline) to CCC (still encoding proline)) is not an “amino acid substitution.” Phrased differently, despite the creation of a new gene encoding the same protein, if the protein has the same amino acid at the particular position that it started with, it is not an amino acid substitution.

[0165] As used herein, the terms “amino acid insertion” or “insertion” refer to the addition of an amino acid residue or sequence at a particular position in a parent polypeptide sequence. For example, -40A designates an insertion of alanine after position 40 and before position 41. As a separate example, D8EPKSS or -8EPKSS designates an insertion of the sequence Glu-Pro-Lys-Ser-Ser after position 8 and before position 9.

[0166] As used herein, the terms “amino acid deletion” or “deletion” refer to the removal of an amino acid or sequence at a particular position in a parent polypeptide sequence. For example, Y40-, Y40#, Y40( ), or Y40del designates a deletion of tyrosine at position 40. As a separate example, EPKSS8-, EPKSS8#, EPKSS8del designates a deletion of the sequence Glu-Pro-Lys-Ser-Ser that begins at position 8.

[0167] As used herein, the terms “percent (%) identity” and “percent (%) sequence identity,” when used in the context of two or more proteins or nucleic acids, refer to a percentage of amino acid residues (or nucleic acids encoding the amino acid residues) in a candidate sequence that are identical with the amino acid residues (or nucleic acids encoding the amino acid residues) in a specific sequence, such as, for example, the amino acid sequence of a parent protein, after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent sequence identity, and not considering any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent sequence identity can be achieved inAttorney Docket: 53080.4002 / WOvarious ways that are within the skill of the art, such as, for example, using publicly available computer software (e.g., BLAST, BLAST-2, ALIGN, or Megalign (DNASTAR) software). Those skilled in the art can determine appropriate parameters for measuring alignment, including any algorithms needed to achieve maximal alignment over the full length of the sequences being compared. In some embodiments, two or more amino acid sequences are at least about 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or even 100% identical.

[0168] As used herein, the term “antibody” is used in the broadest sense and specifically covers monoclonal antibodies (including, but not limited to, “full-length” monoclonal antibodies) polyclonal antibodies, bispecific antibodies, multispecific antibodies, monovalent antibodies, multivalent antibodies, as well as any “antigen binding fragment” thereof so long as they exhibit the desired biological activity (i.e., specific binding to a given target antigen).

[0169] As used herein, the terms “full-length antibody,” “intact antibody,” and “whole antibody,” which can be used interchangeably, refer to the classical “Y-shaped” antibodies comprising two “heavy chains” and two “light chains,” wherein individual instances of the heavy chain comprises, from N-terminus to C-terminus, a variable heavy (VH) domain, a first constant heavy (CHI) domain, and a Fc domain (comprising: (i) an optional hinge region, (ii) a CH2 domain, and (iii) a CH3 domain), and individual instances of the light chain comprises, from N-terminus to C-terminus, a variable light (VL) domain, and a constant light (CL) domain.

[0170] As used herein, the term “antigen binding fragment,” when discussed in the context of a given antibody, refers to the one or more domains of a given antibody that recognizes and specifically binds a target antigen (i.e., the term “antigen binding fragment” generally refers to a fragment of an antibody that comprises an antigen binding domain (and therefore specifically binds a target antigen) but is deficient with respect to one or more domains of a “full-length antibody” (in many exemplary embodiments, the antigen binding fragment lacks one or more Fc domains)). As will be appreciated by those skilled in the art, an antigen binding domain of an antigen binding fragment can take on several different configurations. For example, an antigen binding fragment may comprise a Fab domain (comprising a variable heavy (VH) domain (comprising a first, second, and third heavy complementarity determining regions (vhCDRl-3)), a variable light (VL) domain (comprising a first, second, and third light complementarity determining regions (vlCDRl-3)), a first constant heavy (CHI) domain, and a constant lightAttorney Docket: 53080.4002 / WO(CL) domain), a single-chain variable fragment (comprising a variable heavy (VH) domain (comprising a first, second, and third heavy complementarity determining regions (vhCDRl-3), a linker, and a variable light (VL) domain (comprising a first, second, and third light complementarity determining regions (vlCDRl-3), or a VHH domain (comprising a first, second, and third complementarity determining regions (VHH CDR1-3)). As will also be appreciated by those skilled in the art, the exact structure of an “antigen binding fragment” of an antibody is also dependent upon an antibody’s configuration with respect to valence and specificity. For example, a bispecific, monovalent antibody has two antigen binding domains, wherein a first ABD specifically binds a first target antigen, and a second ABD specifically binds a second target antigen. As such, an antigen binding fragment of a bispecific, monovalent antibody will retain the antigen binding domains directed to the first target antigen and the second target antigen, but otherwise be deficient with respect to one or more domains of a “full-length antibody.” As another nonlimiting example, a monospecific, bivalent antibody has two antigen binding domains, wherein individual instances of the ABDs specifically bind a target antigen. As such, an antigen binding fragment of a monospecific, bivalent antibody will retain the antigen binding domains directed to the target antigen, but otherwise be deficient with respect to one or more domains of a “full-length antibody.” Nonlimiting examples of antigen binding fragments of bispecific antibodies include: F(ab)’2 fragments, tandem scFvs (also referred to as a “BiTE” format), diabodies, DART -format antibody fragments, as well as others known in the relevant art. While the examples describe above are directed to specific combinations of antibody valence and specificity, it is explicitly contemplated that the concepts apply equally to antigen binding fragments derived from antibodies of any combination of valence and specificity.

[0171] As used herein, the term “B cell depleting antibody” refers to an antibody (or antigen binding fragment thereof) configured to specifically bind one or more cell surface antigens (or extracellular domains thereof) expressed by B cells, wherein binding to the B cell effectuates a reduction in B cells by at least about 25% or more. In many embodiments, the B cell depleting antibody effectuates a reduction in circulating B cells. Alternatively, or in addition to, the B cell depleting antibody may effectuate a reduction in tissue-resident B cells. In many instances, the antibody (or antigen binding fragment thereof) is configured such that it specifically binds CD 19 and / or CD20 (i.e., the antibody or antigen binding fragment comprises an anti-CD19 antigen binding domain and / or an anti-CD20 antigen binding domain). In some further instances, theAttorney Docket: 53080.4002 / WOantibody (or antigen binding fragment thereof) is configured such that it specifically binds one or more additional “target antigen(s) of interest” (“TA”). In many embodiments, the B cell depleting antibody effectuates a reduction in B cells through direct cell killing or one or more of the following effector functions: “antibody-dependent cellular cytotoxicity” (ADCC), “antibodydependent cellular phagocytosis” (ADCP), and “complement-dependent cytotoxicity” (CDC).

[0172] As used herein, the terms “GEM-DIMER-formatted antibody,” “superdimeric antibody,” and “tetrahedral antibody,” which can be used interchangeably, refers to any one of the antibody formats and / or any one of the Fc fusion protein formats (to the extent that the Fc fusion protein comprises at least one antigen binding domain, as described in further detail herein) described in U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference in their entirety, with particularity for antibody formats, Fc fusion proteins, and amino acid sequences thereof described therein. Generally, GEM-DIMER-formatted antibodies are polyspecific antibodies (i.e., bispecific or multispecific) of varying or mixed valence (e.g., mono-, bi-, tri-, or tetraval ent for a first given target antigen; mono-, bi-, tri-, or tetravalent for a second given target antigen; mono-, bi-, tri-, or tetravalent for an Nth given target antigen; etc.), and further comprise one or more dimerization domains (also referred to herein as superdimerization domains, which can be used interchangeably).Nonlimiting examples of dimerization domains that find utility in some of the embodiments described herein are described in U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to dimerization domains, leucine zipper domains, collectrin-like domains, collectrin domains, and any amino acid sequences thereof. In some embodiments, the one or more dimerization domains comprise: (i) leucine zipper domain(s), (ii) collectrin-like domain(s), (iii) collectrin domain(s), as well as others known in the relevant art.

[0173] As used herein, the term “Fc fusion protein” refers to a protein comprising an Fc domain, generally linked (such as, for example, through a covalent linkage (e.g., a peptide bond) or a linker domain) to a different protein, such as, for example, a binding moiety to a target protein (such as, for example, tumor necrosis factor receptor for TNFa). In many instances, Fc fusion proteins are configured similarly to antibodies. In such instances, an Fc fusion protein will often comprise: (i) a first monomer, wherein the first monomer comprises a variant Fc domain and a ligand or a binding moiety that specifically binds a ligand; and (ii) a second monomer, whereinAttorney Docket: 53080.4002 / WOthe second monomer comprises an antibody heavy chain (i.e., the second monomer comprises a variable heavy (VH) domain, a first constant heavy (CHI) domain, and a (variant) Fc domain) or a scFv-Fc fusion protein (i.e., a variable heavy (VH) domain, a domain linker, a variable light (VL) domain, and a (variant) Fc domain). In instances where the second monomer comprises an antibody heavy chain, the Fc fusion protein will also comprise an antibody light chain (i.e., a third monomer comprising a variable light (VL) domain and a constant light (CL) domain). In some instances (e.g., in the case of GEM-DIMER-formatted Fc fusion proteins), one or more monomers of a Fc fusion protein may comprise a dimerization domain, as described further in detail herein.

[0174] As used herein, the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies. In other words, the individual antibodies comprising the population are substantially identical and / or bind the same epitope, except for possible naturally-occurring variant antibodies (occurring due to a naturally-occurring mutation or arising during production of a monoclonal antibody preparation), such variants generally being present in minor amounts of the otherwise substantially homogeneous antibody population.

[0175] As used herein, the term “chimeric antibody” refers to an antibody in which a portion of the heavy chain and / or light chain is derived from a particular source or species, while the remainder of the heavy chain and / or light chain is derived from a different source or species.

[0176] As used herein, the term “humanized antibody” refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid resides from human FRs. In certain embodiments, a humanized antibody will comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the HVRs (e.g., CDRs) correspond to those of a non-human antibody, and all or substantially all of the FRs correspond to those of a human antibody. A humanized antibody optionally may comprise at least a portion of an antibody constant region derived from a human antibody. A “humanized form” of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0177] As used herein, the term “human antibody” refers to an antibody which is characterized by an amino acid sequence that corresponds to that of an antibody produced by a human or a human cell or is derived from a non-human source that utilizes human antibody repertoires or other human antibody-encoding sequences. This definition of a human antibody specifically excludes a humanized antibody comprising non-human antigen-binding residues.Attorney Docket: 53080.4002 / WO

[0178] As used herein, the term “naked antibody” refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or radiolabel.

[0179] As used herein, the term “affinity matured antibody” refers to an antibody with one or more modifications (in many instances, one or more amino acid substitutions) in one or more HVRs compared to a parent antibody, which does not possess the modifications, wherein the one or more modifications result in an improvement in the “affinity” of an antibody for its target antigen.

[0180] As used herein, the term “affinity” refers to the “strength” of binding of a given molecule (such as, for example, an anti-CD19 B cell depleting antibody) to its ligand (continuing with the example, in this instance, CD19) and / or the rate at which the molecule associates with and / or dissociates from its ligand. “Binding affinity” is often expressed in terms of the dissociation constant (KD). The binding activity of a B cell depleting antibody of the disclosure can be assayed by any suitable method known in the art, such as, for example, a surface plasmon resonance (SPR) assay, an enzyme-linked immunosorbent assay (ELISA), an ELISpot assay, Biacore assays, KinExA assays, and the like. As some B cell depleting antibodies of the present disclosure are polyspecific (i.e., bispecific or multi specific), such B cell depleting antibodies will exhibit N-number of binding specificities depending on the specific configuration of the B cell depleting antibody (for example, a bispecific, monovalent antibody comprising a first ABD and a second ABD will exhibit a first “affinity” for a first target antigen specifically bound by the first ABD and a second “affinity” for a second target antigen specifically bound by the second ABD).

[0181] As used herein, the terms “specific binding,” “specifically binds to,” or is “specific for” a particular antigen or an “epitope,” which can be used interchangeably, means binding that is measurably different from a non-specific interaction. Specific binding can be measured, for example, by determining binding of a molecule compared to binding of a control molecule, which generally is a molecule of similar structure that does not have binding activity. For example, specific binding can be determined by competition with a control molecule that is similar to the target.

[0182] As used herein, the term “epitope” refers to a determinant that interacts with a specific antigen binding site in the variable region of an antibody molecule known as a paratope.Epitopes are groupings of molecules such as amino acids or sugar side chains and usually haveAttorney Docket: 53080.4002 / WOspecific structural characteristics, as well as specific charge characteristics. A single antigen may have more than one epitope.

[0183] As used herein, the terms “CD 19,” “Cluster of Differentiation 19,” “B-lymphocyte surface antigen B4,” and “T-cell surface antigen LEU- 12,” which can be used interchangeably, are used generally to refer to a transmembrane protein expressed in most B lineage cells (a notable exception being plasma cells, which are terminally differentiated). Since CD 19 is a marker of B cells, the protein has been used to diagnose cancers that arise from this type of cell (i.e., “B cell malignancies”). The majority of B cell malignancies express normal to high levels of CD 19, making it an ideal target of a therapeutic agent, such as, for example, an antibody of the present disclosure, for treating such B cell malignancies. Similarly, due to the expression of CD 19 in autoreactive B cells, which are responsible for producing autoantibodies, it is also an ideal target of a therapeutic agent, such as, for example, a B cell depleting antibody of the present disclosure, for treating select autoimmune diseases (i.e., “autoimmune diseases characterized by B cell pathogenesis”).

[0184] As used herein, the terms “CD20,” “Cluster of Differentiation 20,” “B-lymphocyte antigen CD20,” “MS4A1,” “Bp35,” and “FMC7,” which can be used interchangeably, are used generally to refer to a B-lymphocyte surface molecule that plays a role in the development and differentiation of B cells into plasma cells. Similar to CD 19, CD20 is also a markers of B cells and, as such, the protein has been used to diagnose cancers that arise from this type of cell.Similarly, due to the expression of CD20 in autoreactive B cells, which are responsible for producing autoantibodies, it is also an ideal target of a therapeutic agent, such as, for example, a B cell depleting antibody of the present disclosure, for treating select autoimmune diseases (i.e., “autoimmune diseases characterized by B cell pathogenesis”).

[0185] As used herein, the term “target antigen of interest” (“TA”) refers to one or more antigens expressed by B cells, one or more cells associated with a “B cell malignancy,” and / or one or more cells associated with an “autoimmune disease characterized by B cell pathogenesis.” In instances wherein the B cell depleting antibody comprises a bispecific or multispecific antibody, the B cell depleting antibody may comprises one or more additional antigen binding domains (“ABDs”), wherein individual instances of the one or more additional ABDs specifically bind a target antigen of interest. Nonlimiting examples of suitable target antigens of interest include: (i) a4p7 integrin, (ii) av integrin subunit av 1, (iii) av integrin subunit av03, (iv) av integrinAttorney Docket: 53080.4002 / WOsubunit avP5, (v) av integrin subunit av|36, (vi) av integrin subunit avP8, (vii) activin type IT receptor, (viii) APRIL, (ix) AXL, (x) BAFF, (xi) BAFF / CD19, (xii) BAFF-R, (xiii) BCMA, (xiv) B7-H3, (xv) BLyS, (xvi) CA-125 mimic, (xvii) CCL2, (xviii) CD137, (xix) CD19, (xx) CD20, (xxi) CD20 / CD3, (xxii) CD22, (xxiii) CD23, (xxiv) CD25, (xxv) CD27, (xxvi) CD30, (xxvii) CD38, (xxviii) CD3, (xxix) CD40, (xxx) CD47, (xxxi) CD52, (xxxii) CD73, (xxxiii) CD79b, (xxxiv) CEACAM5, (xxxv) CGRP, (xxxvi) CGRP receptor, (xxxvii) Clostridium difficile toxin A, (xxxviii) Clostridium difficile toxin B, (xxxix) complement C5, (xl) CTGF, (xli) CTLA-4, (xlii) DLL4, (xliii) DR5, (xliv) Ebola virus glycoprotein, (xlv) EGFR, (xlvi) ERBB2, (xlvii) FAP, (xlviii) FGF23, (xlix) Frizzled receptors, (1) GDF15, (li) GFAP, (lii) GD2, (liii) GM-CSF, (liv) GM-CSFRa, (Iv) HER2, (Ivi) HER3, (Ivii) HIV-1 envelope glycoprotein, (Iviii) HIV-1 gpl20, (lix) human a4p7 integrin heterodimer, (lx) human CD161, (Ixi) human CD 19, (Ixii) human PD-L1, (Ixiii) IFNa, (Ixiv) IFNARl, (Ixv) TFNy, (Ixvi) IgE, (Ixvii) IgG4, (Ixviii) IL-ip, (Ixix) IL-12 / IL-23p40, (Ixx) IL-13, (Ixxi) IL-13Ral, (Ixxii) IL-15, (Ixxiii) IL-17A, (Ixxiv) IL-17A / IL-17F, (Ixxv) IL-17RA, (Ixxvi) IL-20, (Ixxvii) IL-22, (Ixxviii) IL-22R, (Ixxix) IL-2 , (Ixxx) IL-31, (Ixxxi) IL-33, (Ixxxii) IL-33R / ST2, (Ixxxiii) IL-4Ra, (Ixxxiv) IL-5, (Ixxxv) IL-5Ra, (Ixxxvi) IL-6, (Ixxxvii) IL-6R, (Ixxxviii) KIR2DL1 / 2 / 3, (Ixxxix) LAG-3, (xc) LINGO-1, (xci) MAdCAM-1, (xcii) MASP-2, (xciii) MET, (xciv) mesothelin, (xcv) myostatin, (xcvi) Nectin-4, (xcvii)NGF, (xcviii) Notch2 / 3, (xcix) OSMRp, (c) 0X40, (ci) P-selectin, (cii) PCSK9, (ciii) PD-1, (civ) PD-L1, (cv) PDGF-B, (cvi) plasma kallikrein, (cvii) RANKL, (cviii) rabies virus glycoprotein, (cix) RGMa, (ex) RSPO3, (cxi) SARS-CoV-2 spike protein, (cxii) SARS-CoV-2 RBD, (cxiii) sclerostin, (cxiv) SLAMF7, (cxv) sortilin, (cxvi) Staphylococcus aureus alpha toxin, (cxvii) TGF-P, (cxviii) TGF-P & PD-L1, (cxix) TIGIT, (exx) ticagrelor, (exxi) TIM-3, (cxxii) tissue factor, (cxxiii) tissue factor pathway inhibitor, (cxxiv) TNFa, (exxv) Trop-2, (cxxvi) TSLP, (cxxvii) VEGF-A, (cxxviii) VEGF-B, (cxxix) VEGFR-2, and (exxx) von Willebrand factor (vWF). Relatedly, Fig. 27 provides a list of exemplary autoimmune diseases characterized by B cell pathogenesis and exemplary antigens that may be targeted by one or more ABDs of aB cell depleting antibody described herein. Similarly, Fig. 28 provides a list of exemplary B cell malignancies and exemplary antigens that may be targeted by one or more ABDs of a B cell depleting antibody described herein.

[0186] As used herein, the term “isolated antibody” refers to an antibody that has been separated from a component of its natural environment. In some embodiments, an antibody is purified toAttorney Docket: 53080.4002 / WOgreater than 95% or 99% purity as determined by, for example, electrophoretic (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatographic (e.g., ion exchange or reverse phase HPLC). For review of methods for assessment of antibody purity, see, e.g., Flatman et al., J. Chromatogr. B 848:79-87 (2007).

[0187] As used herein, the terms “Fab domain” or “Fab fragment,” which can be used interchangeably, collectively refer to: (i) a variable heavy (VH) domain, (ii) a first constant heavy (CHI) domain, (iii) a variable light (VL) domain, and (iv) a constant light domain, wherein the VH domain and VL domain form an antigen binding domain (ABD) that specifically binds a target antigen.

[0188] As used herein, the terms “single-chain Fv” or “scFv,” which can be used interchangeably, refers to an antibody fragment comprising the VH and VL domains of an antibody, wherein the VH and VL domains are present in a single polypeptide chain. Generally, the VH domain and VL domain are linked using a polypeptide linker (see, e.g., SEQ ID NOs: 207-224).

[0189] As used herein, the terms “variable region” or “variable domain,” which can be used interchangeably, refer to the domain of an antibody heavy or light chain that is involved in recognition and specific binding of the antibody (or antigen binding fragment thereof) to its target antigen. The variable domains of the heavy chain (VH domain) and light chain (VL domain) of traditional antibodies generally have similar structures, with each domain comprising four conserved “framework regions” (FRs) and three “hypervariable regions” (HVRs). In some instances, a single VH domain or a VL domain may be sufficient to confer antigen binding specificity (such as, for example, VHH-formatted antigen binding domains). However, in many configurations, a VH / VL domain pair is required to confer antigen binding specificity (such as, for example, Fab- or scFv-formatted antigen binding domains).

[0190] As used herein, the term “hypervariable region” (“HVR”) refers to each of the regions of an antibody variable domain which are hypervariable in sequence and / or form structurally defined loops (“hypervariable loops”). Generally, traditional antibodies comprise a set of six HVRs: (1) three in the VH domain (Hl, H2, and H3), and (2) three in the VL domain (LI, L2, L3). HVRs generally comprise amino acid residues from the hypervariable loops and / or from “complementarity determining regions” (“CDRs”), the latter being of highest sequence variability and / or involved in antigen recognition.Attorney Docket: 53080.4002 / WO

[0191] As used herein, the term “framework region” (“FR”) refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains: FR1, FR2, FR3, and FR3. Generally, the framework regions and complementarity determining regions are arranged in the following configuration: FR1-CDR-FR2-CDR2-FR3 -CDR3 -FR4.

[0192] As used herein, the terms “Fc domain,” “Fc region,” or “Fc,” which can be used interchangeably, is meant the polypeptide comprising the constant region of an antibody, in some instances, excluding all of the first constant heavy domain (i.e., CHI) or a portion thereof, and in some cases, optionally including all or part of the hinge region. For IgG, the Fc domain comprises immunoglobulin domains CH2 and CH3, and optionally all or a portion of the hinge region between CHI and CH3. Thus, in some cases, the Fc domain includes, from N-terminus to C-terminus: (i) CH2-CH3, (ii) hinge-CH2-CH3. In many preferred embodiments, the Fc domain is that from IgGl, or a variant thereof. In some other embodiments, the Fc domain is that from IgG2, IgG3, or IgG4 (or variants of any thereof).

[0193] As used herein, the term “heavy chain constant region” refers to the CHl-hinge-CH2-CH3 portion of an antibody (or fragment thereof), excluding the variable heavy domain. In EU numbering, human IgGl corresponds to amino acid residues 118-448. By “heavy chain constant region fragment” is meant a heavy chain constant region that contains fewer amino acids from either or both of the N- and C-termini but still retains the ability to form a dimer with another heavy chain constant region.

[0194] As used herein, the terms “hinge region,” “antibody hinge region,” “hinge domain,” or “hinge,” which can be used interchangeably, refer to the flexible polypeptide comprising the amino acids between the first and second constant heavy domains of an antibody. Structurally, the IgGl CHI domain ends at EU position 215, and the IgG CH2 domain begins at residue EU position 231. Thus, for IgG, the antibody hinge is herein defined to include positions 216 (E216 in IgGl) to 230 (P230 in IgGl), wherein the numbering is according to the EU index as in Kabat. In some cases, a “hinge fragment” is used, which contains fewer amino acids at either or both of the N- and C-termini of the hinge domain.

[0195] As will be appreciated by those skilled in the art, the exact numbering and placement of the CDRs can be different among different numbering systems. A useful comparison of CDR numbering conventions is described in, for example, Lafranc et al., Dev. Comp. Immunol.Attorney Docket: 53080.4002 / WO27(1): 55-77 (2003), the contents of which are incorporated by reference in their entirety, with particularity for CDR numbering conventions. As will also be appreciated by those skilled in the art, the exact numbering and placement of the heavy chain constant region domains (i.e., CHI, hinge, CH2, and CH3 domains) can be different amount different numbering systems. Useful comparisons of heavy chain constant region numbering are described in, for example, Edelman et al., 1969, Proc Natl Acad Sci USA 63:78-85 and Kabat et al., 1991, Sequences of Proteins of Immunological Interest, 5th Ed., United States Public Health Service, National Institutes of Health, Bethesda, the contents of which are both incorporated by reference in their entirety, with particularity for heavy chain constant region numbering schemes.

[0196] Unless otherwise stated otherwise, throughout the present specification, the Kabat numbering system is generally used when referring to a residue in the variable domain (approximately, residues 1-107 of the light chain variable region, and residues 1-113 of the heavy chain variable region) and the EU numbering system for Fc regions (see, e.g., Kabat et al., supra (1991)).

[0197] Generally, the light chain of an antibody comprises two domains: (i) the variable light (VL) domain, which include light chain CDRs (vlCDRl-3), and (ii) a constant light (CL) domain.

[0198] As used herein, the term “effector function” means a biochemical event that results from the interaction of an antibody Fc region with an Fc receptor or ligand. Effector functions include, but are not limited to, “antibody-dependent cellular cytotoxicity” (ADCC), “antibody-dependent cellular phagocytosis” (ADCP), and “complement-dependent cytotoxicity” (CDC).

[0199] As used herein, the term “antibody-dependent cellular cytotoxicity” (ADCC) refers to the cell-mediated reaction, wherein nonspecific cytotoxic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause lysis of the target cell. Generally, ADCC is correlated with binding to FcyRIIIa, where increased binding to FcyRIIIa leads to an increase in ADCC activity.

[0200] As used herein, the term “antibody-dependent cellular phagocytosis” (ADCP) refers to the cell-mediated reaction wherein nonspecific phagocytic cells that express FcyRs recognize bound antibody on a target cell and subsequently cause phagocytosis of the target cell.

[0201] As used herein, the term “complement-dependent cytotoxicity” (CDC) refers to a mechanism by which an antibody binds a target cells, activating the complement system (anAttorney Docket: 53080.4002 / WOinnate immune defense) to form a membrane attack complex (MAC) that lyses and kills the target cell.

[0202] As used herein, the term “half-life” of an agent can refer to the time it takes for the amount or concentration of an agent to be reduced by half of a starting amount administered into the serum or tissue of an organism or subject, relative to such amount or concentration at the time of administration into the serum or tissue of an organism or subject, or to any other defined time-point. “Half-life” can also refer to the time it takes for the agent to lose half of its pharmacologic, physiologic, or other activity, relative to such activity at the time of administration into the serum or tissue of an organism or subject, or relative to any other defined time-point. Half-life may also refer to the terminal half-life, or terminal elimination rate of an antibody exhibiting a biphasic or 2-compartmental pharmacokinetic behavior, where the terminal elimination rate is reflected in a linear slope on a semilogarithmic concentration-time plot. In some instances, the terminal half-life becomes evident after a distribution phase, which can be the result of distribution throughout various cell compartments, or as a result of target mediated drug disposition (TMDD) which results from specific binding to primary or secondary targets in the body. The half-life can be measured in serum (i.e., “serum half-life”) and / or any one or more selected tissues.

[0203] As used herein, the terms “host cell” and “recombinant cell” refer to an individual cell or a cell culture that can be or has been a recipient of any recombinant vector(s) or isolated polynucleotide(s). A host cell can be a transfected, transformed, transduced, or infected cell of any origin, including, but not limited to, prokaryotic, eukaryotic, mammalian, avian, insect, plant, or bacteria cells, or it can be of any origin that can be used to propagate a nucleic acid described herein. A host cell includes cells transfected or infected in vivo or in vitro with a recombinant vector or a polynucleotide of the invention. A host cell that comprises a recombinant vector of the invention may be called a “recombinant host cell.”

[0204] Host cells can include, without limitation, the cells of mammals, plants, insects, fungi, and bacteria. Bacterial cells include, without limitation, the cells of Gram-positive bacteria, such as, for example, species of the genus Bacillus, Streptomyces, and Staphylococcus, and cells of Gram-negative bacteria, such as, for example, cells of the genus Escherichia and Pseudomonas. Fungal cells can include, without limitation, yeast cells, such as, for example, Saccharomyces, Pichia pastoris, and Hansenula polymorpha. Insect cells can include, without limitation, cells ofAttorney Docket: 53080.4002 / WODrosophila and Sf9 cells. Plant cells include, without limitations, cells from crop plants, medicinal or ornamental plants or bulbs. Suitable mammal cells for the present invention include, but are not limited to, epithelial cell lines (e.g., porcine epithelial cells), osteosarcoma cell lines, neuroblastoma cell lines, epithelial carcinomas, glial cells, liver cell lines, Chinese hamster ovary (CHO) cells, COS cells, BHK cells, HeLa cells, D3 cells of the line of murine embryonic stem cells (mESCs), human embryonic stem cells (e.g., HS293 cells and BG01V cells), NIH 3T3 cells, human embryonic kidney (HEK) 293T cells, human mesenchymal stem cells (hMSCSs), and the like.

[0205] As used herein, the terms “cell,” “cell culture,” “cell line,” and “host cell” refer not only to the particular cell, cell culture, cell line, or host cell, but also to the progeny or potential progeny of such a cell, cell culture, cell line, or host cell, without regard to the number of transfers or passages in culture. It should be understood that not all progeny are exactly identical to the parental cell. This is because certain modifications may occur in succeeding generations due to either mutation (e.g., deliberate or inadvertent mutations) or environmental influences (e.g., methylation or other epigenetic modifications), such that progeny may not, in fact, be identical to the parent cell, but are still included within the scope of the terms as used herein, so long as the progeny retain the same functionality or substantially the same functionality as that of the original cell, cell culture, cell line, or host cell.

[0206] As used herein, the terms “medium” or “culture medium” include any culture medium, solution, solid, semi-solid, or rigid support that may support or contain any host cells, including, but not limited to, bacterial host cells, yeast or fungal host cells, insect host cells, plant host cells, eukaryotic host cells, mammalian host cells, CHO cells, prokaryotic host cells, E. coli host cells, Pseudomonas host cells, and the like, and cell contents. Thus, the term may encompass medium in which the host cell has been grown, (e.g., medium into which a polypeptide has been secreted, including medium either before, during, or after a proliferation step). The term also may encompass buffers or other reagents that contain host cell lysates, such as, for example, in the case where a polynucleotide is produced intracellularly, and the host cells are lysed or disrupted to release the polypeptide.

[0207] As used herein, the term “recombinant,” with respect to a nucleic acid molecule, refers to a polynucleotide of genomic, cDNA, viral, semisynthetic, and / or synthetic origin which, by virtue of its own origin or manipulation, is not associated with all or a portion of theAttorney Docket: 53080.4002 / WOpolynucleotide with which it is associated in nature. The term “recombinant,” as used with respect to a protein or polypeptide, refers to a polypeptide produced by expression of a recombinant polynucleotide. The term “recombinant,” as used with respect to a host cell, refers to a host cell into which a recombinant polynucleotide or vector comprising a recombinant polynucleotide has been introduced.

[0208] As used herein, the term “operably linked” refers to a physical or functional linkage between two or more elements (e.g., polypeptide sequences or polynucleotide sequences) that permits them to operate in their intended fashion. For example, an operable linkage between a polynucleotide of interest and a regulatory sequence (such as, for example, a promoter) is a functional link that allows for expression of the polynucleotide of interest. In this sense, the term “operably linked” refers to the positioning of a regulatory region and a coding sequence to be transcribed so that the regulatory region is effective for regulating transcription or translation of the coding sequence of interest. Thus, a promoter is in an operable linkage with a nucleic acid sequence if it can mediate transcription of the nucleic acid sequence. It should be understood that elements that are operably linked may be contiguous or non-contiguous. In the context of a polypeptide, “operably linked” refers to a physical linkage (e.g., directly, or indirectly linked) between amino acid sequences (e.g., different segments, modules, or domains) to provide for a described activity of the polypeptide.

[0209] As used herein, the terms “subject” or an “individual” for purposes of treatment can generally refer to any animal classified as a mammal (including but not limited to humans, primates, and / or non-human primates), domestic animals, farm animals, zoo animals, research animals, sports animals, and / or pet animals, such as dogs, horses, cats, cows, etc. In many embodiments, the subject is a human subject.

[0210] As used herein, the singular forms “a,” “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an antigen” includes mixtures of antigens; reference to “a pharmaceutically acceptable carrier” includes mixtures of two or more such carriers, and the like. As such, the terms “a” (or “an”), “one or more,” and “at least one” can be used interchangeably herein.

[0211] Furthermore, “and / or” where used herein is to be taken as specific disclosure of each of the two specified features or components with or without the other. Thus, the term “and / or” asAttorney Docket: 53080.4002 / WOused in a phrase such as “A and / or B” herein is intended to include “A and B,” “A or B,” “A (alone)”, and “B (alone)”.

[0212] As used herein, the term “about” a value (or parameter) refers to ±10% of a stated value. When referring to a range of values (or parameters), the term “about” refers to ±10% of the upper limit and -10% of the lower limit of a stated range of values. When a range of values is provided, it is to be understood that each intervening value between the upper and lower limit of that range, and any other stated or intervening value in that stated range, is encompassed within the scope of the present disclosure. Where the stated range includes upper and / or lower limits, ranges excluding either of those included limits are also included in the present disclosure.

[0213] It is appreciated that certain features of the disclosure, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the disclosure, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination. All combinations of the embodiments pertaining to the disclosure are specifically embraced by the present disclosure and are disclosed herein just as if each and every combination was individually and explicitly disclosed. In addition, all sub-combinations of the various embodiments and elements thereof are also specifically embraced by the present disclosure and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.II. OVERVIEW

[0214] It is generally thought that antibodies with short serum half-lives are insufficient to treat autoimmune diseases characterized by B cell pathogenesis, as well as B cell malignancies.However, select B cell depleting antibodies described herein have surprisingly strong effects on B cell depletion, meaning that such antibodies will also have surprising efficacy in treating select B cell autoimmune disease and B cell cancers. Further, the antibodies described herein had the effect of, following depletion of pathological B cells, remodeling of select B cell compartments characterized by an increased ratio of naive B cells to memory B cells. In certain embodiments, such antibodies are B cell depleting antibodies comprising at least one antigen binding domain configured to specifically bind CD 19 or CD20.Attorney Docket: 53080.4002 / WO

[0215] In one exemplary embodiment, provided herein is a method for rapid B cell depletion in a subject in need thereof, wherein the method comprises administering a sufficient amount of a B cell depleting antibody to the subject, wherein the B cell depleting antibody comprises an antigen binding domain that specifically binds CD19. In some further exemplary embodiments, an antiCD 19 B cell depleting antibody described herein has a serum half-life that is less than about 7 days, less than about 2-3 days, or less than about 24 hours. In another exemplary embodiment, the method comprises administering a sufficient amount of a B cell depleting antibody to the subject, wherein the B cell depleting antibody comprises an antigen binding domain that specifically binds CD20. In some further exemplary embodiments, an anti-CD20 B cell depleting antibody described herein has a serum half-life that is less than about 7 days, less than about 2-3 days, or less than about 24 hours. In yet another exemplary embodiment, the method comprises administering a bispecific or multispecific anti-CD19 x anti-TABD B cell depleting antibody, or a bispecific or multispecific anti-CD20 x anti-TABD B cell depleting antibody. In further exemplary embodiments, the bispecific / multispecific B cell depleting antibody described herein has a serum half-life that is less than about 7 days, less than about 2-3 days, or less than about 24 hours.

[0216] Any of the B cell depleting antibodies described herein can also be used for treating autoimmune diseases characterized by B cell pathogenesis or for treating B cell malignancies.TIT. METHOD(S) OF USE

[0217] As will be appreciated by one skilled in the art, any aspects and embodiments of the methods of use described herein can utilize any of the aspects and / or embodiments of the compositions described herein and can further utilize any of the methods of making the compositions described herein.A. Methods for Rapid B Ceil Depletion and Remodeling

[0218] Embodiment (A): In one aspect, the present disclosure provides a method for rapidly depleting circulating B cells in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein: (a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD)Attorney Docket: 53080.4002 / WOselected from a group including: (i) an anti-CD19 ABD, and (ii) an anti-CD20 ABD; (b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; and (c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject.

[0219] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration. In some preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least an 80% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration. In some more preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0220] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 99% (or higher) depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0221] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates a depletion in circulating B cells such that circulating B cells are below a lower level of detectability of an assay within 24 hours of the first administration, and a baseline level of circulating B cells determined prior to the first administration is detectable (i.e., equal to or greater than the lower level of detectability of the assay).

[0222] In some embodiments, the circulating B cells (in need of depletion) comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (also referred to as plasma cells), or any combination thereof.Attorney Docket: 53080.4002 / WO

[0223] In some embodiments, depletion of the circulating B cells occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In some further embodiments, depletion of the circulating B cells occurs for a period of at least 5 or more days. In some other further embodiments, depletion of the circulating B cells occurs for a period of at least 5 or more weeks. In still some other further embodiments, depletion of the circulating B cells occurs for a period of at least 5 or more months.

[0224] In some embodiments, a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, wherein the remodeling is characterized by an increased ratio of circulating CD27' B cells (i.e., naive B cells) to circulating CD27+B cells (i.e., memory B cells) as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration. In some further embodiments, the B cell niche comprises B cells resident to the circulatory system. In still some further embodiments, the remodeling of the B cell niche occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In yet still some further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more days. In yet still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more weeks. In yet still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more months.

[0225] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration. In some preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least an 80% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration. In some more preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells, as compared to the baseline level of tissue-resident B cells determined prior to the first administration.Attorney Docket: 53080.4002 / WO

[0226] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 30% to 40%, 40% to 50%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 99% (or higher) depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration.

[0227] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates a depletion in tissue-resident B cells located in one or more B cell compartments such that the tissue-resident B cells in at least one B cell compartment are below a lower level of detectability of an assay, and a baseline level of tissue-resident B cells determined prior to the first administration is detectable (i.e., equal to or greater than the lower level of detectability of the assay).

[0228] In some embodiments, the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof. In some further embodiments, at least one of the one or more B cell compartments comprises one or more lymph nodes, and the tissue-resident B cells (in need of depletion) comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the spleen, and the tissue-resident B cells (in need of depletion) comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises bone marrow, and the tissue-resident B cells (in need of depletion) comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises mucosa-associated lymphoid tissue (MALT), and the tissue-resident B cells (in need of depletion) comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the thymus, and the tissue-resident B cells (in need of depletion) comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the skin, and the tissue-resident B cells (in need of depletion) comprise:Attorney Docket: 53080.4002 / WO(A) memory B cells, (B) plasmablasts, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the liver, and the tissue-resident B cells (in need of depletion) comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

[0229] In some embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In some further embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for a period of at least 5 or more days. In some other further embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for a period of at least 5 or more weeks. In still some other further embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for a period of at least 5 or more months.

[0230] In some embodiments, at least one of the one or more B cell compartments exhibits remodeling of a B cell niche subsequent to the depletion of tissue-resident B cells, wherein the remodeling is characterized by an increased ratio of tissue-resident CD27‘ B cells to tissueresident CD27+B cells as compared to a baseline ratio of tissue-resident CD27' B cells to tissueresident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells. In some further embodiments, the remodeling of the B cell niche occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In still some further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more days. In still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more weeks. In still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more months.

[0231] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest. In some further embodiments, individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof. In still some further embodiments, individual instances of the one or more additional ABDs are in a Fab format. In still some other further embodiments, individualAttorney Docket: 53080.4002 / WOinstances of the one or more additional ABDs are in a scFv format. In still some other further embodiments, individual instances of the one or more additional ABDs are in a VHH format.

[0232] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest, wherein at least one of the one or more target antigens of interest comprises: (i) a4 7 integrin, (ii) av integrin subunit av 1, (iii) av integrin subunit av03, (iv) av integrin subunit av05, (v) av integrin subunit av06, (vi) av integrin subunit avP8, (vii) activin type II receptor, (viii) APRIL, (ix) AXL, (x) BAFF, (xi) BAFF / CD19, (xii) BAFF-R, (xiii) BCMA, (xiv) B7-H3, (xv) BLyS, (xvi) CA-125 mimic, (xvii) CCL2, (xviii) CD137, (xix) CD19, (xx) CD20, (xxi) CD20 / CD3, (xxii) CD22, (xxiii) CD23, (xxiv) CD25, (xxv) CD27, (xxvi) CD30, (xxvii) CD38, (xxviii) CD3, (xxix) CD40, (xxx) CD47, (xxxi) CD52, (xxxii) CD73, (xxxiii) CD79b, (xxxiv) CEACAM5, (xxxv) CGRP, (xxxvi) CGRP receptor, (xxxvii) Clostridium difficile toxin A, (xxxviii) Clostridium difficile toxin B, (xxxix) complement C5, (xl) CTGF, (xli) CTLA-4, (xlii) DLL4, (xliii) DR5, (xliv) Ebola virus glycoprotein, (xlv) EGFR, (xlvi) ERBB2, (xlvii) FAP, (xlviii) FGF23, (xlix) Frizzled receptors, (1) GDF15, (li) GFAP, (lii) GD2, (liii) GM-CSF, (liv) GM-CSFRa, (Iv) HER2, (Ivi) HER3, (Ivii) HIV-1 envelope glycoprotein, (Iviii) HIV-1 gp!20, (lix) human 4p7 integrin heterodimer, (lx) human CD161, (Ixi) human CD 19, (Ixii) human PD-L1, (Ixiii) IFNa, (Ixiv) IFNAR1, (Ixv) fFNy, (Ixvi) IgE, (Ixvii) IgG4, (Ixviii) IL-ip, (Ixix) IL-12 / IL-23p40, (Ixx) IL-13, (Ixxi) IL-13Ral, (Ixxii) IL-15, (Ixxiii) IL-17A, (Ixxiv) IL-17A / IL-17F, (Ixxv) IL-17RA, (Ixxvi) IL-20, (Ixxvii) IL-22, (Ixxviii) IL-22R, (Ixxix) IL-2 , (Ixxx) IL-31, (Ixxxi) IL-33, (Ixxxii) IL-33R / ST2, (Ixxxiii) IL-4Ra, (Ixxxiv) IL-5, (Ixxxv) IL-5Ra, (Ixxxvi) IL-6, (Ixxxvii) IL-6R, (Ixxxviii) KIR2DL1 / 2 / 3, (Ixxxix) LAG-3, (xc) LINGO-1, (xci) MAdCAM-1, (xcii) MASP-2, (xciii) MET, (xciv) mesothelin, (xcv) myostatin, (xcvi) Nectin-4, (xcvii)NGF, (xcviii) Notch2 / 3, (xcix) OSMRp, (c) 0X40, (ci) P-selectin, (cii) PCSK9, (ciii) PD-1, (civ) PD-L1, (cv) PDGF-B, (cvi) plasma kallikrein, (cvii) RANKL, (cviii) rabies virus glycoprotein, (cix) RGMa, (ex) RSPO3, (cxi) SARS-CoV-2 spike protein, (cxii) SARS-CoV-2 RBD, (cxiii) sclerostin, (cxiv) SLAMF7, (cxv) sortilin, (cxvi) Staphylococcus aureus alpha toxin, (cxvii) TGF-P, (cxviii) TGF-P & PD-L1, (cxix) TIGIT, (exx) ticagrelor, (exxi) TIM-3, (cxxii) tissue factor, (cxxiii) tissue factor pathway inhibitor, (cxxiv) TNFa, (exxv) Trop-2, (cxxvi) TSLP, (cxxvii) VEGF-A, (cxxviii) VEGF-B, (cxxix) VEGFR-2, or (exxx) von Willebrand factor (vWF).Attorney Docket: 53080.4002 / WO

[0233] In some preferred embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, or (xxxvii) CD103.

[0234] In some even more preferred embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, or (xxxvii) human CD 103.

[0235] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered for 5 or fewer consecutive days. In some further embodiments, administration is for 4 or fewer consecutive days, 3 or fewer consecutive days, or for 2 consecutive days.

[0236] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

[0237] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route. In some preferred embodiments, administration is intravenous. In some other preferred embodiments, administration is subcutaneous.

[0238] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered as a bolus injection, as an IV infusion, or as a continuous infusion.

[0239] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, orAttorney Docket: 53080.4002 / WO(iii) less than about 24 hours. In some further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 7 days. In some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 2-3 days. In still some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 24 hours.

[0240] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains. In some further embodiments, at least one of the one or more Fc domains comprises a variant Fc domain. In some other further embodiments, the B cell depleting antibody comprises one or more variant Fc domains (e.g., two or more, three or more, four or more, etc.).

[0241] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that enhance FcyR binding activity. In some further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity comprise: 236A, S239D, S239E, I332E, I332D, S239D / I332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243 A, 243L, 264A, 264V, or 299T. In an exemplary embodiment, the one or more amino acid substitutions that enhance FcyR binding activity comprise S239D / 1332E.Additional amino acid substitutions that enhance FcyR binding activity finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that enhance FcyR binding activity of an antibody.

[0242] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that enhance FcRn activity and / or serum half-life of the B cell depleting antibody. In some further embodiments, the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life of the B cell depleting antibody comprise: (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), or (iii) M428L / N434S (LS). Additional amino acid substitutions that enhance FcRn activity and / or serum half-life finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents ofAttorney Docket: 53080.4002 / WOwhich are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that enhance FcRn activity and / or serum half-life of an antibody.

[0243] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that ablate a Protein A binding site of the variant Fc domain. In some further embodiments, the one or more amino acid substitutions that ablate a Protein A binding site of the variant Fc domain comprise H435R / Y436F (RF). Additional amino acid substitutions that ablate a Protein A binding site of the variant Fc domain finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos.2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that ablate a Protein A binding site of the variant Fc domain of an antibody.

[0244] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that promote heterodimerization of the first (variant) Fc domain with the second (variant) Fc domain. Nonlimiting examples of heterodimerization promoting Fc variants finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication No. 2022 / 0289839, incorporated by reference in its entirety.

[0245] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that ablate FcyR binding activity. In some further embodiments, the one or more amino acid substitutions that ablate FcyR binding activity comprise: (i) P329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv) L234F / L235E / P331S (LFLEPS), or (v) L234F / L235E / P329G (LFLEPG). Additional amino acid substitutions that ablate FcyR binding activity finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos.2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that ablate FcyR binding activity of an antibody.

[0246] In some embodiments, the B cell depleting antibody is a GEM-DIMER-formatted antibody. The contents of U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116 are incorporated by reference in their entirety, with particularity for GEM-DIMER antibody formats described therein. In one exemplary embodiment, the GEM-DIMER-formatted antibody comprises: (i) a first heavy chain comprisingAttorney Docket: 53080.4002 / WOthe amino acid sequence of SEQ ID NO: 81 ; (ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36; (iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125; and (iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116. In some other exemplary embodiments, the GEM-DIMER-formatted antibody comprises any one of protein IDs [21-01]-[21-130], as shown in Fig. 21.

[0247] In many embodiments, the subject comprises a human subject.

[0248] Embodiment (A)(1): In some embodiments, the at least one antigen binding domain (ABD) is an anti-CD19 ABD, and the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement. In some further embodiments, the anti-CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD19 ABD is in a Fab format. In still some other further embodiments, the anti-CD19 ABD is in a scFv format. In still some other further embodiments, the anti-CD19 ABD is in a VHH format.

[0249] In some embodiments, the anti-CD19 ABD specifically binds human CD19. In some further embodiments, the anti-human CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti -human CD 19 ABD is in a Fab format. In still some other further embodiments, the anti-human CD19 ABD is in a scFv format. In still some other further embodiments, the anti -human CD 19 ABD is in a VHH format.

[0250] In some embodiments, the anti-CD19 ABD specifically binds human CD19, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from tafasitamab, obexelimab, or inebilizumab.

[0251] In some embodiments, the anti-CD19 ABD specifically binds human CD19, wherein the anti-human CD19 ABD comprises the CD19-bindning scFv derived from blinatumomab.

[0252] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269,Attorney Docket: 53080.4002 / WOrespectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ IDNOs: 281 and 285, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 194 and 198, respectively.

[0253] In some other embodiments, the anti -CD 19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl -3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), and (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises the amino acid sequences of SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3).

[0254] In some other embodiments, the anti -human CD 19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iii) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113Attorney Docket: 53080.4002 / WO(vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0255] Embodiment (A)(2): In some embodiments, the at least one antigen binding domain (ABD) is an anti-CD20 ABD, and the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement. In some further embodiments, the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD20 ABD is in a Fab format. In still some other further embodiments, the anti-CD20 ABD is in a scFv format. In still some other further embodiments, the anti-CD20 ABD is in a VHH format.

[0256] In some embodiments, the anti-CD20 ABD specifically binds human CD20. In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD20 ABD is in a Fab format. In still some other further embodiments, the anti-human CD20 ABD is in a scFv format. In still some other further embodiments, the anti-human CD20 ABD is in a VHH format.

[0257] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from rituximab, ocrelizumab, obinutuzumab, ofatumumab, or ublituximab.

[0258] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, and (E) SEQ ID NOs: 249 and 253, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 186 and 190.

[0259] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from aAttorney Docket: 53080.4002 / WOVH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ IDNOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl -3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), and (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3)-

[0260] In some other embodiments, the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iii) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0261] Embodiment (A)(3): In some embodiments, the B cell depleting antibody comprises a bispecific antibody (or antigen binding fragment thereof). In some further embodiments, the method comprises administering an anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof).Attorney Docket: 53080.4002 / WO

[0262] In some embodiments, (i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD 19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or (ii) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0263] In some embodiments, the anti-CD19 ABD specifically binds human CD19. In some further embodiments, the anti-human CD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti -human CD 19 ABD is in a Fab format. In still some other further embodiments, the anti-human CD19 ABD is in a scFv format. In still some other further embodiments, the anti -human CD 19 ABD is in a VHH format.

[0264] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from tafasitamab, obexelimab, or inebilizumab.

[0265] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises the CD19-bindning scFv derived from blinatumomab.

[0266] In some embodiments, the anti-CD19 ABD specifically binds human CD19, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 194 and 198, respectively.

[0267] In some other embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a set of complementarity determining regionsAttorney Docket: 53080.4002 / WO(CDRs) from a VH-VL domain pair (vhCDRl -3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), and (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises the amino acid sequences of SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3).

[0268] In some other embodiments, the anti -human CD 19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iii) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0269] In some embodiments, the anti-CD20 ABD specifically binds human CD20. In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD20 ABD is in a FabAttorney Docket: 53080.4002 / WOformat. In still some other further embodiments, the anti-human CD20 ABD is in a scFv format. In still some other further embodiments, the anti-human CD20 ABD is in a VHH format.

[0270] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from rituximab, ocrelizumab, obinutuzumab, ofatumumab, or ublituximab.

[0271] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, and (E) SEQ ID NOs: 249 and 253, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 186 and 190.

[0272] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), and (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3).

[0273] In some other embodiments, the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl -3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iii) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variableAttorney Docket: 53080.4002 / WOlight chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0274] Embodiment (A)(4) In some embodiments, the B cell depleting antibody comprises a multispecific antibody (or antigen binding fragment thereof). In some further embodiments, the method comprises administering a multispecific antibody (or antigen binding fragment thereof), and the multispecific antibody (or antigen binding fragment thereof) comprises: (A) an anti-CD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest.

[0275] In some embodiments, (i) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or (ii) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complementdependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0276] In some embodiments, the anti-CD19 ABD specifically binds human CD 19. In some further embodiments, the anti-human CD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD19 ABD is in a FabAttorney Docket: 53080.4002 / WOformat. In still some other further embodiments, the anti-human CD19 ABD is in a scFv format. In still some other further embodiments, the anti -human CD 19 ABD is in a VHH format.

[0277] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from tafasitamab, obexelimab, or inebilizumab.

[0278] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises the CD19-bindning scFv derived from blinatumomab.

[0279] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 194 and 198, respectively.

[0280] In some other embodiments, the anti -CD 19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRI-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), and (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises the amino acid sequences of SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3).

[0281] In some other embodiments, the anti -human CD 19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iii) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. In some other embodiments, the set ofAttorney Docket: 53080.4002 / WOvariable heavy chain complementarity determining regions (vhCDRl-3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0282] In some embodiments, the anti-CD20 ABD specifically binds human CD20. In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti -human CD20 ABD is in a Fab format. In still some other further embodiments, the anti-human CD20 ABD is in a scFv format. In still some other further embodiments, the anti-human CD20 ABD is in a VHH format.

[0283] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from rituximab, ocrelizumab, obinutuzumab, ofatumumab, or ublituximab.

[0284] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, and (E) SEQ ID NOs: 249 and 253, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 186 and 190.

[0285] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A)Attorney Docket: 53080.4002 / WOSEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), and (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3).

[0286] In some other embodiments, the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl -3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iii) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0287] In some embodiments, individual instances of the one or more additional ABDs that specifically bind one or more target antigens of interest are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof. In some further embodiments, individual instances of the one or more additional ABDs are in a Fab format. In some other further embodiments, individual instances of the one or more additional ABDs are in a scFv format. InAttorney Docket: 53080.4002 / WOsome other further embodiments, individual instances of the one or more additional ABDs are in a VHH format.

[0288] In some embodiments, multispecific antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest, wherein at least one of the one or more target antigens of interest comprises: (i) a4 7 integrin, (ii) av integrin subunit avPL (iii) av integrin subunit avP3, (iv) av integrin subunit avP5, (v) av integrin subunit vP6, (vi) av integrin subunit avP8, (vii) activin type II receptor, (viii) APRIL, (ix) AXL, (x) BAFF, (xi) BAFF / CD19, (xii) BAFF-R, (xiii) BCMA, (xiv) B7-H3, (xv) BLyS, (xvi) CA-125 mimic, (xvii) CCL2, (xviii) CD137, (xix) CD19, (xx) CD20, (xxi) CD20 / CD3, (xxii) CD22, (xxiii) CD23, (xxiv) CD25, (xxv) CD27, (xxvi) CD30, (xxvii) CD38, (xxviii) CD3, (xxix) CD40, (xxx) CD47, (xxxi) CD52, (xxxii) CD73, (xxxiii) CD79b, (xxxiv) CEACAM5, (xxxv) CGRP, (xxxvi) CGRP receptor, (xxxvii) Clostridium difficile toxin A, (xxxviii) Clostridium difficile toxin B, (xxxix) complement C5, (xl) CTGF, (xli) CTLA-4, (xlii) DLL4, (xliii) DR5, (xliv) Ebola virus glycoprotein, (xlv) EGFR, (xlvi) ERBB2, (xlvii) FAP, (xlviii) FGF23, (xlix) Frizzled receptors, (1) GDF15, (li) GFAP, (lii) GD2, (liii) GM-CSF, (liv) GM-CSFRa, (Iv) HER2, (Ivi) HER3, (Ivii) HIV-1 envelope glycoprotein, (Iviii) HIV-1 gpl20, (lix) human a4p7 integrin heterodimer, (lx) human CD161, (Ixi) human CD 19, (Ixii) human PD-Ll, (Ixiii) IFNa, (Ixiv) IFNAR1, (Ixv) IFNy, (Ixvi) IgE, (Ixvii) IgG4, (Ixviii) IL-ip, (Ixix) IL-12 / IL-23p40, (Ixx) IL-13, (Ixxi) IL-13Ral, (Ixxii) IL-15, (Ixxiii) IL-17A, (Ixxiv) IL- 17A / IL- 17F, (Ixxv) IL-17RA, (Ixxvi) IL-20, (Ixxvii) IL-22, (Ixxviii) IL-22R, (Ixxix) IL-2, (Ixxx) IL-31, (Ixxxi) IL-33, (Ixxxii) IL-33R / ST2, (Ixxxiii) IL-4Ra, (Ixxxiv) IL-5, (Ixxxv) IL-5Ra, (Ixxxvi) IL-6, (Ixxxvii) IL-6R, (Ixxxviii) KIR2DL1 / 2 / 3, (Ixxxix) LAG-3, (xc) LINGO-1, (xci) MAdCAM-1, (xcii) MASP-2, (xciii) MET, (xciv) mesothelin, (xcv) myostatin, (xcvi) Nectin-4, (xcvii) NGF, (xcviii) Notch2 / 3, (xcix) OSMRp, (c) 0X40, (ci) P-selectin, (cii) PCSK9, (ciii) PD-1, (civ) PD-Ll, (cv) PDGF-B, (cvi) plasma kallikrein, (cvii) RANKL, (cviii) rabies virus glycoprotein, (cix) RGMa, (ex) RSPO3, (cxi) SARS-CoV-2 spike protein, (cxii) SARS-CoV-2 RBD, (cxiii) sclerostin, (cxiv) SLAMF7, (cxv) sortilin, (cxvi) Staphylococcus aureus alpha toxin, (cxvii) TGF-P, (cxviii) TGF-P & PD-L1, (cxix) TIGIT, (exx) ticagrelor, (exxi) TIM-3, (cxxii) tissue factor, (cxxiii) tissue factor pathway inhibitor, (cxxiv) TNFa, (exxv) Trop-2, (cxxvi) TSLP, (cxxvii) VEGF-A, (cxxviii) VEGF-B, (cxxix) VEGFR-2, or (exxx) von Willebrand factor (vWF).Attorney Docket: 53080.4002 / WO

[0289] In some preferred embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, or (xxxvii) CD103.

[0290] In some even more preferred embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, or (xxxvii) human CD 103.B. Methods for Treating Autoimmune Disease

[0291] Embodiment (B): In another aspect, the present disclosure provides a method for treating an autoimmune disease characterized by B cell pathogenesis in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein: (a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD) selected from a group including: (i) an anti-CD19 ABD, and (ii) an anti-CD20 ABD; (b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; and (c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject, thereby treating the autoimmune disease characterized by B cell pathogenesis in the subject.Attorney Docket: 53080.4002 / WO

[0292] In some embodiments, the autoimmune disease characterized by B cell pathogenesis is selected from a group including: (i) acquired hemophilia, (ii) alopecia areata, (iii) amyloidosis, (iv) anti-NMDA receptor encephalitis (also referred to as autoimmune encephalitis), (v) antiphospholipid syndrome, (vi) autoimmune Addison’s disease, (vii) autoimmune angioedema, (viii) autoimmune autonomic ganglionopathy, (ix) autoimmune encephalitis (also referred to as acute disseminated encephalomyelitis, ADEM), (x) autoimmune gastritis, (xi) autoimmune hemolytic anemia, (xii) autoimmune hepatitis, (xiii) autoimmune hyperlipidemia, (xiv) autoimmune hypophysitis (also referred to as lymphocytic hypophysitis), (xv) autoimmune inner ear disease (also referred to as autoimmune sudden sensorineural hearing loss, Meniere’s disease), (xvi) autoimmune Interstitial Lung Disease (also referred to as fibrosing alveolitis, idiopathic pulmonary fibrosis), (xvii) autoimmune lymphoproliferative syndrome, (xviii) autoimmune myelofibrosis, (xix) autoimmune myocarditis (also referred to as giant cell myocarditis), (xx) autoimmune oophoritis (also referred to as testicular autoimmunity, autoimmune orchitis), (xxi) autoimmune pancreatitis, (xxii) autoimmune polyglandular syndromes (also referred to as Schmidt syndrome), (xxiii) autoimmune progesterone dermatitis, (xxiv) autoimmune retinopathy (also referred to as birdshot chorioretinopathy), (xxv) Balo disease (also referred to as concentric sclerosis), (xxvi) bullous pemphigoid, (xxvii) Castleman disease, (xxviii) celiac disease, (xxix) chronic autoimmune urticaria, (xxx) chronic inflammatory demyelinating polyneuropathy, (xxxi) Churg-Strauss syndrome (also referred to as eosinophilic granulomatosis with polyangiitis, EGPA), (xxxii) Cogan’s syndrome, (xxxiii) cold agglutinin disease, (xxxiv) CREST syndrome (also referred to as limited scleroderma, systemic sclerosis), (xxxv) Cronkhite-Canada syndrome, (xxxvi) cryptogenic organizing pneumonia, (xxxvii) dermatitis herpetiformis, (xxxviii) dermatomyositis (also referred to as juvenile myositis), (xxxix) discoid lupus (also referred to as systemic lupus erythematosus, SLE), (xl) Dressier’s syndrome, (xli) eczema (also referred to as atopic dermatitis), (xlii) essential mixed cryoglobulinemia, (xliii) Evans syndrome, (xliv) giant cell arteritis (also referred to as temporal arteritis, Horton’s disease), (xlv) glomerulonephritis (also referred to as lupus nephritis), (xlvi) Goodpasture’s syndrome, (xlvii) granulomatosis with polyangiitis (also referred to as Wegener’s granulomatosis), (xlviii) Graves’ disease (also referred to as thyroid eye disease, Graves’ ophthalmopathy, thyroid-associated orbitopathy), (xlix) Guillain-Barre syndrome, (1) Hashimoto’s thyroiditis (also referred to as autoimmune thyroiditis), (li) Henoch-SchbnleinAttorney Docket: 53080.4002 / WOpurpura, (lii) Hurst’s disease (also referred to as acute hemorrhagic leukoencephalitis), (liii) IgA nephropathy, (liv) IgG4-related sclerosing disease, (Iv) immune thrombocytopenia (also referred to as autoimmune thrombocytopenia purpura), (Ivi) immune-mediated necrotizing myopathy, (Ivii) inclusion body myositis, (Iviii) juvenile idiopathic arthritis (also referred to as adult-onset Still’s disease), (lix) Kawasaki disease, (lx) Lambert-Eaton myasthenic syndrome, (Ixi) leukocytoclastic vasculitis, (Ixii) lichen planus, (Ixiii) lichen sclerosus, (Ixiv) linear IgA disease, (Ixv) lupus nephritis (also referred to as systemic lupus erythematosus, SLE), (Ixvi) Meniere’s disease (also referred to as autoimmune inner ear disease), (Ixvii) microscopic polyangiitis (also referred to as ANCA-associated vasculitis), (Ixviii) mixed connective tissue disease (also referred to as undifferentiated connective tissue disease), (Ixix) mucous membrane pemphigoid (also referred to as ocular cicatricial pemphigoid), (Ixx) multiple sclerosis, (Ixxi) myasthenia gravis, (Ixxii) neuromyelitis optica (also referred to as Devic’s disease), (Ixxiii) optic neuritis, (Ixxiv) palindromic rheumatism, (Ixxv) paraneoplastic cerebellar degeneration, (Ixxvi) paraneoplastic pemphigus, (Ixxvii) pemphigoid gestationis (also referred to as herpes gestationis), (Ixxviii) pemphigus foliaceus, (Ixxix) pemphigus vulgaris, (Ixxx) pernicious anemia, (Ixxxi) Pityriasis lichenoides et varioliformis Acuta (also referred to as Mucha-Habermann disease), (Ixxxii) POEMS syndrome, (Ixxxiii) polyarteritis nodosa, (Ixxxiv) polymyositis, (Ixxxv) primary biliary cholangitis (also referred to as PBC), (Ixxxvi) primary sclerosing cholangitis, (Ixxxvii) pure red cell aplasia, (Ixxxviii) relapsing polychondritis, (Ixxxix) rheumatoid arthritis, (xc) scleritis, (xci) scleroderma (also referred to as systemic sclerosis, CREST syndrome), (xcii) Sjogren’s syndrome (also referred to as Sjogren disease, SjD), and (xciii) systemic lupus erythematosus (also referred to as SLE, discoid lupus, lupus nephritis).

[0293] In some preferred embodiments, the autoimmune disease characterized by B cell pathogenesis is selected from a group including: (i) systemic lupus erythematosus.

[0294] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration. In some preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least an 80% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined priorAttorney Docket: 53080.4002 / WOto the first administration. Tn some more preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0295] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 99% (or higher) depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

[0296] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates a depletion in circulating B cells such that circulating B cells are below a lower level of detectability of an assay within 24 hours of the first administration, and a baseline level of circulating B cells determined prior to the first administration is detectable (i.e., equal to or greater than the lower level of detectability of the assay).

[0297] In some embodiments, the circulating B cells (in need of depletion) comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (also referred to as plasma cells), or any combination thereof.

[0298] In some embodiments, depletion of the circulating B cells occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In some further embodiments, depletion of the circulating B cells occurs for a period of at least 5 or more days. In some other further embodiments, depletion of the circulating B cells occurs for a period of at least 5 or more weeks. In still some other further embodiments, depletion of the circulating B cells occurs for a period of at least 5 or more months.

[0299] In some embodiments, a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, wherein the remodeling is characterized by an increased ratio of circulating CD27' B cells (i.e., naive B cells) to circulating CD27+B cells (i.e., memory B cells) as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration. In some further embodiments, the B cell niche comprises B cells resident to the circulatory system. In still some further embodiments, the remodeling of the B cell niche occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In yet still some furtherAttorney Docket: 53080.4002 / WOembodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more days. In yet still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more weeks. In yet still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more months.

[0300] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration. In some preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least an 80% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration. In some more preferred embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells, as compared to the baseline level of tissue-resident B cells determined prior to the first administration.

[0301] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 30% to 40%, 40% to 50%, 60% to 70%, 70% to 80%, 80% to 90%, or 90% to 99% (or higher) depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration.

[0302] In some other embodiments, the B cell depleting antibody (or antigen binding fragment thereof) effectuates a depletion in tissue-resident B cells located in one or more B cell compartments such that the tissue-resident B cells in at least one B cell compartment are below a lower level of detectability of an assay, and a baseline level of tissue-resident B cells determined prior to the first administration is detectable (i.e., equal to or greater than the lower level of detectability of the assay).

[0303] In some embodiments, the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof. In some further embodiments, at least one of the one or more B cell compartments comprises one or more lymph.1 Horney Docket: 53080.4002 / WOnodes, and the tissue-resident B cells (in need of depletion) comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the spleen, and the tissue-resident B cells (in need of depletion) comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises bone marrow, and the tissue-resident B cells (in need of depletion) comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises mucosa-associated lymphoid tissue (MALT), and the tissue-resident B cells (in need of depletion) comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the thymus, and the tissue-resident B cells (in need of depletion) comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the skin, and the tissue-resident B cells (in need of depletion) comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof. In some other further embodiments, at least one of the one or more B cell compartments comprises the liver, and the tissue-resident B cells (in need of depletion) comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

[0304] In some embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In some further embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for a period of at least 5 or more days. In some other further embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for a period of at least 5 or more weeks. In still some other further embodiments, depletion in tissue-resident B cells located in one or more B cell compartments occurs for a period of at least 5 or more months.

[0305] In some embodiments, at least one of the one or more B cell compartments exhibits remodeling of a B cell niche subsequent to the depletion of tissue-resident B cells, wherein the remodeling is characterized by an increased ratio of tissue-resident CD27‘ B cells to tissue-Attorney Docket: 53080.4002 / WOresident CD27+B cells as compared to a baseline ratio of tissue-resident CD27‘ B cells to tissueresident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells. In some further embodiments, the remodeling of the B cell niche occurs for: (i) a period of at least 5 or more days, (ii) a period of at least 5 or more weeks, or (iii) a period of at least 5 or more months. In still some further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more days. In still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more weeks. In still some other further embodiments, the remodeling of the B cell niche occurs for a period of at least 5 or more months.

[0306] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest. In some further embodiments, individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof. In still some further embodiments, individual instances of the one or more additional ABDs are in a Fab format. In still some other further embodiments, individual instances of the one or more additional ABDs are in a scFv format. In still some other further embodiments, individual instances of the one or more additional ABDs are in a VHH format.

[0307] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest, wherein at least one of the one or more target antigens of interest comprises: (i) a4[37 integrin, (ii) av integrin subunit av01, (iii) av integrin subunit avP3, (iv) av integrin subunit avP5, (v) av integrin subunit avP6, (vi) av integrin subunit avP8, (vii) activin type II receptor, (viii) APRIL, (ix) AXL, (x) BAFF, (xi) BAFF / CD19, (xii) BAFF-R, (xiii) BCMA, (xiv) B7-H3, (xv) BLyS, (xvi) CA-125 mimic, (xvii) CCL2, (xviii) CD137, (xix) CD19, (xx) CD20, (xxi) CD20 / CD3, (xxii) CD22, (xxiii) CD23, (xxiv) CD25, (xxv) CD27, (xxvi) CD30, (xxvii) CD38, (xxviii) CD3, (xxix) CD40, (xxx) CD47, (xxxi) CD52, (xxxii) CD73, (xxxiii) CD79b, (xxxiv) CEACAM5, (xxxv) CGRP, (xxxvi) CGRP receptor, (xxxvii) Clostridium difficile toxin A, (xxxviii) Clostridium difficile toxin B, (xxxix) complement C5, (xl) CTGF, (xli) CTLA-4, (xlii) DLL4, (xliii) DR5, (xliv) Ebola virus glycoprotein, (xlv) EGFR, (xlvi) ERBB2, (xlvii) FAP, (xlviii) FGF23, (xlix) Frizzled receptors, (1) GDF15, (li) GFAP, (lii) GD2, (liii) GM-CSF, (liv) GM-CSFRa, (Iv) HER2, (Ivi) HER3, (Ivii) HIV-1 envelope glycoprotein,.1 Horney Docket: 53080.4002 / WO(Iviii) HIV-1 gp!20, (lix) human 4p7 integrin heterodimer, (lx) human CD161, (Ixi) human CD 19, (Ixii) human PD-L1, (Ixiii) IFNa, (Ixiv) IFNAR1, (Ixv) TFNy, (Ixvi) IgE, (Ixvii) IgG4, (Ixviii) IL-ip, (Ixix) IL-12 / IL-23p40, (Ixx) IL-13, (Ixxi) IL-13Ral, (Ixxii) IL-15, (Ixxiii) IL-17A, (Ixxiv) IL-17A / IL-17F, (Ixxv) IL-17RA, (Ixxvi) IL-20, (Ixxvii) IL-22, (Ixxviii) IL-22R, (Ixxix) IL-2 , (Ixxx) IL-31, (Ixxxi) IL-33, (Ixxxii) IL-33R / ST2, (Ixxxiii) IL-4Ra, (Ixxxiv) IL-5, (Ixxxv) IL-5Ra, (Ixxxvi) IL-6, (Ixxxvii) IL-6R, (Ixxxviii) KIR2DL1 / 2 / 3, (Ixxxix) LAG-3, (xc) LINGO-1, (xci) MAdCAM-1, (xcii) MASP-2, (xciii) MET, (xciv) mesothelin, (xcv) myostatin, (xcvi) Nectin-4, (xcvii)NGF, (xcviii) Notch2 / 3, (xcix) OSMRp, (c) 0X40, (ci) P-selectin, (cii) PCSK9, (ciii) PD-1, (civ) PD-L1, (cv) PDGF-B, (cvi) plasma kallikrein, (cvii) RANKL, (cviii) rabies virus glycoprotein, (cix) RGMa, (ex) RSPO3, (cxi) SARS-CoV-2 spike protein, (cxii) SARS-CoV-2 RBD, (cxiii) sclerostin, (cxiv) SLAMF7, (cxv) sortilin, (cxvi) Staphylococcus aureus alpha toxin, (cxvii) TGF-P, (cxviii) TGF-P & PD-L1, (cxix) TIGIT, (exx) ticagrelor, (exxi) TIM-3, (cxxii) tissue factor, (cxxiii) tissue factor pathway inhibitor, (cxxiv) TNFa, (exxv) Trop-2, (cxxvi) TSLP, (cxxvii) VEGF-A, (cxxviii) VEGF-B, (cxxix) VEGFR-2, or (exxx) von Willebrand factor (vWF).

[0308] In some preferred embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) 1L-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, or (xxxvii) CD103.

[0309] In some even more preferred embodiments, at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-Attorney Docket: 53080.4002 / WO5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, or (xxxvii) human CD103.

[0310] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered for 5 or fewer consecutive days. In some further embodiments, administration is for 4 or fewer consecutive days, 3 or fewer consecutive days, or for 2 consecutive days.

[0311] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

[0312] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route. In some preferred embodiments, administration is intravenous. In some other preferred embodiments, administration is subcutaneous.

[0313] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) is administered by a bolus injection, as an IV infusion, or as a continuous infusion.

[0314] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours. In some further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than 7 days. In some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 2-3 days. In yet still some other further embodiments, the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is less than about 24 hours.

[0315] In some embodiments, the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains. In some further embodiments, at least one of the one or more Fc domains comprises a variant Fc domain. In some other further embodiments, the B cell depleting antibody comprises one or more variant Fc domains (e.g., two or more, three or more, four or more, etc.).

[0316] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that enhance FcyR binding activity. In some further embodiments, the one or more amino acid substitutions that enhance FcyR binding activity comprise: 236A, S239D, S239E, I332E, I332D, S239D / I332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y,Attorney Docket: 53080.4002 / WO239D, 332E / 330L, 243 A, 243L, 264A, 264V, or 299T. Tn an exemplary embodiment, the one or more amino acid substitutions that enhance FcyR binding activity comprise S239D / I332E.Additional amino acid substitutions that enhance FcyR binding activity finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that enhance FcyR binding activity of an antibody.

[0317] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that enhance FcRn activity and / or serum half-life of the B cell depleting antibody. In some further embodiments, the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life of the B cell depleting antibody comprise: (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), or (iii) M428L / N434S (LS). Additional amino acid substitutions that enhance FcRn activity and / or serum half-life finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that enhance FcRn activity and / or serum half-life of an antibody.

[0318] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that ablate a Protein A binding site of the variant Fc domain. In some further embodiments, the one or more amino acid substitutions that ablate a Protein A binding site of the variant Fc domain comprise H435R / Y436F (RF). Additional amino acid substitutions that ablate a Protein A binding site of the variant Fc domain finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos.2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that ablate a Protein A binding site of the variant Fc domain of an antibody.

[0319] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that promote heterodimerization of the first (variant) Fc domain with the second (variant) Fc domain. Nonlimiting examples of heterodimerization promoting Fc variants finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication No. 2022 / 0289839, incorporated by reference in its entirety.Attorney Docket: 53080.4002 / WO

[0320] In some embodiments, the variant Fc domain(s) comprise(s) one or more amino acid substitutions that ablate FcyR binding activity. In some further embodiments, the one or more amino acid substitutions that ablate FcyR binding activity comprise: (i) P329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv) L234F / L235E / P331S (LFLEPS), or (v) L234F / L235E / P329G (LFLEPG). Additional amino acid substitutions that ablate FcyR binding activity finding utility in some of the embodiments described herein are described in, for example, U.S. Patent Application Publication Nos.2025 / 0179183, 2024 / 0158526, and 2023 / 0220116, the contents of which are incorporated by reference, with particularity for their disclosure pertaining to Fc variants that ablate FcyR binding activity of an antibody.

[0321] In some embodiments, the B cell depleting antibody is a GEM-DIMER-formatted antibody. The contents of U.S. Patent Application Publication Nos. 2025 / 0179183, 2024 / 0158526, and 2023 / 0220116 are incorporated by reference in their entirety, with particularity for GEM-DIMER antibody formats described therein. In one exemplary embodiment, the GEM-DIMER-formatted antibody comprises: (i) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81; (ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36; (iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125; and (iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116. In some other exemplary embodiments, the GEM-DIMER-formatted antibody comprises any one of protein IDs [21-01]-[21 -130], as shown in Fig. 21.

[0322] In many embodiments, the subject comprises a human subject.

[0323] Embodiment (B)(1): In some embodiments, the at least one antigen binding domain (ABD) is an anti -CD 19 ABD, and the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD 19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement. In some further embodiments, the anti-CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD19 ABD is in a Fab format. In still some other further embodiments, the anti-CD19 ABDAttorney Docket: 53080.4002 / WOis in a scFv format. In still some other further embodiments, the anti-CD19 ABD is in a VHH format.

[0324] In some embodiments, the anti-CD19 ABD specifically binds human CD 19. In some further embodiments, the anti-human CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD19 ABD is in a Fab format. In still some other further embodiments, the anti-human CD 19 ABD is in a scFv format. In still some other further embodiments, the anti -human CD 19 ABD is in a VHH format.

[0325] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from tafasitamab, obexelimab, or inebilizumab.

[0326] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises the CD19-bindning scFv derived from blinatumomab.

[0327] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 194 and 198, respectively.

[0328] In some other embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), and (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises the amino acid sequences of SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3).

[0329] In some other embodiments, the anti-human CD19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domainAttorney Docket: 53080.4002 / WOpair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl -3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iii) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0330] Embodiment (B)(2): In some embodiments, the at least one antigen binding domain (ABD) is an anti-CD20 ABD, and the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement. In some further embodiments, the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-CD20 ABD is in a Fab format. In still some other further embodiments, the anti-CD20 ABD is in a scFv format. In still some other further embodiments, the anti-CD20 ABD is in a VHH format.

[0331] In some embodiments, the anti-CD20 ABD specifically binds human CD20. In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti -human CD20 ABD is in a FabAttorney Docket: 53080.4002 / WOformat. In still some other further embodiments, the anti-human CD20 ABD is in a scFv format. In still some other further embodiments, the anti-human CD20 ABD is in a VHH format.

[0332] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from rituximab, ocrelizumab, obinutuzumab, ofatumumab, or ublituximab.

[0333] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, and (E) SEQ ID NOs: 249 and 253, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 186 and 190.

[0334] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), and (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3).

[0335] In some other embodiments, the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl -3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iii) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variableAttorney Docket: 53080.4002 / WOlight chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0336] Embodiment (B)(3): In some embodiments, the B cell depleting antibody comprises a bispecific antibody (or antigen binding fragment thereof). In some further embodiments, the method comprises administering an anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof).

[0337] In some embodiments, (i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD 19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD19 in the presence of complement, and / or (ii) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0338] In some embodiments, the anti-CD19 ABD specifically binds human CD 19. In some further embodiments, the anti-human CD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD19 ABD is in a FabAttorney Docket: 53080.4002 / WOformat. In still some other further embodiments, the anti-human CD19 ABD is in a scFv format. In still some other further embodiments, the anti -human CD 19 ABD is in a VHH format.

[0339] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from tafasitamab, obexelimab, or inebilizumab.

[0340] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises the CD19-bindning scFv derived from blinatumomab.

[0341] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 194 and 198, respectively.

[0342] In some other embodiments, the anti -CD 19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRI-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), and (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises the amino acid sequences of SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3).

[0343] In some other embodiments, the anti -human CD 19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iii) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. In some other embodiments, the set ofAttorney Docket: 53080.4002 / WOvariable heavy chain complementarity determining regions (vhCDRl-3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0344] In some embodiments, the anti-CD20 ABD specifically binds human CD20. In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti -human CD20 ABD is in a Fab format. In still some other further embodiments, the anti-human CD20 ABD is in a scFv format. In still some other further embodiments, the anti-human CD20 ABD is in a VHH format.

[0345] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from rituximab, ocrelizumab, obinutuzumab, ofatumumab, or ublituximab.

[0346] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, and (E) SEQ ID NOs: 249 and 253, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 186 and 190.

[0347] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A).1 Horney Docket: 53080.4002 / WOSEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), and (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3).

[0348] In some other embodiments, the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl -3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iii) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0349] Embodiment (B)(4): In some embodiments, the B cell depleting antibody comprises a multispecific antibody (or antigen binding fragment thereof). In some further embodiments, the method comprises administering a multispecific antibody (or antigen binding fragment thereof), and the multispecific antibody (or antigen binding fragment thereof) comprises: (A) an anti-Attorney Docket: 53080.4002 / WOCD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest.

[0350] In some embodiments, (i) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibodydependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or (ii) the multispecific antibody has one or more of the characteristics selected from a group including: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complementdependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

[0351] In some embodiments, the anti-CD19 ABD specifically binds human CD19. In some further embodiments, the anti-human CD 19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti -human CD 19 ABD is in a Fab format. In still some other further embodiments, the anti-human CD19 ABD is in a scFv format. In still some other further embodiments, the anti -human CD 19 ABD is in a VHH format.

[0352] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from tafasitamab, obexelimab, or inebilizumab.

[0353] In some embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises the CD19-bindning scFv derived from blinatumomab.

[0354] In some embodiments, the anti-CD19 ABD specifically binds human CD19, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 194 and 198, respectively.

[0355] In some other embodiments, the anti-CD19 ABD specifically binds human CD 19, wherein the anti-human CD19 ABD comprises a set of complementarity determining regionsAttorney Docket: 53080.4002 / WO(CDRs) from a VH-VL domain pair (vhCDRl -3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), and (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises the amino acid sequences of SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3).

[0356] In some other embodiments, the anti -human CD 19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and (iii) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 198. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variable light chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 257 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 261, respectively, (ii) amino acid residues 31-35 (vhCDRl), 47-60 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 265 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-101 (vlCDR3) of SEQ ID NO: 269, respectively, (iii) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 273 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 277, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-113 (vhCDR3) of SEQ ID NO: 281 and amino acid residues 24-38 (vlCDRl), 54-60 (vlCDR2), and 93-101 (vlCDR3) of SEQ ID NO: 285, respectively.

[0357] In some embodiments, the anti-CD20 ABD specifically binds human CD20. In some further embodiments, the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format. In still some further embodiments, the anti-human CD20 ABD is in a FabAttorney Docket: 53080.4002 / WOformat. In still some other further embodiments, the anti-human CD20 ABD is in a scFv format. In still some other further embodiments, the anti-human CD20 ABD is in a VHH format.

[0358] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) derived from rituximab, ocrelizumab, obinutuzumab, ofatumumab, or ublituximab.

[0359] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, and (E) SEQ ID NOs: 249 and 253, respectively. In one exemplary embodiment, the VH-VL domain pair comprises the amino acid sequences of SEQ ID NOs: 186 and 190.

[0360] In some embodiments, the anti-CD20 ABD specifically binds human CD20, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), and (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3). In one exemplary embodiment, the set of vhCDRl-3 and vlCDRl-3 comprises SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3).

[0361] In some other embodiments, the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair), wherein: (i) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3); (ii) vhCDRl -3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and (iii) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 190. In some other embodiments, the set of variable heavy chain complementarity determining regions (vhCDRl -3) and the set of variableAttorney Docket: 53080.4002 / WOlight chain complementarity determining regions (vlCDRl-3) are selected from a group including: (i) amino acid residues 26-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 225 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 229, respectively, (ii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-108 (vhCDR3) of SEQ ID NO: 233 and amino acid residues 24-39 (vlCDRl), 55-61 (vlCDR2), and 94-102 (vlCDR3) of SEQ ID NO: 237, respectively, (iii) amino acid residues 31-35 (vhCDRl), 49-66 (vhCDR2), and 99-111 (vhCDR3) of SEQ ID NO: 241 and amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89-97 (vlCDR3) of SEQ ID NO: 245, respectively, and (iv) amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-107 (vhCDR3) of SEQ ID NO: 249 and amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88-96 (vlCDR3) of SEQ ID NO: 253, respectively.

[0362] In some embodiments, individual instances of the one or more additional ABDs that specifically bind one or more target antigens of interest are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof. In some further embodiments, individual instances of the one or more additional ABDs are in a Fab format. In some other further embodiments, individual instances of the one or more additional ABDs are in a scFv format. In some other further embodiments, individual instances of the one or more additional ABDs are in a VHH format.

[0363] In some embodiments, multispecific antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest, wherein at least one of the one or more target antigens of interest comprises: (i) a4|37 integrin, (ii) av integrin subunit avpi, (iii) av integrin subunit av[33, (iv) av integrin subunit avP5, (v) av integrin subunit vP6, (vi) av integrin subunit avP8, (vii) activin type II receptor, (viii) APRIL, (ix) AXL, (x) BAFF, (xi) BAFF / CD19, (xii) BAFF-R, (xiii) BCMA, (xiv) B7-H3, (xv) BLyS, (xvi) CA-125 mimic, (xvii) CCL2, (xviii) CD137, (xix) CD19, (xx) CD20, (xxi) CD20 / CD3, (xxii) CD22, (xxiii) CD23, (xxiv) CD25, (xxv) CD27, (xxvi) CD30, (xxvii) CD38, (xxviii) CD3, (xxix) CD40, (xxx) CD47, (xxxi) CD52, (xxxii) CD73, (xxxiii) CD79b, (xxxiv) CEACAM5, (xxxv) CGRP, (xxxvi) CGRP receptor, (xxxvii) Clostridium difficile toxin A, (xxxviii) Clostridium difficile toxin B, (xxxix) complement C5, (xl) CTGF, (xli) CTLA-4, (xlii) DLL4, (xliii) DR5, (xliv) Ebola virus glycoprotein, (xlv) EGFR, (xlvi) ERBB2, (xlvii) FAP, (xlviii) FGF23, (xlix) Frizzled receptors, (1) GDF15, (li) GFAP, (lii) GD2, (liii) GM-CSF, (liv)Attorney Docket: 53080.4002 / WOGM-CSFRa, (Iv) HER2, (Ivi) HER3, (Ivii) HIV-1 envelope glycoprotein, (Iviii) HIV-1 gp!20, (lix) human a4p7 integrin heterodimer, (lx) human CD161, (Ixi) human CD 19, (Ixii) human PD-Ll, (Ixiii) IFNa, (Ixiv) IFNAR1, (Ixv) IFNy, (Ixvi) IgE, (Ixvii) IgG4, (Ixviii) IL-ip, (Ixix) IL-12 / IL-23p40, (Ixx) IL-13, (Ixxi) IL-13Ral, (Ixxii) IL-15, (Ixxiii) IL-17A, (Ixxiv) IL-17A / IL-17F, (Ixxv) IL-17RA, (Ixxvi) IL-20, (Ixxvii) IL-22, (Ixxviii) IL-22R, (Ixxix) IL -2, (Ixxx) IL-31, (Ixxxi) IL-33, (Ixxxii) IL-33R / ST2, (Ixxxiii) IL-4Ra, (Ixxxiv) IL-5, (Ixxxv) IL-5Ra, (Ixxxvi) IL-6, (Ixxxvii) IL-6R, (Ixxxviii) KIR2DL1 / 2 / 3, (Ixxxix) LAG-3, (xc) LINGO-1, (xci) MAdCAM-1, (xcii) MASP-2, (xciii) MET, (xciv) mesothelin, (xcv) myostatin, (xcvi) Nectin-4, (xcvii) NGF, (xcviii) Notch2 / 3, (xcix) OSMRP, (c) 0X40, (ci) P-selectin, (cii) PCSK9, (ciii) PD-1, (civ) PD-Ll, (cv) PDGF-B, (cvi) plasma kallikrein, (cvii) RANKL, (cviii) rabies virus glycoprotein, (cix) RGMa, (ex) RSPO3, (cxi) SARS-CoV-2 spike protein, (cxii) SARS-CoV-2 RBD, (cxiii) sclerostin, (cxiv) SLAMF7, (cxv) sortilin, (cxvi) Staphylococcus aureus alpha toxin, (cxvii) TGF-P, (cxviii) TGF-P & PD-L1, (cxix) TIGIT, (exx) ticagrelor, (exxi) TIM-3, (cxxii) tissue factor, (cxxiii) tissue factor pathway inhibitor, (cxxiv) TNFa, (exxv) Trop-2, (cxxvi) TSLP, (cxxvii) VEGF-A, (cxxviii) VEGF-B, (cxxix) VEGFR-2, or (exxx) von Willebrand factor (vWF).

[0364] In some preferred embodiments, at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, ...

Claims

1. Attorney Docket: 53080.4002 / WO2.CLAIMS3.WHAT IS CLAIMED IS:

1. A method for rapidly depleting circulating B cells in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein:5.(a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD) selected from the group consisting of: (i) an antiCD 19 ABD, and (ii) an anti-CD20 ABD;6.(b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; and7.(c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject.

2. The method of claim 1, wherein the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

3. The method of any one of claims 1 or 2, wherein the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

4. The method of any one of claims 1-3, wherein a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, characterized by an increased ratio of circulating CD27‘ B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27 B cells determined prior to the first administration.

5. The method of claim 4, wherein the B cell niche comprises B cells resident to the circulatory system.Attorney Docket: 53080.4002 / WO6. The method of any one of claims 1-5, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered for 4 or fewer consecutive days.

7. The method of any one of claim 1-6, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

8. The method of any one of claims 1-7, wherein depletion of the circulating B cells occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

9. The method of any one of claims 1-8, wherein the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration.

10. The method of claim 9, wherein the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof.

11. The method of any one of claims 9 or 10, wherein:18.(i) at least one of the one or more B cell compartments comprises one or more lymph nodes; and19.(ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof.

12. The method of any one of claims 9 or 10, wherein:21.(i) at least one of the one or more B cell compartments comprises the spleen; and22.(ii) the tissue-resident B cells comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof. Attorney Docket: 53080.4002 / WO13. The method of any one of claims 9 or 10, wherein:24.(i) at least one of the one or more B cell compartments comprises bone marrow; and25.(ii) the tissue-resident B cells comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof.

14. The method of any one of claims 9 or 10, wherein:27.(i) at least one of the one or more B cell compartments comprises mucosa-associated lymphoid tissue (MALT); and28.(ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof.

15. The method of any one of claims 9 or 10, wherein:30.(i) at least one of the one or more B cell compartments comprises the thymus; and31.(ii) the tissue-resident B cells comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof.

16. The method of any one of claims 9 or 10, wherein:33.(i) at least one of the one or more B cell compartments comprises the skin; and34.(ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

17. The method of any one of claims 9 or 10, wherein:36.(i) at least one of the one or more B cell compartments comprises the liver; and37.(ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

18. The method of any one of claims 9-17, wherein at least one of the one or more B cellAttorney Docket: 53080.4002 / WO39.compartments exhibits remodeling of a B cell niche, characterized by an increased ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells as compared to a baseline ratio of tissue-resident CD27" B cells to tissue-resident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells.

19. The method of claim 18, wherein the remodeling of the B cell niche occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

20. The method of any one of claims 1-19, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route.

21. The method of any one of claims 1-19, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered as a bolus injection, as an IV infusion, or as a continuous infusion.

22. The method of any one of claims 1-21, wherein the B cell depleting antibody (or antigen binding fragment thereof) has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours.

23. The method of any one of claims 1-22, wherein:45.(i) the at least one antigen binding domain (ABD) is an anti-CD19 ABD; and46.(ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD 19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement.

24. The method of claim 23, wherein the anti-CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

25. The method of any one of claims 1-24, wherein:Attorney Docket: 53080.4002 / WO49.(i) the at least one antigen binding domain (ABD) is an anti-CD20 ABD; and50.(ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

26. The method of claim 25, wherein the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

27. The method of any one of claims 23-26, wherein the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest.

28. The method of claim 27, wherein individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof.

29. The method of any one of claims 27 or 28, wherein at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-0, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD 138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD103.

30. The method of any one of claims 27-29, wherein at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23,Attorney Docket: 53080.4002 / WO56.(xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD103.

31. The method of any one of claims 1-22, wherein the method comprises administering an antiCD 19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof).

32. The method of claim 31, wherein:59.(i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or60.(ii) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

33. The method of any one of claims 1-22, wherein:62.(i) the method comprises administering a multispecific antibody (or antigen binding fragment thereof); and63.(ii) the multispecific antibody (or antigen binding fragment thereof) comprises: (A) an anti-CD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest.

34. The method of claim 33, wherein at least one of the one or more target antigens of interestAttorney Docket: 53080.4002 / WO65.comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD103.

35. The method of any one of claims 33 or 34, wherein at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD103.

36. The method of any one of claims 33-35, wherein:68.(i) the multispecific antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD 19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or69.(ii) the multi specific antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement. Attorney Docket: 53080.4002 / WO37. The method of any one of claims 1-24 or 27-36, wherein the anti-CD19 ABD specifically binds human CD 19.

38. The method of claim 37, wherein the anti-human CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

39. The method of claim 37, wherein the anti-human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively.

40. The method of claim 37, wherein the anti-human CD19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), or (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3).

41. The method of claim 37, wherein:75.(i) the anti-human CD19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair);76.(ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vICDR 1-3);77.(iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and78.(iv) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89- 97 (vlCDR3) of SEQ ID NO:

198. Attorney Docket: 53080.4002 / WO42. The method of any one of claims 1-22 or 25-36, wherein the anti-CD20 ABD specifically binds human CD20.

43. The method of claim 42, wherein the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

44. The method of claim 42, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, or (E) SEQ ID NOs: 249 and 253, respectively.

45. The method of claim 42, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), or (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3).

46. The method of claim 42, wherein:84.(i) the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair);85.(ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vICDR 1-3);86.(iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and87.(iv) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88- 96 (vlCDR3) of SEQ ID NO:

190. Attorney Docket: 53080.4002 / WO47. The method of any one of claims 1-46, wherein the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains.

48. The method of claim 47, wherein the one or more Fc domains comprise one or more variant Fc domains.

49. The method of claim 48, wherein the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity.

50. The method of claim 49, wherein the one or more amino acid substitutions that enhance FcyR binding activity comprises one or more amino acid substitution mutations selected from the group consisting of 236A, S239D, S239E, I332E, I332D, S239D / I332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243A, 243L, 264A, 264V, and 299T.

51. The method of claim 50, wherein the one or more amino acid substitutions that enhance FcyR binding activity are S239D / I332E.

52. The method of any one of claims 48-51, wherein the one or more Fc domains comprises one or more amino acid substitutions that enhance FcRn activity and / or serum half-life.

53. The method of claim 52, wherein the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life comprises one or more amino acid substitution mutations selected from the group consisting of: (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), and (iii) M428L / N434S (LS).

54. The method of any one of claims 48-53, wherein the one or more Fc domains comprises one or more amino acid substitutions that ablate a Protein A binding site of at least one of the one or more Fc domains.

55. The method of claim 54, wherein the one or more amino acid substitutions that ablate a Protein A binding site comprise H435R / Y436F (RF).

56. The method of any one of claims 48-55, wherein the one or more Fc domains comprises one or more amino acid substitutions that promote heterodimerization of a first Fc domain with aAttorney Docket: 53080.4002 / WO98.second Fc domain.

57. The method of any one of claims 48 or 52-56, wherein the one or more Fc domains comprises one or more amino acid substitutions that ablate FcyR binding activity.

58. The method of claim 57, wherein the one or more amino acid substitutions that ablate FcyR binding activity are selected from the group consisting of: (i) P329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv) L234F / L235E / P331S (LFLEPS), and (v) L234F / L235E / P329G (LFLEPG).

59. The method of any one of claims 1-58, wherein the B cell depleting antibody is a GEM-DIMER-formatted antibody.

60. The method of claim 59, wherein the GEM-DIMER-formatted antibody comprises:103.(i) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81;104.(ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36;105.(iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125; and106.(iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116.

61. The method of any one of claims 1-60, wherein the subject is a human subject.

62. A method for treating an autoimmune disease characterized by B cell pathogenesis in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein:109.(a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD) selected from the group consisting of: (i) an antiCD 19 ABD, and (ii) an anti-CD20 ABD;110.(b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as Attorney Docket: 53080.4002 / WO111.compared to a baseline level of circulating B cells determined prior to the first administration; and112.(c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject,113.thereby treating the autoimmune disease characterized by B cell pathogenesis in the subject.

63. The method of claim 62, wherein the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

64. The method of any one of claims 62 or 63, wherein the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

65. The method of any one of claims 62-64, wherein a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, characterized by an increased ratio of circulating CD27' B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration.

66. The method of claim 65, wherein the B cell niche comprises B cells resident to the circulatory system.

67. The method of any one of claims 62-66, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered for 4 or fewer consecutive days.

68. The method of any one of claims 62-67, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

69. The method of any one of claims 62-68, wherein depletion of the circulating B cells occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.Attorney Docket: 53080.4002 / WO70. The method of any one of claims 62-69, wherein the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration.

71. The method of claim 70, wherein the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof.

72. The method of any one of claims 70 or 71, wherein:124.(i) at least one of the one or more B cell compartments comprises one or more lymph nodes; and125.(ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof.

73. The method of any one of claims 70 or 71 , wherein:127.(i) at least one of the one or more B cell compartments comprises the spleen; and128.(ii) the tissue-resident B cells comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof.

74. The method of any one of claims 70 or 71, wherein:130.(i) at least one of the one or more B cell compartments comprises bone marrow; and131.(ii) the tissue-resident B cells comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof.

75. The method of any one of claims 70 or 71, wherein:133.(i) at least one of the one or more B cell compartments comprises mucosa-associated Attorney Docket: 53080.4002 / WO134.lymphoid tissue (MALT); and135.(ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof.

76. The method of any one of claims 70 or 71, wherein:137.(i) at least one of the one or more B cell compartments comprises the thymus; and138.(ii) the tissue-resident B cells comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof.

77. The method of any one of claims 70 or 71, wherein:140.(i) at least one of the one or more B cell compartments comprises the skin; and141.(ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

78. The method of any one of claims 70 or 71, wherein:143.(i) at least one of the one or more B cell compartments comprises the liver; and144.(ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

79. The method of any one of claims 70-78, wherein at least one of the one or more B cell compartments exhibits remodeling of a B cell niche, characterized by an increased ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells as compared to a baseline ratio of tissue-resident CD27" B cells to tissue-resident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells.

80. The method of claim 79, wherein the remodeling of the B cell niche occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.Attorney Docket: 53080.4002 / WO81. The method of any one of claims 62-80, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route.

82. The method of any one of claims 62-80, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered as a bolus injection, as an IV infusion, or as a continuous infusion.

83. The method of any one of claims 62-82, wherein the B cell depleting antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours.

84. The method of any one of claims 62-83, wherein:151.(i) the at least one antigen binding domain (ABD) is an anti-CD19 ABD; and152.(ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement.

85. The method of claim 84, wherein the anti-CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

86. The method of any one of claims 62-83, wherein:155.(i) the at least one antigen binding domain (ABD) is an anti-CD20 ABD; and156.(ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement. Attorney Docket: 53080.4002 / WO87. The method of claim 86, wherein the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

88. The method of any one of claims 84-87, wherein the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest.

89. The method of claim 88, wherein individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof.

90. The method of any one of claims 88 or 89, wherein at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF- , (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17 A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD 138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD 103.

91. The method of any one of claims 88-90, wherein at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD103.

92. The method of any one of claims 62-83, wherein the method comprises administering an anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof).

93. The method of claim 92, wherein:Attorney Docket: 53080.4002 / WO164.(i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or165.(ii) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

94. The method of any one of claims 62-83, wherein:167.(i) the method comprises administering a multispecific antibody (or antigen binding fragment thereof); and168.(ii) the multi specific antibody (or antigen binding fragment thereof) comprises: (A) an anti-CD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest.

95. The method of claim 94, wherein at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-P, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD103.

96. The method of any one of claims 94 or 95, wherein at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) humanAttorney Docket: 53080.4002 / WO171.C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human TL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD103.

97. The method of any one of claims 94-96, wherein:173.(i) the multispecific antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD 19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or174.(ii) the multispecific antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

98. The method of any one of claims 62-85 or 88-97, wherein the anti-CD19 ABD specifically binds human CD 19.

99. The method of claim 98, wherein the anti-human CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

100. The method of claim 98, wherein the anti -human CD 19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acidAttorney Docket: 53080.4002 / WO178.sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277, respectively, or (E) SEQ ID NOs: 281 and 285, respectively.

101. The method of claim 98, wherein the anti -human CD 19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), or (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3).

102. The method of claim 98, wherein:181.(i) the anti-human CD19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair);182.(ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3);183.(iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and184.(iv) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89- 97 (vlCDR3) of SEQ ID NO: 198.

103. The method of any one of claims 62-83 or 86-97, wherein the anti-CD20 ABD specifically binds human CD20.

104. The method of claim 103, wherein the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

105. The method of claim 103, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acidAttorney Docket: 53080.4002 / WO188.sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245, respectively, or (E) SEQ ID NOs: 249 and 253, respectively.

106. The method of claim 103, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), or (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3).

107. The method of claim 103, wherein:191.(i) the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair);192.(ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3);193.(iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and194.(iv) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88- 96 (vlCDR3) of SEQ ID NO: 190.

108. The method of any one of claims 62-107, wherein the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains.

109. The method of claim 108, wherein the one or more Fc domains comprise one or more variant Fc domains.

110. The method of claim 109, wherein the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity.Attorney Docket: 53080.4002 / WO111. The method of claim 110, wherein the one or more amino acid substitutions that enhance FcyR binding activity comprises one or more amino acid substitution mutations selected from the group consisting of: 236A, S239D, S239E, I332E, I332D, S239D / I332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243A, 243L, 264A, 264V, and 299T.

112. The method of claim 111, wherein the one or more amino acid substitutions that enhance FcyR binding activity are S239D / I332E.

113. The method of any one of claims 109-112, wherein the one or more Fc domains comprises one or more amino acid substitutions that enhance FcRn activity and / or serum half-life.

114. The method of claim 113, wherein the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life comprises one or more amino acid substitution mutations selected from the group consisting of (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), and (iii) M428L / N434S (LS).

115. The method of any one of claims 109-114, wherein the one or more Fc domains comprises one or more amino acid substitutions that ablate a Protein A binding site of at least one of the one or more Fc domains.

116. The method of claim 115, wherein the one or more amino acid substitutions that ablate a Protein A binding site comprise H435R / Y436F (RF).

117. The method of any one of claims 109-116, wherein the one or more Fc domains comprises one or more amino acid substitutions that promote heterodimerization of a first Fc domain with a second Fc domain.

118. The method of any one of claims 109 or 113-117, wherein the one or more Fc domains comprises one or more amino acid substitutions that ablate FcyR binding activity.

119. The method of claim 118, wherein the one or more amino acid substitutions that ablate FcyR binding activity are selected from the group consisting of: (i) P329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv)Attorney Docket: 53080.4002 / WO207.L234F / L235E / P331 S (LFLEPS), and (v) L234F / L235E / P329G (LFLEPG).

120. The method of any one of claims 62-119, wherein the B cell depleting antibody is a GEM-DIMER-formatted antibody.

121. The method of claim 120, wherein the GEM-DIMER-formatted antibody comprises:210.(i) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81;211.(ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36;212.(iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125; and213.(iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116.

122. The method of any one of claims 62-121, wherein the autoimmune disease characterized by B cell pathogenesis is selected from the group consisting of: (i) acquired hemophilia, (ii) alopecia areata, (iii) amyloidosis, (iv) anti-NMDA receptor encephalitis, (v) antiphospholipid syndrome, (vi) autoimmune Addison’s disease, (vii) autoimmune angioedema, (viii) autoimmune autonomic ganglionopathy, (ix) autoimmune encephalitis, (x) autoimmune gastritis, (xi) autoimmune hemolytic anemia, (xii) autoimmune hepatitis, (xiii) autoimmune hyperlipidemia, (xiv) autoimmune hypophysitis, (xv) autoimmune inner ear disease, (xvi) autoimmune Interstitial Lung Disease, (xvii) autoimmune lymphoproliferative syndrome, (xviii) autoimmune myelofibrosis, (xix) autoimmune myocarditis, (xx) autoimmune oophoritis, (xxi) autoimmune pancreatitis, (xxii) autoimmune polyglandular syndromes, (xxiii) autoimmune progesterone dermatitis, (xxiv) autoimmune retinopathy, (xxv) Balo disease, (xxvi) bullous pemphigoid, (xxvii) Castleman disease, (xxviii) celiac disease, (xxix) chronic autoimmune urticaria, (xxx) chronic inflammatory demyelinating polyneuropathy, (xxxi) Churg-Strauss syndrome, (xxxii) Cogan’s syndrome, (xxxiii) cold agglutinin disease, (xxxiv) CREST syndrome, (xxxv) Cronkhite-Canada syndrome, (xxxvi) cryptogenic organizing pneumonia, (xxxvii) dermatitis herpetiformis, (xxxviii) dermatomyositis, (xxxix) discoid lupus, (xl) Dressier’s syndrome, (xli) eczema, (xlii) essential mixed cryoglobulinemia, (xliii) Evans syndrome, (xliv) giant cell arteritis, (xlv) glomerulonephritis, (xlvi) Goodpasture’s syndrome, (xlvii) granulomatosis with polyangiitis, (xlviii) Graves’ disease, (xlix) Guillain-Barre syndrome, (1) Hashimoto’s thyroiditis,Attorney Docket: 53080.4002 / WO215.(li) Henoch-Schonlein purpura, (lii) Hurst’s disease, (liii) IgA nephropathy, (liv) TgG4-related sclerosing disease, (Iv) immune thrombocytopenia, (Ivi) immune-mediated necrotizing myopathy, (Ivii) inclusion body myositis, (Iviii) juvenile idiopathic arthritis, (lix) Kawasaki disease, (lx) Lambert-Eaton myasthenic syndrome, (Ixi) leukocytoclastic vasculitis, (Ixii) lichen planus, (Ixiii) lichen sclerosus, (Ixiv) linear IgA disease, (Ixv) lupus nephritis, (Ixvi) Meniere’s disease, (Ixvii) microscopic polyangiitis, (Ixviii) mixed connective tissue disease, (Ixix) mucous membrane pemphigoid, (Ixx) multiple sclerosis, (Ixxi) myasthenia gravis, (Ixxii) neuromyelitis optica, (Ixxiii) optic neuritis, (Ixxiv) palindromic rheumatism, (Ixxv) paraneoplastic cerebellar degeneration, (Ixxvi) paraneoplastic pemphigus, (Ixxvii) pemphigoid gestationis, (Ixxviii) pemphigus foliaceus, (Ixxix) pemphigus vulgaris, (Ixxx) pernicious anemia, (Ixxxi) Pityriasis lichenoides et varioliformis acuta, (Ixxxii) POEMS syndrome, (Ixxxiii) polyarteritis nodosa, (Ixxxiv) polymyositis, (Ixxxv) primary biliary cholangitis, (Ixxxvi) primary sclerosing cholangitis, (Ixxxvii) pure red cell aplasia, (Ixxxviii) relapsing polychondritis, (Ixxxix) rheumatoid arthritis, (xc) scleritis, (xci) scleroderma, (xcii) Sjogren’s syndrome, and (xciii) systemic lupus erythematosus.

123. The method of claim 122, wherein the autoimmune disease characterized by B cell pathogenesis is systemic lupus erythematosus (SLE).

124. The method of any one of claims 62-123, wherein the subject is a human subject.

125. A method for treating a B cell malignancy in a subject in need thereof, wherein the method comprises administering a B cell depleting antibody (or antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the subject, wherein:219.(a) the B cell depleting antibody (or antigen binding fragment thereof) comprises at least one antigen binding domain (ABD) selected from the group consisting of (i) an antiCD 19 ABD, and (ii) an anti-CD20 ABD;220.(b) the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration; and Attorney Docket: 53080.4002 / WO221.(c) the B cell depleting antibody (or antigen binding fragment thereof) is administered for 10 or fewer consecutive days to the subject,222.thereby treating the B cell malignancy in the subject.

126. The method of claim 125, wherein the B cell depleting antibody (or antigen binding fragment thereof) effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

127. The method of any one of claims 125 or 126, wherein the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

128. The method of any one of claims 125-127, wherein a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells, characterized by an increased ratio of circulating CD27‘ B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration.

129. The method of claim 128, wherein the B cell niche comprises B cells resident to the circulatory system.

130. The method of any one of claims 125-129, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered for 4 or fewer consecutive days.

131. The method of any one of claims 125-130, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered 5, 4, 3, or fewer times to the subject.

132. The method of any one of claims 125-131, wherein depletion of the circulating B cells occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

133. The method of any one of claims 125-132, wherein the B cell depleting antibody (or antigen binding fragment thereof) further effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%,Attorney Docket: 53080.4002 / WO231.91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to the baseline level of tissue-resident B cells determined prior to the first administration.

134. The method of claim 133, wherein the one or more B cell compartments comprise: (i) one or more lymph nodes, (ii) the spleen, (iii) bone marrow, (iv) mucosa-associated lymphoid tissue (MALT), (v) the thymus, (vi) the skin, (vii) the liver, or any combination thereof.

135. The method of any one of claims 133 or 134, wherein:234.(i) at least one of the one or more B cell compartments comprises one or more lymph nodes; and235.(ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, or any combination thereof.

136. The method of any one of claims 133 or 134, wherein:237.(i) at least one of the one or more B cell compartments comprises the spleen; and238.(ii) the tissue-resident B cells comprise: (A) follicular B cells, (B) marginal zone B cells, (C) memory B cells, or any combination thereof.

137. The method of any one of claims 133 or 134, wherein:240.(i) at least one of the one or more B cell compartments comprises bone marrow; and241.(ii) the tissue-resident B cells comprise: (A) pro-B cells, (B) immature B cells, (C) plasmablasts, (D) memory B cells, or any combination thereof.

138. The method of any one of claims 133 or 134, wherein:243.(i) at least one of the one or more B cell compartments comprises mucosa-associated lymphoid tissue (MALT); and Attorney Docket: 53080.4002 / WO244.(ii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) memory B cells, (D) plasmablasts, or any combination thereof.

139. The method of any one of claims 133 or 134, wherein:246.(i) at least one of the one or more B cell compartments comprises the thymus; and247.(ii) the tissue-resident B cells comprise: (A) transitional B cells, (B) mature B cells, or any combination thereof.

140. The method of any one of claims 133 or 134, wherein:249.(i) at least one of the one or more B cell compartments comprises the skin; and250.(ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

141. The method of any one of claims 133 or 134, wherein:252.(i) at least one of the one or more B cell compartments comprises the liver; and253.(ii) the tissue-resident B cells comprise: (A) memory B cells, (B) plasmablasts, or any combination thereof.

142. The method of any one of claims 133-141, wherein at least one of the one or more B cell compartments exhibits remodeling of a B cell niche, characterized by an increased ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells as compared to a baseline ratio of tissue-resident CD27' B cells to tissue-resident CD27+B cells determined prior to the first administration, subsequent to the depletion of tissue-resident B cells.

143. The method of claim 142, wherein the remodeling of the B cell niche occurs for: (i) a period of at least five or more days, (ii) a period of at least five or more weeks, or (iii) a period of at least five or more months.

144. The method of any one of claims 125-143, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered by an intravenous or subcutaneous route.Attorney Docket: 53080.4002 / WO145. The method of any one of claims 125-143, wherein the B cell depleting antibody (or antigen binding fragment thereof) is administered as a bolus injection, as an IV infusion, or as a continuous infusion.

146. The method of any one of claims 125-145, wherein the B cell depleting antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours.

147. The method of any one of claims 125-146, wherein:260.(i) the at least one antigen binding domain (ABD) is an anti-CD19 ABD; and261.(ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement.

148. The method of claim 147, wherein the anti-CD19 ABD is in: (i) aFab format, (ii) a scFv format, or (iii) a VHH format.

149. The method of any one of claims 125-146, wherein:264.(i) the at least one antigen binding domain (ABD) is an anti-CD20 ABD; and265.(ii) the B cell depleting antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

150. The method of claim 149, wherein the anti-CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.Attorney Docket: 53080.4002 / WO151. The method of any one of claims 147-150, wherein the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more additional ABDs that specifically bind one or more target antigens of interest.

152. The method of claim 151, wherein individual instances of the one or more additional ABDs are in: (i) a Fab format, (ii) a scFv format, (iii) a VHH format, or any combination thereof.

153. The method of any one of claims 151 or 152, wherein at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF- , (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral , (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD 103.

154. The method of any one of claims 151-153, wherein at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv) human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD 103.

155. The method of any one of claims 125-146, wherein the method comprises administering an anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof).

156. The method of claim 155, wherein:273.(i) the anti-CD19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of: (A) capable Attorney Docket: 53080.4002 / WO274.of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD 19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or275.(ii) the anti -CD 19 x anti-CD20 bispecific antibody (or antigen binding fragment thereof) has one or more of the characteristics selected from the group consisting of (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

157. The method of any one of claims 125-146, wherein:277.(i) the method comprises administering a multispecific antibody (or antigen binding fragment thereof); and278.(ii) the multispecific antibody (or antigen binding fragment thereof) comprises: (A) an anti-CD19 ABD, (B) an anti-CD20 ABD, and (C) one or more additional ABDs that specifically bind one or more target antigens of interest.

158. The method of claim 157, wherein at least one of the one or more target antigens of interest comprises: (i) BAFF, (ii) CD40, (iii) C5, (iv) C5a, (v) C5aRl, (vi) FcRn, (vii) IL-6, (viii) IL-6R, (ix) TSLP, (x) 0X40, (xi) CD38, (xii) CD79b, (xiii) BCMA, (xiv) SLAMF7, (xv) IgE, (xvi) plasma kallikrein, (xvii) TGF-0, (xviii) CD22, (xix) BLyS, (xx) APRIL, (xxi) IL-17A, (xxii) IL-23, (xxiii) CTLA-4, (xxiv) CD30, (xxv) CD23, (xxvi) CD52, (xxvii) CD138, (xxviii) IL-4Ra, (xxix) IL-13, (xxx) IL-13Ral, (xxxi) IL-5Ra, (xxxii) IL-5, (xxxiii) IGF-1R, (xxxiv) IgG4, (xxxv) TNFa, (xxxvi) CD25, and (xxxvii) CD103.

159. The method of any one of claims 157 or 158, wherein at least one of the one or more target antigens of interest comprises: (i) human BAFF, (ii) human CD40, (iii) human C5, (iv) human C5a, (v) human C5aRl, (vi) human FcRn, (vii) human IL-6, (viii) human IL-6R, (ix) human TSLP, (x) human 0X40, (xi) human CD38, (xii) human CD79b, (xiii) human BCMA, (xiv)Attorney Docket: 53080.4002 / WO281.human SLAMF7, (xv) human IgE, (xvi) human plasma kallikrein, (xvii) human TGF-P, (xviii) human CD22, (xix) human BLyS, (xx) human APRIL, (xxi) human IL-17A, (xxii) human IL-23, (xxiii) human CTLA-4, (xxiv) human CD30, (xxv) human CD23, (xxvi) human CD52, (xxvii) human CD138, (xxviii) human IL-4Ra, (xxix) human IL-13, (xxx) human IL-13Ral, (xxxi) human IL-5Ra, (xxxii) human IL-5, (xxxiii) human IGF-1R, (xxxiv) human IgG4, (xxxv) human TNFa, (xxxvi) human CD25, and (xxxvii) human CD 103.

160. The method of any one of claims 157-159, wherein:283.(i) the multispecific antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD 19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and / or284.(ii) the multi specific antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

161. The method of any one of claims 125-148 or 151-160, wherein the anti-CD19 ABD specifically binds human CD 19.

162. The method of claim 161, wherein the anti-human CD19 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

163. The method of claim 161, wherein the anti-human CD19 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 194 and 198, respectively, (B) SEQ ID NOs: 257 and 261, respectively, (C) SEQ ID NOs: 265 and 269, respectively, (D) SEQ ID NOs: 273 and 277,Attorney Docket: 53080.4002 / WO288.respectively, or (E) SEQ IDNOs: 281 and 285, respectively.

164. The method of claim 161, wherein the anti-human CD19 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 195-197 (vhCDRl-3) and SEQ ID NOs: 199-201 (vlCDRl-3), (B) SEQ ID NOs: 258-260 (vhCDRl-3) and SEQ ID NOs: 262-264 (vlCDRl-3), (iii) SEQ ID NOs: 266-268 (vhCDRl-3) and SEQ ID NOs: 270-272 (vlCDRl-3), (iv) SEQ ID NOs: 274-276 (vhCDRl-3) and SEQ ID NOs: 278-280 (vlCDRl-3), or (v) SEQ ID NOs: 282-284 (vhCDRl-3) and SEQ ID NOs: 286-288 (vlCDRl-3).

165. The method of claim 161, wherein:291.(i) the anti-human CD19 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair);292.(ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3);293.(iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-65 (vhCDR2), and 98-108 (vhCDR3) of SEQ ID NO: 194; and294.(iv) vlCDRl-3 consist of amino acid residues 24-34 (vlCDRl), 50-56 (vlCDR2), and 89- 97 (vlCDR3) of SEQ ID NO: 198.

166. The method of any one of claims 125-146 or 149-160, wherein the anti-CD20 ABD specifically binds human CD20.

167. The method of claim 166, wherein the anti-human CD20 ABD is in: (i) a Fab format, (ii) a scFv format, or (iii) a VHH format.

168. The method of claim 166, wherein the anti-human CD20 ABD comprises a variable heavy (VH) and variable light (VL) domain pair (VH-VL domain pair) comprising the amino acid sequences of: (A) SEQ ID NOs: 186 and 190, respectively, (B) SEQ ID NOs: 225 and 229, respectively, (C) SEQ ID NOs: 233 and 237, respectively, (D) SEQ ID NOs: 241 and 245,Attorney Docket: 53080.4002 / WO298.respectively, or (E) SEQ ID NOs: 249 and 253, respectively.

169. The method of claim 166, wherein the anti-human CD20 ABD comprises a set of complementarity determining regions (CDRs) from a VH-VL domain pair (vhCDRl-3 and vlCDRl-3) comprising the amino acid sequences of: (A) SEQ ID NOs: 187-189 (vhCDRl-3) and SEQ ID NOs: 191-193 (vlCDRl-3), (B) SEQ ID NOs: 226-228 (vhCDRl-3) and SEQ ID NOs: 230-232 (vlCDRl-3), (C) SEQ ID NOs: 234-236 (vhCDRl-3) and SEQ ID NOs: 238-240 (vlCDRl-3), (D) SEQ ID NOs: 242-244 (vhCDRl-3) and SEQ ID NOs: 246-248 (vlCDRl-3), or (E) SEQ ID NOs: 250-252 (vhCDRl-3) and SEQ ID NOs: 254-256 (vlCDRl-3).

170. The method of claim 166, wherein:301.(i) the anti-human CD20 ABD comprises a variable heavy domain and a variable light domain pair (VH-VL domain pair);302.(ii) the VH-VL domain pair comprises a set of variable heavy chain complementarity determining regions (vhCDRl-3) and a set of variable light chain complementarity determining regions (vlCDRl-3);303.(iii) vhCDRl-3 consist of amino acid residues 31-35 (vhCDRl), 50-66 (vhCDR2), and 99-110 (vhCDR3) of SEQ ID NO: 186; and304.(iv) vlCDRl-3 consist of amino acid residues 24-33 (vlCDRl), 49-55 (vlCDR2), and 88- 96 (vlCDR3) of SEQ ID NO: 190.

171. The method of any one of claims 125-170, wherein the B cell depleting antibody (or antigen binding fragment thereof) comprises one or more Fc domains.

172. The method of claim 171, wherein the one or more Fc domains comprise one or more variant Fc domains.

173. The method of claim 172, wherein the one or more variant Fc domains comprise one or more amino acid substitutions that enhance FcyR binding activity.

174. The method of claim 173, wherein the one or more amino acid substitutions that enhanceAttorney Docket: 53080.4002 / WO309.FcyR binding activity comprises one or more amino acid substitution mutations selected from the group consisting of: 236A, S239D, S239E, I332E, I332D, S239D / I332E, 267D, 267E, 328F, 267E / 328F, 236A / 332E, 239D / 332E / 330Y, 239D, 332E / 330L, 243A, 243L, 264A, 264V, and 299T.

175. The method of claim 174, wherein the one or more amino acid substitutions that enhance FcyR binding activity are S239D / I332E.

176. The method of any one of claims 172-175, wherein the one or more Fc domains comprises one or more amino acid substitutions that enhance FcRn activity and / or serum half-life.

177. The method of claim 176, wherein the one or more amino acid substitutions that enhance FcRn activity and / or serum half-life comprises one or more amino acid substitution mutations selected from the group consisting of: (i) M252Y / S254T / T256E (YTE), (ii) L309D / Q311H / N434S (DHS), and (iii) M428L / N434S (LS).

178. The method of any one of claims 172-177, wherein the one or more Fc domains comprises one or more amino acid substitutions that ablate a Protein A binding site of at least one of the one or more Fc domains.

179. The method of claim 178, wherein the one or more amino acid substitutions that ablate a Protein A binding site comprise H435R / Y436F (RF).

180. The method of any one of claims 172-179, wherein the one or more Fc domains comprises one or more amino acid substitutions that promote heterodimerization of a first Fc domain with a second Fc domain.

181. The method of any one of claims 172 or 176-180, wherein the one or more Fc domains comprises one or more amino acid substitutions that ablate FcvR binding activity.

182. The method of claim 181, wherein the one or more amino acid substitutions that ablate FcyR binding activity are selected from the group consisting of: (i) P329G / L234A / L235A (PGLALA), (ii) L234A / L235A (LALA), (iii) P331S / L234A / L235A (PSLALA), (iv) L234F / L235E / P331S (LFLEPS), and (v) L234F / L235E / P329G (LFLEPG).Attorney Docket: 53080.4002 / WO183. The method of any one of claims 125-182, wherein the B cell depleting antibody is a GEM-DIMER-formatted antibody.

184. The method of claim 183, wherein the GEM-DIMER-formatted antibody comprises:320.(i) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81;321.(ii) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36;322.(iii) a first light chain comprising the amino acid sequence of SEQ ID NO: 125; and323.(iv) a second light chain comprising the amino acid sequence of SEQ ID NO: 116.

185. The method of any one of claims 125-184, wherein the B cell malignancy is selected from the group consisting of: (i) diffuse large B-cell lymphoma (DLBCL), (ii) chronic lymphocytic leukemia (CLL), (iii) follicular lymphoma, (iv) mantle cell lymphoma, (v) marginal zone lymphoma, (vi) Burkitt lymphoma, (vii) Hodgkin lymphoma, (viii) Waldenstrom macroglobulinemia, (ix) multiple myeloma, (x) hairy cell leukemia, (xi) acute lymphoblastic leukemia (B-ALL), (xii) primary central nervous system lymphoma (PCNSL), (xiii) small lymphocytic lymphoma (SLL), (xiv) lymphoplasmacytic lymphoma, and (xv) primary mediastinal B-cell lymphoma.

186. The method of any one of claims 125-185, wherein the subject is a human subject.

187. A method for rapidly depleting circulating B cells in a human subject in need thereof, wherein the method comprises intravenously or subcutaneously administering a bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody in an amount sufficient to deplete circulating B cells in the human subject, wherein:327.(i) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody comprises:328.(A) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81,329.(B) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36, Attorney Docket: 53080.4002 / WO330.(C) a first light chain comprising the amino acid sequence of SEQ ID NO: 125, and331.(D) a second light chain comprising the amino acid sequence of SEQ ID NO: 116;332.(ii) the bispecific anti-human CD 19 x anti -human CD20 GEM-DIMER-formatted antibody effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration;333.(iii) depletion of the circulating B cells occurs for a period of at least 5 or more days; and334.(iv) the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody is administered for 4 or fewer consecutive days to the human subject.

188. The method of claim 187, wherein the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

189. The method of any one of claims 187 or 188, wherein depletion of the circulating B cells occurs for a period of: (i) at least 5 or more weeks, or (ii) at least 5 or more months.

190. The method of any one of claims 187-189, wherein the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

191. The method of any one of claims 187-190, wherein:339.(i) a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells;340.(ii) the B cell niche comprises B cells resident to the circulatory system; and341.(iii) the remodeling is characterized by an increased ratio of circulating CD27' B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27’ B cells to Attorney Docket: 53080.4002 / WO342.circulating CD27+B cells determined prior to the first administration.

192. The method of any one of claims 187-191, wherein:344.(i) the bispecific anti-human CD 19 x anti -human CD20 GEM-DIMER-formatted antibody effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to a baseline level of tissue-resident B cells located in the one or more B cell compartments determined prior to the first administration;345.(ii) the one or more B cell compartments comprise: (A) one or more lymph nodes, (B) the spleen, (C) bone marrow, (D) mucosa-associated lymphoid tissue (MALT), (E) the thymus, (F) the skin, (G) the liver, or any combination thereof; and346.(iii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, (G) follicular B cells, (H) marginal zoneB cells, (I) memory B cells, (J) pro-B cells, (K) immature B cells, or any combination thereof.

193. The method of any one of claims 187-192, wherein:348.(i) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and349.(ii) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity Attorney Docket: 53080.4002 / WO350.(CDC) of cells expressing CD20 in the presence of complement.

194. The method of any one of claims 187-193, wherein the bispecific anti-human CD19 x antihuman CD20 GEM-DIMER-formatted antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours.

195. A method for treating an autoimmune disease characterized by B cell pathogenesis in a human subject in need thereof, wherein the method comprises administering a bispecific antihuman CD 19 x anti-human CD20 GEM-DIMER-formatted antibody in an amount sufficient to deplete circulating B cells in the human subject, wherein:353.(i) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody comprises:354.(A) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81,355.(B) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36,356.(C) a first light chain comprising the amino acid sequence of SEQ ID NO: 125, and357.(D) a second light chain comprising the amino acid sequence of SEQ ID NO: 116;358.(ii) the bispecific anti -human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration;359.(iii) depletion of the circulating B cells occurs for a period of at least 5 or more days; and360.(iv) the bispecific anti -human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody is administered for 4 or fewer consecutive days to the human subject,361.thereby treating the autoimmune disease characterized by B cell pathogenesis in the human subject. Attorney Docket: 53080.4002 / WO196. The method of claim 195, wherein the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

197. The method of any one of claims 195 or 196, wherein depletion of the circulating B cells occurs for a period of: (i) at least 5 or more weeks, or (ii) at least 5 or more months.

198. The method of any one of claims 195-197, wherein the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

199. The method of any one of claims 195-198, wherein:366.(i) a B cell niche exhibits remodeling subsequent to the depletion of the circulating B cells;367.(ii) the B cell niche comprises B cells resident to the circulatory system; and368.(iii) the remodeling is characterized by an increased ratio of circulating CD27' B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27' B cells to circulating CD27+B cells determined prior to the first administration.

200. The method of any one of claims 195-199, wherein:370.(i) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to a baseline level of tissue-resident B cells located in the one or more B cell compartments determined prior to the first administration;371.(ii) the one or more B cell compartments comprise: (A) one or more lymph nodes, (B) the spleen, (C) bone marrow, (D) mucosa-associated lymphoid tissue (MALT), (E) the thymus, (F) the skin, (G) the liver, or any combination thereof; and Attorney Docket: 53080.4002 / WO372.(iii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, (G) follicular B cells, (H) marginal zone B cells, (I) memory B cells, (J) pro-B cells, (K) immature B cells, or any combination thereof.

201. The method of any one of claims 195-200, wherein:374.(i) the bispecific anti-human CD 19 x anti -human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and375.(ii) the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antib ody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

202. The method of any one of claims 195-201, wherein the bispecific anti-human CD 19 x antihuman CD20 GEM-DIMER-formatted antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours.

203. The method of any one of claims 195-202, wherein the autoimmune disease characterized by B cell pathogenesis comprises systemic lupus erythematosus (SLE).

204. A method for treating a B cell malignancy in a human subject in need thereof, wherein the method comprises administering a B cell depleting antibody (antigen binding fragment thereof) in an amount sufficient to deplete circulating B cells in the human subject, wherein:379.(i) the bispecific anti-human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody comprises: Attorney Docket: 53080.4002 / WO380.(A) a first heavy chain comprising the amino acid sequence of SEQ ID NO: 81,381.(B) a second heavy chain comprising the amino acid sequence of SEQ ID NO: 36,382.(C) a first light chain comprising the amino acid sequence of SEQ ID NO: 125, and383.(D) a second light chain comprising the amino acid sequence of SEQ ID NO: 116;384.(ii) the bispecific anti -human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 50% depletion in circulating B cells within 24 hours of a first administration, as compared to a baseline level of circulating B cells determined prior to the first administration;385.(iii) depletion of the circulating B cells occurs for a period of at least 5 or more days; and386.(iv) the bispecific anti -human CD 19 x anti-human CD20 GEM-DIMER-formatted antibody is administered for 4 or fewer consecutive days to the human subject,387.thereby treating the B cell malignancy in the human subject.

205. The method of claim 204, wherein the bispecific anti -human CD 19 x anti -human CD20 GEM-DIMER-formatted antibody effectuates at least a 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in circulating B cells within 24 hours of the first administration, as compared to the baseline level of circulating B cells determined prior to the first administration.

206. The method of any one of claims 204 or 205, wherein depletion of the circulating B cells occurs for a period of: (i) at least 5 or more weeks, or (ii) at least 5 or more months.

207. The method of any one of claims 204-206, wherein the circulating B cells comprise: (i) naive B cells, (ii) memory B cells, (iii) plasmablasts (plasma cells), or any combination thereof.

208. The method of any one of claims 204-207, wherein:392.(i) a B cell niche exhibits remodeling subsequent to the depletion of the circulating B Attorney Docket: 53080.4002 / WO393.cells;394.(ii) the B cell niche comprises B cells resident to the circulatory system; and395.(iii) the remodeling is characterized by an increased ratio of circulating CD27' B cells to circulating CD27+B cells as compared to a baseline ratio of circulating CD27’ B cells to circulating CD27+B cells determined prior to the first administration.

209. The method of any one of claims 204-208, wherein:397.(i) the bispecific anti-human CD 19 * anti-human CD20 GEM-DIMER-formatted antibody effectuates at least a 30%, 40%, 50%, 60%, 70%, 80%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher depletion in tissue-resident B cells located in one or more B cell compartments, as compared to a baseline level of tissue-resident B cells located in the one or more B cell compartments determined prior to the first administration;398.(ii) the one or more B cell compartments comprise: (A) one or more lymph nodes, (B) the spleen, (C) bone marrow, (D) mucosa-associated lymphoid tissue (MALT), (E) the thymus, (F) the skin, (G) the liver, or any combination thereof; and399.(iii) the tissue-resident B cells comprise: (A) naive B cells, (B) activated B cells, (C) centroblasts, (D) centrocytes, (E) plasmablasts, (F) marginal zone-like B cells, (G) follicular B cells, (H) marginal zoneB cells, (I) memory B cells, (J) pro-B cells, (K) immature B cells, or any combination thereof.

210. The method of any one of claims 204-209, wherein:401.(i) the bispecific anti-human CD 19 x anti -human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antib ody-dependent cellular cytotoxicity (ADCC) of cells expressing CD19, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD19, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD 19 in the presence of complement, and Attorney Docket: 53080.4002 / WO402.(ii) the bispecific anti-human CD19 x anti-human CD20 GEM-DIMER-formatted antibody has one or more of the characteristics selected from the group consisting of: (A) capable of inducing antibody-dependent cellular cytotoxicity (ADCC) of cells expressing CD20, (B) capable of inducing antibody-dependent cellular phagocytosis (ADCP) of cells expressing CD20, and (C) capable of inducing complement-dependent cytotoxicity (CDC) of cells expressing CD20 in the presence of complement.

211. The method of any one of claims 204-210, wherein the bispecific anti-human CD 19 x antihuman CD20 GEM-DIMER-formatted antibody has a serum half-life that is: (i) less than about 7 days, (ii) less than about 2-3 days, or (iii) less than about 24 hours.

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