Chimeric antigen receptor specific for BAFF-R and CD19, and methods and uses thereof

Abstract

B-cell activating factor receptor (BAFF-R) binding molecules are provided, particularly human antibodies specific to BAFF-R, including antibody fragments. The present disclosure further relates to recombinant receptors, including chimeric antigen receptors (CARs), containing such antibodies or fragments, and polynucleotides encoding antibodies, antigen-binding fragments, or receptors specific to BAFF-R. Also provided are CARs containing extracellular binding domains that bind to BAFF-R and the B lymphocyte antigen CD19 (CD19), genetically engineered cells expressing such CARs, and their use in adoptive cell therapy.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority from U.S. Provisional Patent Application No. 63 / 432,342, filed December 13, 2022, entitled "Chimeric Antigen Receptors Specific for BAFF-R and CD19, and Methods and Uses Thereof," the contents of which are incorporated by reference in their entirety.

[0002] Incorporation by Reference of Sequence Listing This application is filed with a Sequence Listing in electronic format. The Sequence Listing is provided as a file named 735042023340SeqList.xml, created on December 11, 2023, and is 181,862 bytes in size. The information in the electronic format of the Sequence Listing is incorporated herein by reference in its entirety.

[0003] In some embodiments, the present disclosure relates to chimeric antigen receptors (CARs) containing an extracellular binding domain that binds to B-cell activating factor receptor (BAFF-R) and the B-lymphocyte antigen CD19 (CD19). The present disclosure further relates to BAFF-R binding molecules, particularly anti-BAFF-R antibodies, including antibody fragments. The present disclosure also provides genetically engineered cells, such as T cells, containing the provided CARs, as well as related methods and uses in adoptive cell therapy. [Background technology]

[0004] CAR-T cell therapy has been shown to be effective for treating cancer.However, due to the different characteristics of tumor cells, CAR-T therapy focusing on targeting a single antigen may be insufficient.In addition, tumor cells can downregulate or mutate the CAR-T target antigen expressed on cell surface to avoid detection.Therefore, it is necessary to produce CAR-T cells that simultaneously express two different targets.An embodiment that meets this need is provided. Summary of the Invention [Means for solving the problem]

[0005] A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the extracellular binding domain comprising (i) the V region of the BAFF-R binding domain; H region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain L region, (ii) V of the BAFF-R binding domain; L region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain H region, (iii) V of the BAFF-R binding domain H region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain L region, (iv) V of the BAFF-R binding domain L region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain H region, (v) V of the CD19-binding domain L region, V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, and V of the CD19-binding domain H region, (vi) V of the CD19-binding domain H region, V of the BAFF-R binding domain H region, V of the BAFF-R binding domainL region, and V of the CD19-binding domain L region, (vii) V of the CD19-binding domain L region, V of the CD19-binding domain H region, V of the BAFF-R binding domain H region, and V of the BAFF-R binding domain L region (viii) V of the CD19-binding domain L region, V of the CD19-binding domain H region, V of the BAFF-R binding domain L region, and V of the BAFF-R binding domain H region, (ix) V of the CD19-binding domain H region, V of the CD19-binding domain L region, V of the BAFF-R binding domain H region, and V of the BAFF-R binding domain L region, (x) V of the CD19-binding domain H region, V of the CD19-binding domain L region, V of the BAFF-R binding domain L region, and V of the BAFF-R binding domain H region, (xi) V of the BAFF-R binding domain L region, V of the BAFF-R binding domain H region, V of the CD19-binding domain H region, and V of the CD19-binding domain L region, (xii) V of the BAFF-R binding domain L region, V of the BAFF-R binding domain H region, V of the CD19-binding domain L region, and V of the CD19-binding domain H region, (xiii) V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, V of the CD19-binding domain H region, and V of the CD19-binding domain L region, (xiv) V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, V of the CD19-binding domain Lregion, and V of the CD19-binding domain H region (xv) V of the CD19-binding domain L region, V of the BAFF-R binding domain L region, V of the BAFF-R binding domain H region, and V of the CD19-binding domain H region, or (xvi) V of the CD19-binding domain H region, V of the BAFF-R binding domain L region, V of the BAFF-R binding domain H region, and V of the CD19-binding domain L Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0006] A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the extracellular binding domain comprising (i) the V region of the BAFF-R binding domain; H region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain L region, (ii) V of the BAFF-R binding domain; L region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain H region, (iii) V of the BAFF-R binding domain H region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain L region, or (iv) V of the BAFF-R binding domainL region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain H Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0007] A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the extracellular binding domain comprising the V region of the BAFF-R binding domain; H region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain L Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0008] A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the extracellular binding domain comprising the V region of the BAFF-R binding domain; L region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain HProvided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0009] A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the extracellular binding domain comprising the V region of the BAFF-R binding domain; H region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain L Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0010] A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the extracellular binding domain comprising the V region of the BAFF-R binding domain; L region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain H Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0011] A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the extracellular binding domain comprising (i) the V region of the BAFF-R binding domain; H region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain L region, or (ii) the V of the BAFF-R binding domain L region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain H Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0012] In some embodiments, the extracellular binding domain is the V of the BAFF-R binding domain. L region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain H The regions are included in this order from the amino terminus to the carboxy terminus.

[0013] In some embodiments, the extracellular binding domain is the V of the BAFF-R binding domain. H region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain L The regions are included in this order from the amino terminus to the carboxy terminus.

[0014] In some embodiments, the extracellular binding domain is the V of the BAFF-R binding domain. H region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain L The regions are included in this order from the amino terminus to the carboxy terminus.

[0015] In some embodiments, the extracellular binding domain is the V of the BAFF-R binding domain. L region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain H The regions are included in this order from the amino terminus to the carboxy terminus.

[0016] In some of any of the embodiments, (i) the V of the BAFF-R binding domain H The regions include CDR-H1, CDR-H2, and CDR-H3, each of which contains the sequence contained within SEQ ID NO: 1, and the V of the BAFF-R binding domain. L The region comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises a sequence contained within SEQ ID NO:2; or (ii) the V region of the BAFF-R binding domain. H The regions include CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 3, and the V of the BAFF-R binding domain. L The region comprises CDR-L1, CDR-L2, and CDR-L3, each having a sequence contained within SEQ ID NO: 4; or (iii) the V region of the BAFF-R binding domain. H The regions include CDR-H1, CDR-H2, and CDR-H3, each having the sequence contained within SEQ ID NO: 5, and the V of the BAFF-R binding domain. L The region comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO: 6; or (iv) the V of the BAFF-R binding domain. HThe regions include CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 7, and the V of the BAFF-R binding domain. L The region comprises CDR-L1, CDR-L2, and CDR-L3, each comprising a sequence contained within SEQ ID NO: 8; or (v) V of the BAFF-R binding domain. H The regions include CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 9, and the V of the BAFF-R binding domain. L The regions include CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO:10.

[0017] In some of any of the embodiments, each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition.

[0018] Also disclosed is a bispecific CAR comprising an extracellular binding domain, a transmembrane domain, a spacer, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the CD19-binding domain comprising (i) the V region of the BAFF-R-binding domain; H The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained in SEQ ID NO: 1. L (ii) the V region of the BAFF-R binding domain comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises a sequence contained within SEQ ID NO:2; or H The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 3. L(iii) the V region of the BAFF-R binding domain comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO: 4; or H The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 5. L (iv) the V region of the BAFF-R binding domain, H The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 7. L the region comprises CDR-L1, CDR-L2, and CDR-L3, each comprising a sequence contained within SEQ ID NO: 8; or (v) the V of the BAFF-R binding domain H The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 9. L Provided herein is a bispecific CAR, wherein the regions comprise CDR-L1, CDR-L2, and CDR-L3, each comprising a sequence contained within SEQ ID NO:10.

[0019] In some embodiments, each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition. H The region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 16, 17 and 18, respectively, and the V of the BAFF-R binding domain L The region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 19, 20 and 21, respectively, or (ii) the V region of the BAFF-R binding domain. H The region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 22, 23 and 24, respectively, and includes the V of the BAFF-R binding domain. LThe region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 25, 26 and 27, respectively, or (iii) the V of the BAFF-R binding domain. H The region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 28, 29 and 30, respectively, and the V of the BAFF-R binding domain L The region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 31, 26 and 27, respectively, or (iv) the V of the BAFF-R binding domain. H The region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 22, 32 and 24, respectively, and includes the V of the BAFF-R binding domain. L The region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 33, 26 and 34, respectively; or (v) the V of the BAFF-R binding domain. H The region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 35, 36 and 37, respectively, and the V of the BAFF-R binding domain L The regions include the sequences of CDR-L1, CDR-L2 and CDR-L3 shown in SEQ ID NOs: 38, 39 and 40, respectively.

[0020] Also disclosed is a bispecific CAR comprising an extracellular binding domain, a transmembrane domain, a spacer, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19, the CD19-binding domain comprising (i) the V region of the BAFF-R-binding domain; H The region comprises the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 16, 17 and 18, respectively, and the V of the BAFF-R binding domain L(ii) the V region of the BAFF-R binding domain comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 19, 20 and 21, respectively; H The region comprises the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 22, 23 and 24, respectively, and the V of the BAFF-R binding domain L (iii) the V region of the BAFF-R binding domain; H The region comprises the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 28, 29 and 30, respectively, and the V of the BAFF-R binding domain L (iv) the V region of the BAFF-R binding domain; H The region comprises the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 22, 32 and 24, respectively, and the V of the BAFF-R binding domain L (v) the V region of the BAFF-R binding domain; H The region comprises the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 35, 36 and 37, respectively, and the V of the BAFF-R binding domain L Provided herein is a bispecific CAR, the regions of which comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 38, 39 and 40, respectively.

[0021] In some of any of the embodiments, the extracellular binding domain comprises (i) the V of the BAFF-R binding domain H region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain L region, (ii) V of the BAFF-R binding domain; Lregion, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain H region, (iii) V of the BAFF-R binding domain H region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain L region, (iv) V of the BAFF-R binding domain L region, V of the CD19-binding domain H region, V of the CD19-binding domain L region, and V of the BAFF-R binding domain H region, (v) V of the CD19-binding domain L region, V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, and V of the CD19-binding domain H region, (vi) V of the CD19-binding domain H region, V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, and V of the CD19-binding domain L region, (vii) V of the CD19-binding domain L region, V of the CD19-binding domain H region, V of the BAFF-R binding domain H region, and V of the BAFF-R binding domain L region (viii) V of the CD19-binding domain L region, V of the CD19-binding domain H region, V of the BAFF-R binding domain L region, and V of the BAFF-R binding domain H region, (ix) V of the CD19-binding domain H region, V of the CD19-binding domain L region, V of the BAFF-R binding domain H region, and V of the BAFF-R binding domain L region, (x) V of the CD19-binding domain H region, V of the CD19-binding domainL region, V of the BAFF-R binding domain L region, and V of the BAFF-R binding domain H region, (xi) V of the BAFF-R binding domain L region, V of the BAFF-R binding domain H region, V of the CD19-binding domain H region, and V of the CD19-binding domain L region, (xii) V of the BAFF-R binding domain L region, V of the BAFF-R binding domain H region, V of the CD19-binding domain L region, and V of the CD19-binding domain H region, (xiii) V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, V of the CD19-binding domain H region, and V of the CD19-binding domain L region, (xiv) V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, V of the CD19-binding domain L region, and V of the CD19-binding domain H (xv) the VL region of the CD19-binding domain, the VL region of the BAFF-R-binding domain, the VH region of the BAFF-R-binding domain, and the VH region of the CD19-binding domain, or (xvi) the VH region of the CD19-binding domain, the VL region of the BAFF-R-binding domain, the VH region of the BAFF-R-binding domain, and the VL region of the CD19-binding domain, in this order from the amino terminus to the carboxy terminus.

[0022] In some of any of the embodiments, (i) the V of the BAFF-R binding domain H The region comprises the sequence set forth in SEQ ID NO: 1 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and includes the V of the BAFF-R binding domain. LThe region comprises the sequence set forth in SEQ ID NO:2 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2; or (ii) a V region of the BAFF-R binding domain. H The region comprises the sequence set forth in SEQ ID NO:3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:3, and includes the V of the BAFF-R binding domain. L The region comprises the sequence set forth in SEQ ID NO:4 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:4; or (iii) a V region of the BAFF-R binding domain. H The region comprises the sequence set forth in SEQ ID NO: 5 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5, and includes the V of the BAFF-R binding domain. L The region comprises the sequence set forth in SEQ ID NO:6 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:6; or (iv) a V region of the BAFF-R binding domain. H The region comprises the sequence set forth in SEQ ID NO:7 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:7, and includes the V of the BAFF-R binding domain. L The region comprises the sequence set forth in SEQ ID NO:8 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:8; or (v) a V of the BAFF-R binding domain. HThe region comprises the sequence set forth in SEQ ID NO: 9 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and includes the V of the BAFF-R binding domain. L The region includes the sequence set forth in SEQ ID NO:10 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:10.

[0023] In some of any of the embodiments, (i) the V of the BAFF-R binding domain H The region comprises the sequence shown in SEQ ID NO: 1 and is the V of the BAFF-R binding domain. L The region comprises the sequence set forth in SEQ ID NO: 2, or (ii) the V of the BAFF-R binding domain. H comprises the sequence shown in SEQ ID NO: 3, and the V of the BAFF-R binding domain L The region comprises the sequence set forth in SEQ ID NO: 4, or (iii) the V of the BAFF-R binding domain H The region comprises the sequence shown in SEQ ID NO: 5 and is the V L The region comprises the sequence set forth in SEQ ID NO: 6, or (iv) the V of the BAFF-R binding domain. H The region comprises the sequence shown in SEQ ID NO: 7 and is the V of the BAFF-R binding domain. L The region comprises the sequence set forth in SEQ ID NO: 8, or (v) the V of the BAFF-R binding domain H The region comprises the sequence shown in SEQ ID NO: 9 and is the V of the BAFF-R binding domain. L The region comprises the sequence shown in SEQ ID NO:10.

[0024] In some of the embodiments, the extracellular binding domain is the V of the BAFF-R binding domain. H region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain LIn some embodiments, the extracellular binding domain comprises the V region of the BAFF-R binding domain from the amino terminus to the carboxy terminus. L region, V of the CD19-binding domain L region, V of the CD19-binding domain H region, and V of the BAFF-R binding domain H The region is comprised from the amino terminus to the carboxy terminus.

[0025] In some of any of the embodiments, the extracellular binding domain is the V of the CD19 binding domain. L region, V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, and V of the CD19-binding domain H In some embodiments, the extracellular binding domain comprises the V region of the CD19 binding domain from the amino terminus to the carboxy terminus. H region, V of the BAFF-R binding domain H region, V of the BAFF-R binding domain L region, and V of the CD19-binding domain L The region is comprised from the amino terminus to the carboxy terminus.

[0026] In some of any of the embodiments, the extracellular binding domain is the V of the CD19 binding domain. L region, V of the CD19-binding domain H region, V of the BAFF-R binding domain H region, and V of the BAFF-R binding domain L In some embodiments, the extracellular binding domain comprises the V region of the CD19 binding domain from the amino terminus to the carboxy terminus. L region, V of the CD19-binding domain H region, V of the BAFF-R binding domain L region, and V of the BAFF-R binding domain H The region is comprised from the amino terminus to the carboxy terminus.

[0027] In some of the optional embodiments, the V of the BAFF-R binding domain HThe region includes the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 22, 23 and 24, respectively, and includes the V of the BAFF-R binding domain. L The regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 25, 26 and 27, respectively. H The region comprises the sequence set forth in SEQ ID NO:3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:3, and includes the V of the BAFF-R binding domain. L The region includes the sequence set forth in SEQ ID NO:4 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:4.

[0028] In some of the optional embodiments, the V of the BAFF-R binding domain H comprises the sequence shown in SEQ ID NO: 3, and the V of the BAFF-R binding domain L The region comprises the sequence set forth in SEQ ID NO: 4. In some of any of the embodiments, the V of the BAFF-R binding domain H The region comprises the sequence set forth in SEQ ID NO: 5 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 5, and includes the V of the BAFF-R binding domain. L The region includes the sequence set forth in SEQ ID NO:6 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:6.

[0029] In some of the optional embodiments, the V of the BAFF-R binding domain HThe region includes the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 28, 29 and 30, respectively, and includes the V of the BAFF-R binding domain. L The regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 31, 26 and 27, respectively. H The region comprises the sequence shown in SEQ ID NO: 5 and is the V L The region comprises the sequence shown in SEQ ID NO:6.

[0030] In some of the optional embodiments, the V of the BAFF-R binding domain H The region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 16, 17 and 18, respectively, and the V of the BAFF-R binding domain L The regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 19, 20 and 21, respectively. H The region comprises the sequence set forth in SEQ ID NO: 1 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and includes the V of the BAFF-R binding domain. L The region includes the sequence set forth in SEQ ID NO:2 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2.

[0031] In some of the optional embodiments, the V of the BAFF-R binding domain H The region comprises the sequence shown in SEQ ID NO: 1 and is the V of the BAFF-R binding domain. L The region comprises the sequence shown in SEQ ID NO: 2. In some of any of the embodiments, the V of the BAFF-R binding domain HThe region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 22, 32 and 24, respectively, and includes the V of the BAFF-R binding domain. L The regions include the CDR-L1, CDR-L2 and CDR-L3 sequences shown in SEQ ID NOs: 33, 26 and 34, respectively.

[0032] In some of the optional embodiments, the V of the BAFF-R binding domain H The region comprises the sequence set forth in SEQ ID NO:7 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:7, and includes the V of the BAFF-R binding domain. L The region comprises the sequence set forth in SEQ ID NO: 8 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 8. In some of any embodiment, the V of the BAFF-R binding domain H The region comprises the sequence shown in SEQ ID NO: 7 and is the V of the BAFF-R binding domain. L The region comprises the sequence shown in SEQ ID NO:8.

[0033] In some of the optional embodiments, the V of the BAFF-R binding domain H The region includes the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 35, 36 and 37, respectively, and the V of the BAFF-R binding domain L The regions include the sequences of CDR-L1, CDR-L2 and CDR-L3 shown in SEQ ID NOs: 38, 39 and 40, respectively.

[0034] In some of the optional embodiments, the V of the BAFF-R binding domain H The region comprises the sequence set forth in SEQ ID NO: 9 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 9, and includes the V of the BAFF-R binding domain.L The region comprises the sequence set forth in SEQ ID NO: 10 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10. In some of any embodiment, the V of the BAFF-R binding domain H The region comprises the sequence shown in SEQ ID NO: 9 and is the V of the BAFF-R binding domain. L The region comprises the sequence shown in SEQ ID NO:10.

[0035] In some of the optional embodiments, the V of the BAFF-R binding domain H The V region of the BAFF-R binding domain is connected to the V region of the BAFF-R binding domain via an intradomain linker. L In some embodiments, the VH region of the CD19 binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each comprising a sequence contained within SEQ ID NO: 41, and the VH region of the CD19 binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each comprising a sequence contained within SEQ ID NO: 41. L The regions include CDR-L1, CDR-L2, and CDR-L3, each comprising the sequence contained within SEQ ID NO:42.

[0036] In some of any of the embodiments, each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition.

[0037] In some of the optional embodiments, the V of the CD19 binding domain H The regions include the sequences of CDR-H1, CDR-H2 and CDR-H3 shown in SEQ ID NOs: 41, 44 and 46, respectively, and the V of the CD19 binding domain L The regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 47, 49 and 51, respectively. In some of any of the embodiments, (i) the V of the CD19 binding domain HThe region comprises the sequence set forth in SEQ ID NO: 41 or a sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 41; and (ii) a V region of the CD19-binding domain. L The region comprises the sequence set forth in SEQ ID NO:42 or a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:42.

[0038] In some of the optional embodiments, the V of the CD19 binding domain H The region comprises the sequence shown in SEQ ID NO: 41 and is the V L The region comprises the sequence shown in SEQ ID NO:42.

[0039] Also disclosed is a bispecific CAR comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is a heavy chain variable (V H ) region and the light chain variable (V L a B cell activating factor receptor (BAFF-R) binding domain that binds to the B cell activating factor receptor (BAFF-R), including a V H Area and V L a CD19-binding domain that binds to CD19 comprising the V region, and an extracellular binding domain comprising the V region of the BAFF-R-binding domain comprising the sequence set forth in SEQ ID NO: 3 H region, V of the CD-19 binding domain comprising the sequence set forth in SEQ ID NO: 42 L region, V of the CD19-binding domain comprising the sequence set forth in SEQ ID NO: 41 H region, and the V region of the BAFF-R binding domain comprising the sequence set forth in SEQ ID NO:4 L Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0040] Also provided is a bispecific CAR comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is V H and V LBAFF-R binding domain containing V H and V L and the extracellular binding domain comprises a V of the BAFF-R binding domain comprising the sequence set forth in SEQ ID NO: 6. L region, V of the CD-19 binding domain comprising the sequence set forth in SEQ ID NO: 42 L region, V of the CD19-binding domain comprising the sequence set forth in SEQ ID NO: 41 H region, and the V of the BAFF-R binding domain comprising the sequence set forth in SEQ ID NO:5 H Provided herein is a bispecific CAR comprising the regions in this order from amino terminus to carboxy terminus.

[0041] In some of the optional embodiments, the V of the CD19 binding domain H The V region of the CD19-binding domain is connected to the V region of the CD19-binding domain via an intradomain linker. L In some embodiments, the intradomain linker is a flexible linker. In some embodiments, the intradomain linker is 5-25 amino acids in length. In some embodiments, the intradomain linker is 12-18 amino acids in length. In some embodiments, the intradomain linker comprises the sequence set forth in SEQ ID NO: 58. In some embodiments, the intradomain linker comprises the sequence set forth in SEQ ID NO: 59.

[0042] In some of any of the embodiments, the VH or VL region of the BAFF-R binding domain is connected to the VH or VL region of the CD19 binding domain by an interdomain linker.

[0043] In some of any of the embodiments, (i) the V of the BAFF-R binding domain H The V region of the CD19-binding domain is separated by an interdomain linker. L connected to the region or (i) V of the BAFF-R binding domain H The V region of the CD19-binding domain is separated by an interdomain linker. H connected to the region or (iii) the V of the BAFF-R binding domainL The V region of the CD19-binding domain is separated by an interdomain linker. L connected to the region, or (iv) V of the BAFF-R binding domain L The V region of the CD19-binding domain is separated by an interdomain linker. H is connected to the area.

[0044] In some embodiments, the interdomain linker is a flexible peptide linker. In some embodiments, the interdomain linker is 5 to 25 amino acids in length, inclusive. In some embodiments, the interdomain linker is 5 to 15 amino acids in length, inclusive. In some embodiments, the interdomain linker is a G4S linker (SEQ ID NO: 60), a G4S2 linker (SEQ ID NO: 61), or a (G4S)4 linker (SEQ ID NO: 62). In some embodiments, the interdomain linker is set forth in SEQ ID NO: 60. In some embodiments, the interdomain linker is set forth in SEQ ID NO: 61.

[0045] In some of any of the embodiments, the spacer is sandwiched between the extracellular binding domain and the transmembrane domain. In some of any of the embodiments, the spacer comprises a hinge region sequence. In some of any of the embodiments, the spacer comprises the hinge region of an immunoglobulin or a variant thereof. In some embodiments, the immunoglobulin hinge region is an IgG4 hinge region, optionally a human IgG4 hinge region, or a variant thereof. In some of any of the embodiments, the spacer comprises a mutant IgG4 hinge region comprising a substitution of amino acids CPSC to CPPC compared to a wild-type IgG4 hinge region.

[0046] In some embodiments, the spacer is 15 amino acids or less than about 15 amino acids in length. In some embodiments, the spacer is 12-15 amino acids in length. In some embodiments, the spacer comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 52, optionally the spacer has the sequence set forth in SEQ ID NO: 52. In some embodiments, the spacer is 200-250 amino acids in length, or 220-240 amino acids in length. In some embodiments, the spacer comprises an immunoglobulin hinge region, an immunoglobulin CH2 region or a chimeric CH2 region of two different immunoglobulins, and an immunoglobulin CH3 region. In some embodiments, the spacer comprises an IgG4 hinge region or a variant thereof, a chimeric CH2 region comprising part of an IgG4 CH2 and part of an IgG2 CH2 (IgG2 / 4 CH2 region), and an IgG4 CH3 region.

[0047] In some of any of the embodiments, the spacer comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percent identity to SEQ ID NO: 53, optionally the spacer has the sequence set forth in SEQ ID NO: 53. In some of any of the embodiments, the transmembrane domain comprises a transmembrane domain derived from CD28, optionally human CD28. In some of any of the embodiments, the transmembrane domain is or comprises SEQ ID NO: 55, or an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percent sequence identity to SEQ ID NO: 55. In some of any of the embodiments, the transmembrane domain is set forth in SEQ ID NO: 55.

[0048] In some embodiments, the intracellular signaling domain comprises an intracellular signaling domain capable of inducing a primary activation signal in a T cell. In some embodiments, the intracellular signaling domain is a domain derived from a T cell receptor (TCR) component and / or comprises an immunoreceptor tyrosine-based activation motif (ITAM). In some embodiments, the intracellular signaling domain is the cytoplasmic signaling domain of the CD3 zeta (CD3ζ) chain, optionally the human CD3ζ chain.

[0049] In some of any of the embodiments, the intracellular signaling domain comprises the sequence set forth in SEQ ID NO: 57, or an amino acid sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 57. In some of any of the embodiments, the intracellular signaling domain is set forth in SEQ ID NO: 57. In some of any of the embodiments, the intracellular signaling region further comprises a costimulatory signaling region. In some embodiments, the costimulatory signaling region is between the transmembrane region and the intracellular signaling domain.

[0050] In some embodiments, the costimulatory signaling region comprises the intracellular signaling domain of a T cell costimulatory molecule, or a signaling portion thereof. In some embodiments, the costimulatory signaling region comprises the intracellular signaling domain of 4-1BB, optionally human 4-1BB. In some embodiments, the costimulatory signaling region comprises the sequence set forth in SEQ ID NO:56, or an amino acid sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO:56. In some embodiments, the costimulatory signaling region is set forth in SEQ ID NO:56.

[0051] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:94 or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:94.

[0052] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:95 or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:95.

[0053] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:96, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:96.

[0054] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:97 or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:97.

[0055] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:98 or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:98.

[0056] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:99 or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:99.

[0057] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 100, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 100.

[0058] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 101 or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 101.

[0059] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 102, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 102.

[0060] Also provided herein is a bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 103, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 103.

[0061] In some of any of the embodiments, binding of the BAFF-R domain to BAFF in the presence of soluble BAFF is reduced by no more than 10% compared to binding in the absence of soluble BAFF. In some of any of the embodiments, binding of the CD19 domain to CD19 in the presence of FMC63 scFv is reduced by no more than 30% compared to binding in the absence of FMC63 scFv.

[0062] Also provided are polynucleotides encoding any of the bispecific CARs provided herein. In some embodiments, the polynucleotides are optimized by splice site elimination. In some embodiments, the polynucleotides are codon-optimized for expression in human cells.

[0063] Also provided are vectors comprising any of the polynucleotides provided herein. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector (e.g., a lentiviral vector).

[0064] Also provided are cells comprising any of the bispecific CARs provided herein.

[0065] Also provided are cells comprising any of the polynucleotides provided herein or the vectors provided herein. In some embodiments, the cells are immune cells. In some embodiments, the cells are lymphocytes. In some embodiments, the cells are NK cells or T cells. In some embodiments, the cells are T cells. In some embodiments, the T cells are CD4+ T cells or CD8+ T cells. In some embodiments, the cells are primary cells. In some embodiments, the cells exhibit cytotoxic activity against CD19+ cells, BAFF-R+ cells, and CD19+ / BAFF-R+ cells.

[0066] Also provided are compositions comprising a plurality of the cells provided herein. In some embodiments, the compositions further comprise a pharmaceutically acceptable excipient. In some embodiments, the compositions comprise CD4+ T cells and CD8+ T cells. In some embodiments, the ratio of CD4+ T cells to CD8+ T cells is 1:3 to 3:1 or about 1:3 to 3:1, optionally 1:2 to 2:1 or about 1:2 to 2:1, optionally 1:1 or about 1:1.

[0067] In some of any of the embodiments, the composition may comprise greater than or greater than about 90%, greater than or greater than about 90%, greater than or greater than about 95%, or greater than or greater than about 98% of the cells in the composition are CD3+ T cells. In some of any of the embodiments, the composition may comprise at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the cells in the composition express a CAR.

[0068] In some of any of the embodiments, the composition can include that among a plurality of cells in the composition that express the bispecific CAR, at or about 10%, 9% or about 9%, 8% or about 8%, 7% or about 7%, 5% or about 5%, 4% or about 4%, 3% or about 3%, 2% or about 2%, or less than 1% or about 1% of the plurality of cells exhibit tonic signaling and / or antigen-independent activity or signaling.

[0069] In some of the optional embodiments, the composition comprises about 1.0×10 7 Bispecific CAR-expressing T cells ~1.2 x 10 9 Bispecific CAR-expressing T cells, approximately 1.0 × 10 7 Bispecific CAR-expressing T cells ~6.5 x 10 8 Bispecific CAR-expressing T cells, approximately 1.5 × 10 7 Bispecific CAR-expressing T cells ~6.5 x 10 8 Bispecific CAR-expressing T cells, approximately 1.5 × 10 7 Bispecific CAR-expressing T cells ~6.0 x 10 8 Bispecific CAR-expressing T cells, approximately 2.5 × 10 7 Bispecific CAR-expressing T cells ~6.0 x 10 8 Bispecific CAR-expressing T cells, approximately 5.0 × 10 7 Bispecific CAR-expressing T cells ~6.0 x 10 8 Bispecific CAR-expressing T cells, approximately 1.25 × 10 7 Bispecific CAR-expressing T cells ~1.2 x 10 9 Bispecific CAR-expressing T cells, approximately 1.5 × 10 7 Bispecific CAR-expressing T cells ~1.2 x 10 9 Bispecific CAR-expressing T cells, approximately 5.0 × 10 7 Bispecific CAR-expressing T cells ~4.5 x 10 8 Bispecific CAR-expressing T cells, or approximately 1.5 x 10 8 Bispecific CAR-expressing T cells ~3.0 x 10 8 bispecific CAR-expressing T cells (each inclusive).

[0070] In some of the optional embodiments, the composition comprises 1.5×10 7 Or about 1.5 x 10 7 , 2.5×10 7 Or about 2.5 x 10 7 , 5.0×10 7 or approximately 5.0 x 10 7 , 7.5×10 7 Or about 7.5 x 10 7 , 1.5×10 8 Or about 1.5 x 10 8 , 2.25×10 8 Or about 2.25 x 10 8 , 3.0×10 8 Or about 3.0 x 10 8 , 4.5×10 8 or about 4.5 x 10 8 , 6.0×10 8 or approximately 6.0 x 10 8 , 8.0×10 8 or approximately 8.0 x 10 8 , or 1.2 × 10 9 or about 1.2 x 10 9 The bispecific CAR-expressing T cells may comprise:

[0071] Also provided herein are methods of treating a disease or disorder in a subject, comprising administering any of the cells provided herein or any of the compositions provided herein to a subject in need thereof.

[0072] Also provided herein is a method of treatment, comprising administering any of the bispecific CARs provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein to a subject with a disease or disorder. In some embodiments, the disease or disorder is cancer or an autoimmune disease. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a BAFF-R-expressing cancer, a CD19-expressing cancer, or a BAFF-R and CD19-expressing cancer. In some embodiments, the cancer is a lymphoma or leukemia. In some embodiments, the lymphoma is a large B-cell lymphoma. In some embodiments, the lymphoma is a non-Hodgkin's lymphoma.

[0073] In some of any of the embodiments, the disease or disorder is an autoimmune disease.

[0074] Also provided herein are any of the cells provided herein or any of the compositions provided herein for use in treating a disease or disorder. Also provided herein are uses of any of the cells provided herein or any of the compositions provided herein for the manufacture of a medicament for treating a disease or disorder. In some of any of the embodiments, the disease or disorder is cancer or an autoimmune disease. In some of the embodiments, the disease or disorder is cancer. In some of the embodiments, the cancer is a BAFF-R-expressing cancer, a CD19-expressing cancer, or a BAFF-R and CD19-expressing cancer. In some of the embodiments, the cancer is a lymphoma or leukemia. In some of the embodiments, the lymphoma is a large B-cell lymphoma. In some of the embodiments, the lymphoma is a non-Hodgkin's lymphoma.

[0075] In some of any of the embodiments, the disease or disorder is an autoimmune disease.

[0076] Also provided herein is the use of any of the cells provided herein or any of the compositions provided herein for the treatment of a disease or disorder. Also provided herein is any of the bispecific CARs provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein for use in the treatment of a disease or disorder. Also provided herein is the use of any of the bispecific CARs provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein for the manufacture of a medicament for treating a disease or disorder. Also provided herein is the use of any of the bispecific CARs provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein for the treatment of a disease or disorder.

[0077] In some embodiments, the disease or disorder is cancer or an autoimmune disease. In some embodiments, the disease or disorder is cancer. In some embodiments, the cancer is a BAFF-R-expressing cancer, a CD19-expressing cancer, or a BAFF-R and CD19-expressing cancer. In some embodiments, the cancer is a lymphoma or leukemia. In some embodiments, the lymphoma is a large B-cell lymphoma. In some embodiments, the lymphoma is a non-Hodgkin's lymphoma.

[0078] In some of any of the embodiments, the disease or disorder is an autoimmune disease.

[0079] Also provided herein are kits comprising any of the bispecific CARs provided herein, any of the polynucleotides provided herein, any of the vectors provided herein, any of the cells provided herein, or any of the compositions provided herein, and instructions for use, where appropriate, the instructions are for administering any of the bispecific CARs, any of the cells, or any of the compositions, as appropriate, in accordance with any of the methods for use, any of the cells, any of the compositions, any of the bispecific CARs, any of the polynucleotides, or any of the vectors or any of the uses provided herein.

[0080] Also provided herein are articles of manufacture comprising any of the bispecific CARs provided herein, any of the polynucleotides provided herein, any of the vectors provided herein, any of the cells provided herein, or any of the compositions provided herein, or any of the kits provided herein.

[0081] In addition, the heavy chain variable region (V H ) and the light chain variable region (V L ), a B-cell activating factor receptor (BAFF-R) comprising: (i) V H comprises CDR-H1, CDR-H2 and CDR-H3, each having a sequence contained within SEQ ID NO: 1; L the region comprises light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3) contained within SEQ ID NO: 2; or (ii) V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 3, and V L the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 4, or (iii) V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 5, Lthe region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 6; or (iv) V H The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 7, and V L the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 8; or (v) V H comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 9, and V L Provided herein is an antibody, or antigen-binding portion thereof, that binds to BAFF-R, the region comprising CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:10.

[0082] In some embodiments, V H comprises CDR-H1, CDR-H2, and CDR-H3, each having the sequence contained within SEQ ID NO: 1; L comprises CDR-L1, CDR-L2, and CDR-L3, each having a sequence contained within SEQ ID NO: 2. H comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 3, and V L comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 4. In some embodiments, V H The region includes CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 5, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 6. H The region includes CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 7, and L The region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 8. In some embodiments, H The region includes CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 9, and L The regions include CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:10.

[0083] In some embodiments, each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition. In some embodiments, the antibody or antigen-binding fragment thereof has a CDR length of about 10 -7 M ~ about 10 -11 K of M D binds to BAFF-R.

[0084] Also, V H and V L BAFF-R, comprising: (i) V H comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 16, 17 and 18, respectively; L comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 19, 20 and 21, respectively; or (ii) V H comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 22, 23 and 24, respectively; L comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 25, 26 and 27, respectively; or (iii) V H comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 28, 29 and 30, respectively; L (iv) the region comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 31, 26 and 27, respectively; or H comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 22, 32 and 24, respectively; L comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 33, 26 and 34, respectively; or (v) V H comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 35, 36 and 37, respectively; LProvided herein is an antibody, or antigen-binding portion thereof, that specifically binds to BAFF-R, comprising CDR-L1, CDR-L2, and CDR-L3 having the sequences set forth in SEQ ID NOs: 38, 39, and 40, respectively.

[0085] In some optional embodiments, V H The regions include CDR-H1, CDR-H2 and CDR-H3 containing the sequences set forth in SEQ ID NOs: 16, 17 and 18, respectively; L The regions include CDR-L1, CDR-L2, and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 19, 20, and 21, respectively. H The regions include CDR-H1, CDR-H2 and CDR-H3 containing the sequences set forth in SEQ ID NOs: 22, 23 and 24, respectively; L The regions include CDR-L1, CDR-L2 and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 25, 26 and 27, respectively.

[0086] In some optional embodiments, V H The regions include CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 28, 29 and 30, respectively; L The regions include CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 31, 26, and 27, respectively. H The regions include CDR-H1, CDR-H2 and CDR-H3 containing the sequences set forth in SEQ ID NOs: 22, 32 and 24, respectively; L The regions include CDR-L1, CDR-L2 and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 33, 26 and 34, respectively.

[0087] In some optional embodiments, V H The regions include CDR-H1, CDR-H2 and CDR-H3 containing the sequences set forth in SEQ ID NOs: 35, 36 and 37, respectively; L The regions include CDR-L1, CDR-L2 and CDR-L3, which comprise the sequences set forth in SEQ ID NOs: 38, 39 and 40, respectively.

[0088] In some optional embodiments, (i) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 1, and V L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2; or (ii) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 3 or about this percentage; L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4; or (iii) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 5 or about this percentage; L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6; or (iv) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 7, or about this percentage; Lis or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 8; or (v) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 9, or about this percentage; L is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 10.

[0089] Also, V H and V L BAFF-R, comprising: (i) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 1, and V L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2; or (ii) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 3 or about this percentage; L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 4; or (iii) VH is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 5, and V L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6; or (iv) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 7, and V L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 8; or (v) V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 9, and V L Provided herein are antibodies or antigen-binding portions thereof that specifically bind to BAFF-R, which are or comprise an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or about this percentage identity to SEQ ID NO: 10.

[0090] In some optional embodiments, V His or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 1, and V L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 2. In some embodiments, V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 3 or about this percentage; L is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO:4 or about this percentage.

[0091] In some optional embodiments, V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 5 or about this percentage; L is or comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 6. In some embodiments, V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 7, or about this percentage; Lis or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:8.

[0092] In some optional embodiments, V H is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96, 97%, 98% or 99% identity to SEQ ID NO: 9, or about this percentage; L is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 10.

[0093] In some optional embodiments, (i) V H and V L are or contain the sequences set forth in SEQ ID NOs: 1 and 2, respectively; or (ii) V H and V L are or contain the sequences set forth in SEQ ID NOs: 3 and 4, respectively; or (iii) V H and V L are or contain the sequences set forth in SEQ ID NOs: 5 and 6, respectively; or (iv) V H and V L are or comprise the sequences set forth in SEQ ID NOs: 7 and 8, respectively; or (v) V H and V L are or comprise the sequences set forth in SEQ ID NOs: 9 and 10, respectively.

[0094] Also, V H and V L BAFF-R, comprising: (i) V H and V Lare or contain the sequences set forth in SEQ ID NOs: 1 and 2, respectively; or (ii) V H and V L are or contain the sequences set forth in SEQ ID NOs: 3 and 4, respectively; or (iii) V H and V L are or contain the sequences set forth in SEQ ID NOs: 5 and 6, respectively; or (iv) V H and V L are or comprise the sequences set forth in SEQ ID NOs: 7 and 8, respectively; or (v) V H and V L Provided herein are antibodies, or antigen-binding portions thereof, that specifically bind to BAFF-R, which is or comprises the sequence set forth in SEQ ID NOs: 9 and 10, respectively.

[0095] In some optional embodiments, V H and V L are or comprise the sequences set forth in SEQ ID NOs: 1 and 2, respectively. In some of any of the embodiments, V H and V L are or comprise the sequences set forth in SEQ ID NOs: 3 and 4, respectively. H and V L are or comprise the sequences set forth in SEQ ID NOs: 5 and 6, respectively. H and V L are or comprise the sequences set forth in SEQ ID NOs: 7 and 8, respectively. H and V L are or comprise the sequences set forth in SEQ ID NOs: 9 and 10, respectively.

[0096] In some embodiments, the antibody is a full-length antibody. In some embodiments, the antibody is an antigen-binding fragment. In some embodiments, the BAFF-R antibody or antigen-binding portion thereof may be recombinant. In some embodiments, the V H and V Lis human or derived from a human protein. In some of any of the embodiments, the antigen-binding portion comprises a single chain variable fragment (scFv).

[0097] In some optional embodiments, V H is V L In some of the optional embodiments, V H is V L In some of the optional embodiments, V H and V L are connected by a flexible linker. In some of any of the embodiments, the flexible linker comprises the sequence set forth in SEQ ID NO:58.

[0098] In some embodiments, the antigen-binding portion is or comprises the sequence set forth in SEQ ID NO: 11, 12, 13, 14, or 15, or an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 11, 12, 13, 14, or 15. In some embodiments, the antigen-binding portion is or comprises the sequence set forth in SEQ ID NO: 11. In some embodiments, the antigen-binding portion is or comprises the sequence set forth in SEQ ID NO: 12. In some embodiments, the antigen-binding portion is or comprises the sequence set forth in SEQ ID NO: 13. In some embodiments, the antigen-binding portion is or comprises the sequence set forth in SEQ ID NO: 14. In some embodiments, the antigen-binding portion is or comprises the sequence set forth in SEQ ID NO: 15.

[0099] In some of any of the embodiments, the anti-BAFF-R antibody or antigen-binding portion thereof specifically binds to the human B-cell activating factor receptor (BAFF-R) protein. In some of any of the embodiments, the human BAFF-R protein comprises the amino acid sequence set forth in SEQ ID NO: 120.

[0100] Also provided herein are pharmaceutical compositions comprising any of the antibodies or antigen-binding portions thereof provided herein and a pharmaceutical carrier.

[0101] Also provided herein is a chimeric antigen receptor (CAR) comprising any of the antibodies or antigen-binding portions thereof provided herein, any of the extracellular antigen-binding domains provided herein comprising a transmembrane domain and an intracellular signaling domain. In some embodiments, the intracellular signaling domain comprises an intracellular signaling domain capable of inducing a primary activation signal in T cells.

[0102] In some of any of the embodiments, the intracellular signaling domain is a domain derived from a T cell receptor (TCR) component and / or comprises an immunoreceptor tyrosine-based activation motif (ITAM). In some embodiments, the intracellular signaling domain is the cytoplasmic signaling domain of the CD3 zeta (CD3ζ) chain, optionally the human CD3ζ chain. In some embodiments, the intracellular signaling region further comprises a costimulatory signaling region.

[0103] In some embodiments, the costimulatory signaling region is between the transmembrane region and the intracellular signaling domain. In some embodiments, the costimulatory signaling region comprises the intracellular signaling domain of a T cell costimulatory molecule, or a signaling portion thereof. In some embodiments, the costimulatory signaling region comprises the intracellular signaling domain of 4-1BB, optionally human 4-1BB.

[0104] Also provided herein is a conjugate comprising any of the antibodies or antigen-binding portions thereof provided herein and a heterologous molecule or moiety. In some of any of the embodiments, the heterologous molecule or moiety is a therapeutic moiety.

[0105] Also provided herein are nucleic acids encoding any of the antibodies or antigen-binding portions thereof provided herein.

[0106] Also provided herein are polynucleotides comprising any of the nucleic acids provided herein.

[0107] Also provided herein are polynucleotides comprising any of the nucleic acids encoding any of the conjugates provided herein. In some embodiments, the polynucleotides are optimized by splice site elimination. In some embodiments, the polynucleotides are codon-optimized for expression in human cells.

[0108] Also provided herein are expression vectors comprising any of the nucleic acids provided herein.

[0109] Also provided herein is a vector comprising any of the polynucleotides provided herein. In some embodiments, the vector is a viral vector. In some embodiments, the viral vector is a retroviral vector or a lentiviral vector.

[0110] Also provided herein are cells comprising any of the antibodies or antigen-binding portions thereof provided herein, any of the CARs provided herein, or any of the conjugates provided herein.

[0111] Also provided herein is a cell comprising any of the polynucleotides provided herein or any of the vectors provided herein. In some embodiments, the cell is an immune cell. In some embodiments, the cell can be a lymphocyte. In some embodiments, the cell can be a NK cell or a T cell. In some embodiments, the cell is a T cell, and the T cell is a CD4+ T cell or a CD8+ T cell. In some embodiments, the cell is a primary cell obtained from a subject.

[0112] Also provided herein are compositions comprising any of the cells provided herein.

[0113] Also provided herein are compositions comprising any of the antibodies or antigen-binding fragments thereof provided herein, any of the CARs provided herein, or any of the conjugates provided herein. In some embodiments, the compositions may further comprise a pharmaceutically acceptable excipient. In some embodiments, the compositions comprise CD4+ and CD8+ T cells, and the ratio of CD4+ T cells to CD8+ T cells is 1:3 to 3:1 or about 1:3 to 3:1, optionally 1:2 to 2:1 or about 1:2 to 2:1, optionally 1:1 or about 1:1.

[0114] Also provided herein is a method for producing an antibody or antigen-binding portion thereof that specifically binds to BAFF-R, comprising culturing under suitable conditions any of the host cells provided herein and obtaining the product expressed by the host cell.

[0115] Also provided herein are methods for preparing a BAFF-R targeting drug, an anti-BAFF-R antibody drug conjugate (ADC), a multifunctional anti-BAFF-R antibody, a reagent for diagnosing a BAFF-R-expressing tumor, or an anti-BAFF-R chimeric antigen receptor (CAR)-modified immune cell, the method comprising providing any of the antibodies or antigen-binding portions thereof provided herein and incorporating the antibody or antigen-binding portion thereof into the BAFF-R targeting drug, anti-BAFF-R ADC, multifunctional anti-BAFF-R antibody, a reagent for diagnosing a BAFF-R-expressing tumor, or anti-BAFF-R chimeric antigen receptor (CAR)-modified immune cell.

[0116] Also provided herein are methods of treatment comprising administering any of the cells provided herein or any of the compositions provided herein to a subject having a disease or disorder associated with BAFF-R.

[0117] Also provided herein are any of the cells provided herein or any of the compositions provided herein for use in treating a disease or disorder associated with BAFF-R.

[0118] Also provided herein is the use of any of the cells provided herein or any of the compositions provided herein for the manufacture of a medicament for treating a disease or disorder associated with BAFF-R.

[0119] Also provided herein is the use of any of the cells provided herein or any of the compositions provided herein for the treatment of a disease or disorder associated with BAFF-R.

[0120] Also provided herein are methods of treatment comprising administering any of the antibodies or antigen-binding portions thereof provided herein, any of the pharmaceutical compositions provided herein, any of the CARs provided herein, any of the conjugates provided herein, any of the nucleic acids provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein to a subject having a disease or disorder associated with BAFF-R.

[0121] Also provided herein is any of the anti-BAFF-R antibodies or antigen-binding portions thereof provided herein, any of the pharmaceutical compositions provided herein, any of the CARs provided herein, any of the conjugates provided herein, any of the nucleic acids provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein for use in treating a disease or disorder associated with BAFF-R.

[0122] Also provided herein is the use of any of the anti-BAFF-R antibodies or antigen-binding portions thereof provided herein, any of the pharmaceutical compositions provided herein, any of the CARs provided herein, any of the conjugates provided herein, any of the nucleic acids provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein for the manufacture of a medicament for treating a disease or disorder associated with BAFF-R.

[0123] Also provided herein is the use of any of the antibodies or antigen-binding portions thereof provided herein, any of the pharmaceutical compositions provided herein, any of the CARs provided herein, any of the conjugates provided herein, any of the nucleic acids provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein for the treatment of diseases or disorders associated with BAFF-R.In some of any of the embodiments, the disease or disorder associated with BAFF-R is cancer.In some of any of the embodiments, the cancer is BAFF-R-expressing cancer.

[0124] Also provided herein are kits comprising any of the antibodies or antigen-binding portions thereof provided herein, any of the pharmaceutical compositions provided herein, any of the CARs provided herein, any of the conjugates provided herein, any of the nucleic acids provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein, any of the cells provided herein, or any of the compositions provided herein, and instructions for use, where appropriate, the instructions are for administering the antibody or antigen-binding portion thereof, conjugate, cell, or composition according to the methods, for any use provided herein, or for any use provided herein, as appropriate.

[0125] Also provided herein are articles of manufacture comprising any of the antibodies or antigen-binding portions thereof provided herein, any of the pharmaceutical compositions provided herein, any of the CARs provided herein, any of the conjugates provided herein, any of the nucleic acids provided herein, any of the polynucleotides provided herein, or any of the vectors provided herein, any of the cells provided herein, any of the compositions provided herein, or any of the kits provided herein. [Brief explanation of the drawings]

[0126] [Figure 1] Figure 1 shows activation of Jurkat T cells containing constructs encoding a Nur77 knock-in reporter and various anti-BAFF-R CARs HEK293 when co-cultured with target cells. [Figure 2] FIG. 2 shows a schematic representation of the orientation of BAFF-R and CD19 binders in either a linear bispecific design (left) or a loop bispecific design (right). [Figure 3] Figure 3 shows the ability of bispecific CARs to be stimulated by BAFF-R- CD19+ cells, BAFF-R+ CD19- cells, neither cell population, or both cell populations in Jurkat T cells containing a Nur77 knock-in reporter. [Figure 4] Figures 4A-4G show the cell-killing ability (Figures 4A, 4C, 4E, and 4F) and ability to induce cytokine production (Figures 4B, 4D, and 4G) of 30 selected bispecific CARs. [Figure 5] Figures 5A-5C show the cytolytic activity of bispecific CAR-expressing T cells when cocultured with a B-cell cancer cell line (Granta-519). The cytolytic activity of bispecific CAR-expressing T cells cocultured at a 1:2 effector:target ratio with Granta cells expressing both BAFF-R and CD19 (Figure 5A), Granta cells with a CD19 knockout (KO) and therefore expressing only BAFF-R (Figure 5B), or Granta cells with a BAFF-R KO and therefore expressing only CD19 (Figure 5C). [Figure 6]Figures 6A-6C show the levels of cytokine production by T cells expressing various CAR receptors after co-incubation with a B-cell cancer cell line (Granta-519). Shown are IFNγ (Figure 6A), IL-2 (Figure 6B), and TNF-γ (Figure 6C) production by CAR-T cells after co-incubation with Granta cells expressing BAFF-R only (CD19 KO), CD19 only (BAFF-R KO), or both BAFF-R and CD19. [Figure 7] 7A-7B show the expression levels of BAFF-R (FIG. 7A) and CD19 (FIG. 7B) in various cell lines, including Granta, Nalm-6, and RL cell lines. [Figure 8] Figure 8 shows the effect of soluble BAFF on selected anti-CD19 / anti-BAFF-R bispecific CARs. [Figure 9] Figures 9A-9D show the therapeutic effects of selected bispecific CAR T cells in tumor mouse models. Seven selected bispecific CAR T cells were administered at two different doses to mice in the Raji (Figure 9A) or Nalm6 (Figure 9B) mouse models. Four selected bispecific CAR T cells were administered at two different doses to mice in the Raji (Figure 9C) or Nalm6 (Figure 9D) mouse models. DETAILED DESCRIPTION OF THE INVENTION

[0127] Provided herein are bispecific chimeric antigen receptors (CARs) that target or are directed against B cell activating factor receptor (BAFF-R) and CD19, as well as BAFF-R and / or CD19-expressing cells and diseases. Also provided are cells, such as T cells, engineered to express the provided bispecific CARs, and compositions containing such cells. BAFF-R is expressed in most mature B cells and in certain diseases or conditions, such as B cell lymphoproliferative disorders. Among the provided embodiments are approaches useful in treating diseases and conditions and / or targeting such cell types, including chimeric antigen receptors (CARs), including nucleic acid molecules encoding BAFF-R and CD19 binding domains, as well as the encoded receptors (such as the encoded CARs), and compositions and products comprising them. Receptors are generally expressed using antibodies specific for BAFF-R and CD19 [heavy chain variable (V)]. H ) regions, single domain antibody fragments, and single chain fragments including scFv, and V HH

[0013] Also provided are cells, such as engineered or recombinant cells, that express such BAFF-R and CD19 binding receptors, e.g., bispecific CARs, and / or contain nucleic acids encoding such receptors, as well as compositions and articles of manufacture and therapeutic doses containing such cells.

[0128] Embodiments provided herein relate to CAR T cells that target both BAFF-R and CD19 for the treatment of cancer, specifically B-cell cancers. While CD19 CAR-T cell therapy has been effective in treating human subjects with B-cell malignancies, some patients relapse due to loss of the CAR-specific antigen on cancer cells ("escape") or poor CAR-T cell performance. BAFF-R is one of three known receptors for BAFF, a regulator of both B-cell and T-cell function. BAFF-R is a B-cell survival receptor and is highly expressed in B-cell malignancies. Targeting a second antigen may overcome antigen downregulation or loss, thus reducing the chance of immune escape.

[0129] A cell therapy approach utilizing a bispecific CAR targeting both BAFF-R and CD19 expressed on autologous primary T cells is provided for use as a therapeutic agent against cancer cells. In some cases, simultaneous targeting of both antigens as provided herein may improve the depth and durability of overall patient response, in addition to minimizing relapse due to antigen escape. As evidenced by data from CAR T cell trials in B-cell malignancies, a mechanism of resistance to CAR T cell therapy may be loss or downregulation ("escape") of the target antigen (Robbie G. Majzner and Crystal L. Mackall, Cancer Discov August 22, 2018; DOI 10.1158 / 2159-8290.CD-18-0442). Such dual-targeting strategies can achieve synergistic or improved tumor responses based on targeting two antigens compared to approaches requiring targeting only a single antigen. A dual targeting approach may be advantageous to overcome problems due to potential antigen loss in cancer and / or to maximize antigen targeting.

[0130] In some situations, recombinant receptors may exhibit antigen-independent activity or signaling (also known as "tonic signaling"), which can result in undesirable effects, such as increased differentiation and / or exhaustion of T cells expressing the recombinant receptor. In some embodiments, such activity can limit the activity, efficacy, or potency of T cells. In some cases, during engineering and ex vivo expansion of cells for recombinant receptor expression, the cells may exhibit a phenotype indicative of exhaustion due to tonic signaling through the recombinant receptor. In some cases, alternative or additional cancer-targeted T cell therapy approaches are needed. Among the chimeric antigen receptors provided are chimeric receptors that exhibit high expression of both the CD19-binding domain and the BAFF-R-binding domain and low tonic signaling, thereby minimizing the potential for antigen-independent (tonic) signaling. In particular, the bispecific CARs provided herein include CARs with high antigen-dependent activation and minimal tonic signaling.

[0131] Among the embodiments provided are approaches useful for treating diseases and conditions and / or targeting such cell types, including nucleic acid molecules encoding bispecific chimeric antigen receptors (CARs) that bind both BAFF-R and CD19, as well as the encoded receptors (such as the encoded CARs), and compositions and products comprising the same. The receptors are generally antibodies specific for BAFF-R and CD19 [heavy chain variable (V)]. H ) regions, single domain antibody fragments, and antigen-binding antibody fragments such as single-chain fragments including single-chain variable fragments (scFvs). Also provided are cells, such as engineered or recombinant cells, that express such CARs and / or contain nucleic acids encoding such receptors, as well as compositions and articles of manufacture and therapeutic doses containing such cells.

[0132] All publications, including patent documents, scientific articles, and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. To the extent that a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in a patent, application, published application, or other publication incorporated herein by reference, the definition set forth herein takes precedence over the definition incorporated herein by reference.

[0133] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0134] I. BAFF-R targeting antibody Anti-BAFF-R antibodies are provided herein. Some antibodies contain a heavy chain variable region (V H ) and / or light chain variable region (V L In some embodiments, the antibody is a V, such as a single chain Fv fragment (scFv), or one containing a portion thereof. H and V L Antibodies include antibodies that specifically bind to BAFF-R, e.g., human BAFF-R. Among the anti-BAFF-R antibodies provided are human antibodies, or antibodies that are modified forms or variants of human antibodies. Antibodies include isolated antibodies. BAFF-R-binding molecules containing such antibodies are also provided, including single-chain proteins, fusion proteins, conjugates, and / or recombinant receptors, such as chimeric receptors, including antigen receptors. In some embodiments, BAFF-R-binding molecules include isolated molecules.

[0135] Also provided are BAFF-R-binding cell surface proteins, such as BAFF-R-binding recombinant receptors. The BAFF-R-binding cell surface proteins may contain a provided antibody (e.g., an antigen-binding antibody fragment) that specifically binds to BAFF-R, such as a BAFF-R protein, such as a human BAFF-R protein. In some examples, the recombinant receptor is a chimeric antigen receptor, such as one containing an anti-BAFF-R antibody or an antigen-binding fragment thereof.

[0136] The term "antibody" is used herein in the broadest sense and includes intact antibodies as well as antigen-binding (Fab) fragments, F(ab')2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rIgG) fragments, heavy chain variable (V) fragments capable of specifically binding to an antigen. H ) regions, single chain antibody fragments including single chain variable fragments (scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody, V HH "antibody" encompasses polyclonal and monoclonal antibodies, including functional (antigen-binding) antibody fragments, including fragments of the antibody itself. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, multispecific, e.g., bispecific or trispecific, antibodies, diabodies, triabodies, and tetrabodies, tandem di-scFvs, tandem tri-scFvs, and the like. Unless otherwise stated, the term "antibody" should be understood to encompass functional antibody fragments, also referred to herein as "antigen-binding fragments." The term also encompasses complete or full-length antibodies, including antibodies of any class or subclass, including IgG and its subclasses, IgM, IgE, IgA, and IgD.

[0137] The terms "complementarity-determining region" and "CDR" are synonymous with "hypervariable region" or "HVR" and are known to refer to non-contiguous sequences of amino acids in an antibody variable region, conferring antigen specificity and / or binding affinity. Generally, there are three CDRs (CDR-H1, CDR-H2, CDR-H3) in each heavy chain variable region and three CDRs (CDR-L1, CDR-L2, CDR-L3) in each light chain variable region. The terms "framework region" and "FR" are known to refer to the non-CDR portions of the heavy and light chain variable regions. Generally, there are four FRs (FR-H1, FR-H2, FR-H3, and FR-H4) in each full-length heavy chain variable region and four FRs (FR-L1, FR-L2, FR-L3, and FR-L4) in each full-length light chain variable region.

[0138] The precise amino acid sequence boundaries of a given CDR or FR may be determined by Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD ("Kabat" numbering scheme); Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48 ("Chothia" numbering scheme); MacCallum et al., J. Mol. Biol, 1996; 262:732-745 ("Contact" numbering scheme); Lefranc MP et al., Dev Comp Immunol, 2003; 27(1):55-77 ("IMGT" numbering scheme); Honegger A and Pluckthun A, J Mol Biol, 2001; 309(3):657-70 ("Aho" numbering scheme), Martin et al., PNAS, 1989; 86(23):9268-9272 ("AbM" numbering scheme), and Ye et al., Nucleic Acids Res. 2013; 41(Web Server issue):W34-40 ("IgBLAST" numbering scheme).Details regarding various numbering schemes are also provided in, for example, Jarasch et al., Proteins, 2017; 85(1):65-71, Martin et al., Bioinformatics tools for antibody engineering. In: Dubel, S. (editor) Handbook of Therapeutic Antibodies, Vol. 1. Wiley-VCH, Weinheim, Germany, Martin, ACR (2010). Protein Sequence and Structure Analysis of Antibody Variable Domains. In: Kontermann, R., Dubel, S. (eds) Antibody Engineering. Springer Protocols Handbooks. Springer, Berlin, Heidelberg, and Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] bioinf.org.uk / abs / info.html, all of which are incorporated by reference in their entirety. A variety of prediction algorithm tools are available and known for numbering antibody residues and CDRs (e.g., AbYsis, Abnum, AbYmod, AbRSA, IgBLAST, IMGT, or ANARCI).

[0139] The boundaries of a given CDR or FR may vary depending on the scheme used for identification. For example, the Kabat scheme is based on a structural algorithm, while the Chothia scheme is based on structural information. Both the Kabat and Chothia schemes use numbering based on the most common antibody region sequence lengths, sometimes with insertions. Insertions in a sequence relative to the standard numbering scheme are indicated using an insertion letter code. For example, residues inserted between residues L30 and L31 are indicated as L31A, L31B, etc. Deletions in a sequence relative to the standard numbering scheme are accommodated by skipping a number. The two schemes place certain insertions and deletions ("indels") in different positions, resulting in different numbering. For example, the Chothia numbering scheme is nearly identical to the Kabat numbering scheme, except that insertions are placed in structural positions and morphologically equivalent residues are assigned the same number. The Contact scheme is based on the analysis of complex crystal structures and is similar in many aspects to the Chothia numbering scheme. The AbM scheme is a compromise between the Kabat and Chothia definitions based on using Oxford Molecular's AbMd antibody modeling software. The IgBLAST scheme is based on matching germline V, D, and J genes and can be determined using the National Center for Biotechnology Information (NCBI)'s IgBLAST tool.

[0140] In some embodiments, Kabat numbering may be determined by known sequence rules, e.g., as described in Kabat et al. (1991), "Sequences of Proteins of Immunological Interest," 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD.In some embodiments, the Kabat numbering scheme in some aspects may include any of the following rules for designating CDRs: CDR-L1 begins at about residue 24 of the light chain and is always preceded by a C residue and always followed by a W residue; the end of CDR-L1 is defined by three residues (the W residue is followed by Y, L, or F, which may be followed by Q or L); CDR-1 has a length of 10-17 residues; CDR-L2 always begins 16 residues after the end of CDR-L1; the two residues before CDR-L2 are I and L. and Y, but can also be V and Y, I and K, or I and F; CDR-L2 is always 7 residues long; CDR-L3 always begins 33 residues after the end of CDR-L2 and is always preceded by a C residue and strictly followed by an FGXG sequence motif (where X is any amino acid); CDR-L3 has a length of 7 to 11 residues; CDR-H1 begins at about position 26 of the heavy chain; the first amino acid of CDR-H1 is always 9 residues after the conserved C residue; CDR-H1 is followed by an invariant W residue, followed by It is typically followed by V, but can also be I or A; CDR-H1 has a length of 5 to 7 residues; CDR-H2 always begins 15 residues after the end of CDR-H1; the first residue of CDR-H2 is usually preceded by the sequence motif LEWIG, although some variation exists; the end of CDR-H2 is defined by a three-residue motif—the first residue of the three-residue motif can be either K or R, the second residue of the three-residue motif can be L, I, V, F, T, or A, and the third residue of the three-residue motif can be T, S, I, or A; CDR-H2 has a length of 16 to 19 residues; CDR-H3 always starts 33 residues after the end of CDR-H2 and is always 3 residues after the C residue - the first residue of CDR-H3 is preceded by a conserved C residue followed by two residues (usually AR); residues following CDR-H3 are strictly followed by a WGXG sequence motif (where X is any amino acid); CDR-H3 typically has a length of 3 to 25 residues; CDR-H3 can be much longer than 25 residues.

[0141] In some cases, the exact boundary position of a particular CDR according to the Chothia numbering scheme may vary based on different definitions of CDRs (see, e.g., Martin, ACR, Antibody Information: How to identify the CDRs by looking at a sequence [online] bioinf.org.uk / abs / info.html). For example, in some cases, the boundary position of CDR-L1 according to the Chothia numbering scheme may be L26-L32 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Lesk AM J Mol Biol, 1987; 196(4):901-17). In some cases, the boundary position of CDR-L1 may be L25-L32 (Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some cases, the CDR-L2 boundary position may be L50 to L52, and the CDR-L3 boundary position may be L91 to L96 (Chothia et al., Science, 1986; 233(4765):755-8, Chothia C. and Lesk AM J Mol Biol, 1987; 196(4):901-17, and Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some cases, the boundary positions of CDR-H1 may be H26 to H32 according to the Chothia numbering scheme (Chothia et al., Science, 1986; 233(4765):755-8, Chothia C. and Lesk AM J Mol Biol, 1987; 196(4):901-17, and Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48).In some cases, the CDR-H2 boundary position may be H53 to H55 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Lesk AM J Mol Biol, 1987, 196(4):901-17), H52a to H55 (Tramontano et al., J Mol Biol, 1990, 215(1):175-82), or H52 to H56 (Al-Lazikani et al., J Mol Biol, 1997; 273(4):927-48). In some cases, the CDR-H3 boundary position may be H96 to H101 (Chothia et al., Science, 1986; 233(4765):755-8 and Chothia C. and Lesk AM J Mol Biol, 1987; 196(4):901-17). In some cases, the CDR-H3 boundary position may be H92 to H104 (Morea et al., Biophys Chem, 1997; 68(1-3):9-16 and Morea et al., J Mol Biol., 1998; 275(2):269-944).

[0142] Table 1 below illustrates exemplary numbering and lists exemplary boundary positions for CDR-L1, CDR-L2, CDR-L3, and CDR-H1, CDR-H2, and CDR-H3 identified by the Kabat, Chothia, AbM, and Contact schemes, respectively. For CDR-H1, residue numbering is listed using both the Kabat and Chothia numbering schemes. FRs are located between the CDRs; for example, FR-L1 precedes CDR-L1, FR-L2 is located between CDR-L1 and CDR-L2, FR-L3 is located between CDR-L2 and CDR-L3, etc. Note that the Kabat numbering scheme shown places the insertion at H35A and H35B, so the ends of the Chothia CDR-H1 loop, when numbered using the Kabat numbering convention shown, vary from H32 to H34 depending on the length of the loop.

[0143] [Table 1]

[0144] Thus, unless otherwise specified, the "CDR" or "complementarity determining region" or each particular CDR (e.g., CDR-H1, CDR-H2, CDR-H3) of a given antibody or region thereof, such as a variable region, should be understood to encompass one (or a particular) complementarity determining region as defined by any of the above schemes or other known schemes. For example, if a particular CDR (e.g., CDR-H3) is a CDR of a given V H or V L When a variable region amino acid sequence is described as containing the amino acid sequence of a corresponding CDR in the variable region, it is understood that such CDR has the sequence of the corresponding CDR (e.g., CDR-H3) in the variable region, as defined by either the scheme described above or other known schemes. In some embodiments, an antibody or antigen-binding portion thereof may be H The amino acid sequence of the CDR-H1, CDR-H2, and CDR-H3 regions is contained within the CDR-H1 region. L When describing a region containing CDR-L1, CDR-L2, and CDR-L3 amino acid sequences, the CDRs may be defined by any of the above-mentioned schemes, such as Kabat, Chothia, AbM, IgBLAST, IMGT, or contact methods, or other known schemes. In some embodiments, specific CDR sequences are identified. While exemplary CDR sequences of the provided antibodies are described using various numbering schemes, it is understood that the provided antibodies may contain CDRs described according to any of the above-mentioned numbering schemes or other known numbering schemes.

[0145] Similarly, unless otherwise specified, it should be understood that the FRs or each particular FR (e.g., FR-H1, FR-H2, FR-H3, FR-H4, FR-L1, FR-L2, FR-L3, and / or FR-L4) of a given antibody or region thereof, such as a variable region, encompass one (or particular) framework region defined by any known scheme. In some cases, a scheme for identifying a particular CDR, FR, or FRs or CDRs is specified, such as CDRs defined by the Kabat, Chothia, AbM, IgBLAST, IMGT, or Contact method or other known scheme. In other cases, the particular amino acid sequence of the CDR or FR is provided. In some embodiments, an antibody or antigen-binding fragment thereof is characterized by a given V H The amino acid sequence of a given V includes FR-H1, FR-H2, FR-H3, and FR-H4. L When described as including FR-L1, FR-L2, FR-L3, and FR-L4 contained within a region amino acid sequence, the CDRs may be defined by any of the aforementioned schemes, such as the Kabat, Chothia, AbM, IgBLAST, IMGT, or contact method, or other known schemes.

[0146] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable regions of the heavy and light chains of a native antibody (V H and V L ) have generally similar structures, with each domain containing four conserved framework regions (FRs) and three CDRs (see, e.g., Kindt et al. Kuby Immunology, 6th ed., W.H. Freeman and Co., page 91 (2007)). H or V L A V domain may be sufficient to confer antigen-binding specificity. Furthermore, an antibody that binds to a particular antigen may have a V domain that is sufficient to confer antigen-binding specificity. H or V LDomains isolated using complementary V L or V H Libraries of domains can be screened individually. See, e.g., Portolano et al., J. Immunol. 150:880-887 (1993); Clarkson et al., Nature 352:624-628 (1991).

[0147] Among the antibodies provided are antibody fragments. An "antibody fragment" or "antigen-binding fragment" refers to a molecule other than a natural antibody that contains a portion of a natural antibody that binds to the antigen to which the natural antibody binds. Examples of antibody fragments include Fv, Fab, Fab', Fab'-SH, F(ab')2; diabodies; linear antibodies; heavy chain variable (V) antibodies; and the like. H ) regions, single-chain antibody molecules such as scFvs, and V H In some embodiments, the antibody comprises a variable heavy chain (VH), ... H ) region and the variable light chain (V L In certain embodiments, the antibody is or comprises an antibody fragment comprising a heavy chain variable (V) region, such as an scFv. H ) region and / or light chain variable (V L ) region.

[0148] A single domain antibody (sdAb) is an antibody fragment that contains all or part of the heavy chain variable region or all or part of the light chain variable region of an antibody. In certain embodiments, a single domain antibody is a human single domain antibody.

[0149] Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of natural antibodies and production by recombinant host cells. In some embodiments, the antibody is a recombinantly produced fragment, such as a fragment containing a non-naturally occurring configuration, such as two or more antibody regions or chains connected by a synthetic linker, e.g., a peptide linker, and / or a configuration that cannot be produced by enzymatic digestion of a naturally occurring native antibody. In some aspects, the antibody fragment is an scFv.

[0150] A "humanized" antibody is an antibody in which all or substantially all CDR amino acid residues are derived from non-human CDRs and all or substantially all FR amino acid residues are derived from human FRs. A humanized antibody may optionally contain at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of a non-human antibody refers to a variant of a non-human antibody that has undergone humanization, typically to reduce immunogenicity in humans while retaining the specificity and affinity of the parent non-human antibody. In some embodiments, some FR residues in a humanized antibody are substituted with the corresponding residues of a non-human antibody (e.g., the antibody from which the CDR residues are derived), e.g., to retain or improve the specificity or affinity of the antibody.

[0151] Among the antibodies provided are human antibodies. A "human antibody" is an antibody having an amino acid sequence corresponding to an antibody produced by a human or human cell, or by a non-human source that utilizes a human antibody repertoire, including a human antibody library, or other human antibody coding sequence. The term excludes humanized forms of non-human antibodies that contain non-human antigen-binding regions, such as those in which all or substantially all CDRs are non-human. The term includes antigen-binding fragments of human antibodies.

[0152] Human antibodies can be prepared by administering immunogens to transgenic animals that have been modified to produce natural human antibodies or natural antibodies with human variable regions in response to antigen challenge. Such animals typically contain all or part of human immunoglobulin loci, which replace endogenous immunoglobulin loci or are extrachromosomally present or randomly integrated into the animal's chromosomes. In such transgenic animals, the endogenous immunoglobulin loci are generally inactivated. Human antibodies can also be derived from human antibody libraries, including phage display and cell-free libraries, which contain antibody coding sequences derived from the human repertoire.

[0153] Among the antibodies provided are monoclonal antibodies, including monoclonal antibody fragments. As used herein, the term "monoclonal antibody" refers to an antibody obtained from or within a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical, except for variants that contain naturally occurring mutations or that may arise during the production of the monoclonal antibody preparation, such variants generally being present in minor amounts. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different epitopes, each monoclonal antibody of a monoclonal antibody preparation is directed against a single epitope on an antigen. This term should not be construed as requiring production of the antibody by any particular method. Monoclonal antibodies can be produced by a variety of techniques, including, but not limited to, hybridoma, recombinant DNA methods, phage display, and other antibody display methods.

[0154] A. Exemplary Antibodies In some embodiments, the antibody, e.g., anti-BAFF-R antibody, e.g., antigen-binding antibody fragment, comprises a heavy and / or light chain variable region (V H Or V L) sequence, or a sufficient antigen-binding portion thereof. In some embodiments, the antibody, e.g., anti-BAFF-R antibody, e.g., antigen-binding antibody fragment, is a single chain fragment, such as a single chain Fv (scFv) fragment. In some aspects, the scFv contains a V H and V L Includes.

[0155] In some embodiments, the anti-BAFF-R antibody, e.g., antigen-binding antibody fragment, comprises a V nucleotide sequence containing the heavy chain complementarity determining region 1 (CDR-H1), heavy chain complementarity determining region 2 (CDR-H2), and / or heavy chain complementarity determining region 3 (CDR-H3) described above. H In some embodiments, the anti-BAFF-R antibody, e.g., antigen-binding antibody fragment, comprises a V sequence containing the described CDR-H1, CDR-H2, and CDR-H3. H In some embodiments, an anti-BAFF-R antibody, e.g., an antigen-binding antibody fragment, comprises a V sequence containing the light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2), and / or light chain complementarity determining region 3 (CDR-L3) described above. L In some embodiments, the anti-BAFF-R antibody, e.g., antigen-binding antibody fragment, comprises a V sequence containing the described CDR-L1, CDR-L2, and CDR-L3. L The sequence or a sufficient antigen-binding portion thereof.

[0156] In some embodiments, the anti-BAFF-R antibody, e.g., antigen-binding antibody fragment, comprises a V molecule containing the described CDR-H1, CDR-H2, and / or CDR-H3. H V containing the sequence and containing the CDR-L1, CDR-L2 and / or CDR-L3 as described L In some embodiments, the anti-BAFF-R antibody, e.g., antigen-binding antibody fragment, comprises a V sequence containing the described CDR-H1, CDR-H2, and CDR-H3. H V containing the sequence and containing the CDR-L1, CDR-L2 and CDR-L3 described LAlso, some antibodies have sequences that are at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identical to such sequences.

[0157] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 1. H ) region or as set forth in SEQ ID NO: 1, or such a V H V containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H V having an amino acid sequence that has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity with the amino acids in the region H It has an area.

[0158] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO:3. H ) region, or V shown in SEQ ID NO:3 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H It has an area.

[0159] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO:5. H ) region, or V shown in SEQ ID NO:5 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H It has an area.

[0160] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO:7. H ) region, or V shown in SEQ ID NO: 7 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H It has an area.

[0161] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO:9. H ) region, or V shown in SEQ ID NO: 9 Hor about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H It has an area.

[0162] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to Kabat numbering. H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to Chothia numbering. H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to AbM numbering.

[0163] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable heavy chain (VH1) comprising a CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 16, a CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 17, and a CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 18. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V ) region comprising the amino acid sequences set forth in SEQ ID NOs: 16, 17, and 18. H Includes the area.

[0164] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is V shown in SEQ ID NO: 1. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO: 1. H Includes the area.

[0165] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable heavy chain (VH1) comprising a CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 22, a CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 23, and a CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 24. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 22, 23, and 24. H Includes the area.

[0166] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is shown in SEQ ID NO: 3. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:3. H Includes the area.

[0167] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable heavy chain (VH1) comprising a CDR-H1 having the amino acid sequence set forth in SEQ ID NO:28, a CDR-H2 having the amino acid sequence set forth in SEQ ID NO:29, and a CDR-H3 having the amino acid sequence set forth in SEQ ID NO:30. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V ) region comprising the amino acid sequence set forth in SEQ ID NOs: 28, 29, and 30. H Includes the area.

[0168] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is V shown in SEQ ID NO: 5. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:5. H Includes the area.

[0169] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable heavy chain (VH1) comprising a CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 22, a CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 32, and a CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 24. H In some embodiments, the antibody or antigen-binding fragment thereof has a V region comprising the amino acid sequence set forth in SEQ ID NOs: 22, 32, and 24. H Includes the area.

[0170] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, VH The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is shown in SEQ ID NO: 7. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:7. H Includes the area.

[0171] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable heavy chain (VH1) comprising a CDR-H1 having the amino acid sequence set forth in SEQ ID NO: 35, a CDR-H2 having the amino acid sequence set forth in SEQ ID NO: 36, and a CDR-H3 having the amino acid sequence set forth in SEQ ID NO: 37. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequences set forth in SEQ ID NOs: 35, 36, and 37. H Includes the area.

[0172] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is shown in SEQ ID NO: 9. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:9. H Includes the area.

[0173] In some embodiments, V H The antibody or antibody fragment comprising the V region further comprises a light chain or a sufficient antigen-binding portion thereof. For example, in some embodiments, the antibody or antigen-binding fragment thereof comprises a V H Area and V L Area, or V H Area and V L In such an embodiment, the V H The domain sequence is the V H In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0174] In some embodiments, the anti-BAFF-R antibody or antigen-binding fragment thereof is selected from the group consisting of the V H For example, in some embodiments, the antibody or antigen-binding fragment thereof contains either a V H domain and variable light chain (V L ) area, or V H Area and V L In such an embodiment, the V H The domain sequence is the V HIn some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0175] In some embodiments, the anti-BAFF-R antibody or antigen-binding fragment thereof comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO:2. L ) region, or V shown in SEQ ID NO:2 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L It has an area.

[0176] In some embodiments, the anti-BAFF-R antibody or antigen-binding fragment thereof comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO:4. L ) region, or V shown in SEQ ID NO: 4 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L It has an area.

[0177] In some embodiments, the anti-BAFF-R antibody or antigen-binding fragment thereof comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO:6. L ) region, or V shown in SEQ ID NO:6 Lor about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L It has an area.

[0178] In some embodiments, the anti-BAFF-R antibody or antigen-binding fragment thereof comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO:8. L ) region, or V shown in SEQ ID NO: 8 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L It has an area.

[0179] In some embodiments, the anti-BAFF-R antibody or antigen-binding fragment thereof comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 10. L ) region, or V shown in SEQ ID NO: 10 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence LIt has an area.

[0180] In some embodiments, the V of the antibody or antigen-binding fragment thereof L The V region comprises CDR-L1, CDR-L2 and / or CDR-L3 according to Kabat numbering. L The V region comprises CDR-L1, CDR-L2 and / or CDR-L3 according to Chothia numbering. L The regions include CDR-L1, CDR-L2 and / or CDR-L3 according to AbM numbering.

[0181] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 19, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 20, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 21. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V ) region comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO:2. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0182] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable light chain (V) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO:25, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO:26, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO:27. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V ) region comprising the amino acid sequence set forth in SEQ ID NOs: 25, 26, and 27. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO:4. LEach of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0183] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable light chain (V) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 27. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V ) region comprising the amino acid sequence set forth in SEQ ID NOs: 31, 26, and 27. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO:6. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0184] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable light chain (V) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 33, 26, and 34. L In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO:8. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0185] In some embodiments, the anti-BAFF-R antibody or antigen-binding antibody fragment thereof comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 39, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 40. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V ) region comprising the amino acid sequence set forth in SEQ ID NOs: 38, 39, and 40.L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO: 10. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0186] V having at least 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 1. H V region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:2. L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising the region.

[0187] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO: 1 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 2. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the region amino acid sequence.

[0188] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 1 and is a V region of the antibody or antigen-binding fragment thereof. LThe V region comprises the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 1 and 2, respectively, or have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0189] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences shown in SEQ ID NOs: 1 and 2, respectively.

[0190] V having at least 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:3. H V region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:4. L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising the region.

[0191] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:3 HThe amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 4. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the region amino acid sequence.

[0192] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 3 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 3 and 4, respectively, or have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0193] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences shown in SEQ ID NOs: 3 and 4, respectively.

[0194] V having at least 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:5. Hand V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:6. L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising the region.

[0195] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:5 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 6. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the region amino acid sequence.

[0196] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 5 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 5 and 6, respectively, or have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0197] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V LThe regions comprise the amino acid sequences shown in SEQ ID NOs: 5 and 6, respectively.

[0198] V having at least 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7. H V region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising the region.

[0199] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:7 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 8. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the region amino acid sequence.

[0200] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 7 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V LThe regions comprise the amino acid sequences set forth in SEQ ID NOs: 7 and 8, respectively, or have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0201] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences shown in SEQ ID NOs: 7 and 8, respectively.

[0202] V having at least 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9. H and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10. L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising the region.

[0203] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:9 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 10. LThe amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the region amino acid sequence.

[0204] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 9 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 9 and 10, respectively, or have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0205] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 9 and 10, respectively.

[0206] V comprising the sequence set forth in SEQ ID NO: 1 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to the amino acid sequence set forth in SEQ ID NO: 1. H a V region comprising the sequence set forth in SEQ ID NO:2 or an amino acid sequence having at least or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:2;L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising regions. In some embodiments, the BAFF-R antibody comprises a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively. H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 19, 20 and 21, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 1, L The region comprises the sequence shown in SEQ ID NO:2.

[0207] V comprising the sequence set forth in SEQ ID NO:3 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to the amino acid sequence set forth in SEQ ID NO:3. H a V region comprising the sequence set forth in SEQ ID NO:4 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:4; L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising regions. In some embodiments, the BAFF-R antibody comprises a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively. H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 25, 26 and 27, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 3, L The region comprises the sequence shown in SEQ ID NO:4.

[0208] V comprising the sequence set forth in SEQ ID NO:5 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to the amino acid sequence set forth in SEQ ID NO:5. H a V region comprising the sequence set forth in SEQ ID NO:6 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:6; L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising regions. In some embodiments, the BAFF-R antibody comprises a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively. H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 31, 26 and 27, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 5, L The region comprises the sequence shown in SEQ ID NO:6.

[0209] V comprising the sequence set forth in SEQ ID NO: 7 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to the amino acid sequence set forth in SEQ ID NO: 7. Ha V region comprising the sequence set forth in SEQ ID NO:8 or an amino acid sequence having at least or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:8; L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising regions. In some embodiments, the BAFF-R antibody comprises a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 22, 32, and 24, respectively. H and a V region having CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 33, 26, and 34, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 7, L The region comprises the sequence shown in SEQ ID NO:8.

[0210] V comprising the sequence set forth in SEQ ID NO:9 or an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to the amino acid sequence set forth in SEQ ID NO:9. H a V region comprising the sequence set forth in SEQ ID NO:10, or an amino acid sequence having at least or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identity to SEQ ID NO:10; L Provided herein are anti-BAFF-R antibodies or antigen-binding fragments thereof comprising regions. In some embodiments, the BAFF-R antibody comprises a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 35, 36, and 37, respectively.H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 38, 39 and 40, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 9, L The region comprises the sequence shown in SEQ ID NO:10.

[0211] In some embodiments, the antibody or antigen-binding fragment thereof is a single-chain antibody fragment, such as a single-chain variable fragment (scFv) or a diabody or a single-domain antibody (sdAb). H In some embodiments, the antibody or antigen-binding fragment is a single domain antibody comprising only the heavy chain variable (V H ) region and the light chain variable (V L In some embodiments, the single-chain antibody fragment (e.g., scFv) is an scFv comprising a heavy chain variable (V H ) region and the light chain variable (V L The linker comprises one or more linkers connecting two antibody domains or regions, such as the α- and β-domains. The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker. Some linkers are rich in glycine and serine, and / or in some cases, threonine. In some embodiments, the linker further comprises charged residues, such as lysine and / or glutamic acid, which may improve solubility. In some embodiments, the linker further comprises one or more prolines.

[0212] The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker such as one rich in glycine and serine. In some embodiments, the BAFF-R binding domain is V H Area and V L In some embodiments, the BAFF-R binding domain comprises a V H Area and V L One of the regions, the linker, and V HArea and V L and the other of the regions, in that order from N-terminus to C-terminus. In some embodiments, the linker is set forth in SEQ ID NO: 58. Thus, in some embodiments, the BAFF-R binding domain comprises V H Area and V L one of the regions, a linker shown in SEQ ID NO: 58, and V H Area and V L The other of the regions is included in that order from N-terminus to C-terminus.

[0213] In some aspects, a linker rich in glycine and serine (and / or threonine) comprises at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of such amino acids. In some embodiments, the linker comprises at least 50%, 55%, 60%, 70%, or 75% or approximately 50%, 55%, 60%, 70%, or 75% glycine, serine, and / or threonine. In some embodiments, the linker is substantially entirely composed of glycine, serine, and / or threonine. Linkers are generally about 5 to about 50 amino acids in length, typically 10 or about 10 to 30 or about 30 amino acids, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30, and in some instances, 10 to 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS, SEQ ID NO: 60), e.g., 2, 3, 4, and 5 repeats of such a sequence. Exemplary linkers include those having or consisting of the sequence set forth in SEQ ID NO: 58 (GGGGSGGGGSGGGGS). Further exemplary linkers include those having or consisting of the sequence set forth in SEQ ID NO: 59 (GSTSGSGKPGSGEGSTKG), SEQ ID NO: 61 (GGGGSGGGGS), and SEQ ID NO: 62 (GGGGSGGGGSGGGGSGGGGS).

[0214] Thus, in some embodiments, provided embodiments include single-chain antibody fragments, e.g., scFvs, comprising one or more of the foregoing linkers, such as glycine / serine-rich linkers, including linkers with repeats of GGGS (SEQ ID NO: 60), such as the linkers set forth in SEQ ID NOs: 58, 61, or 62. In some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 58. In some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 60. In some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 61. In some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 62.

[0215] In some embodiments, V H The region is V L In some embodiments, the V H The region is V L In certain embodiments, the fragment, e.g., an scFv, may be carboxy-terminal to the V H A region or a portion thereof followed by a linker, followed by V L In other embodiments, the fragment, e.g., an scFv, may be followed by a V L A region or a portion thereof followed by a linker, followed by V H The region or part thereof may follow.

[0216] In some embodiments, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NOs: 11-15, or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NOs: 11-15. In some aspects, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 11 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 11. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 11. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:11. In some aspects, the scFvs provided herein comprise the amino acid sequence set forth in SEQ ID NO: 12 or have an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 12. In some embodiments, the scFvs provided herein comprise the amino acid sequence set forth in SEQ ID NO: 12.In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 12.

[0217] In some aspects, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 13 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 14 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 14. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 14. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 14.In some aspects, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 15 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 15. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 15. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 15.

[0218] Among the anti-BAFF-R antibodies are human antibodies. In some embodiments of the provided human anti-BAFF-R antibodies, e.g., antigen-binding fragments, the human antibody comprises a V segment that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence encoded by a germline nucleotide human heavy chain J segment. HV segments containing a region and / or a portion having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment and / or a portion having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment. L In some embodiments, the V H The portions of the regions correspond to CDR-H1, CDR-H2 and / or CDR-H3. H The portions of the regions correspond to framework region 1 (FR1), FR2, FR2, and / or FR4. L The portions of the regions correspond to CDR-L1, CDR-L2 and / or CDR-L3. L The portions of the regions correspond to FR1, FR2, FR2 and / or FR4.

[0219] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-H1 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-H1 region in a sequence encoded by a germline nucleotide human heavy chain V segment. For example, a human antibody, in some embodiments, contains a CDR-H1 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-H1 region in a sequence encoded by a germline nucleotide human heavy chain V segment.

[0220] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-H2 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-H2 region in a sequence encoded by a germline nucleotide human heavy chain V segment. For example, a human antibody, in some embodiments, contains a CDR-H2 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-H2 region in a sequence encoded by a germline nucleotide human heavy chain V segment.

[0221] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-H3 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-H3 region in a sequence encoded by a germline nucleotide human heavy chain V, D, and J segment. For example, a human antibody, in some embodiments, contains a CDR-H3 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-H3 region in a sequence encoded by a germline nucleotide human heavy chain V, D, and J segment.

[0222] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-L1 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-L1 region in a sequence encoded by a germline nucleotide human light chain V segment. For example, a human antibody, in some embodiments, contains a CDR-L1 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-L1 region in a sequence encoded by a germline nucleotide human light chain V segment.

[0223] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-L2 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-L2 region in a sequence encoded by a germline nucleotide human light chain V segment. For example, a human antibody, in some embodiments, contains a CDR-L2 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-L2 region in a sequence encoded by a germline nucleotide human light chain V segment.

[0224] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-L3 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-L3 region in a sequence encoded by a germline nucleotide human light chain V and J segment. For example, in some embodiments, a human antibody contains a CDR-L3 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-L3 region in a sequence encoded by a germline nucleotide human light chain V and J segment.

[0225] In some embodiments, human antibodies, e.g., antigen-binding fragments, contain framework regions that contain human germline gene segment sequences. For example, in some embodiments, human antibodies contain V and / or J segments in which the framework regions, e.g., FR1, FR2, FR3, and FR4, have at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to framework regions encoded by human germline antibody segments, such as V and / or J segments. H In some embodiments, a human antibody comprises a V segment, in which the framework regions, e.g., FR1, FR2, FR3, and FR4, have at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to framework regions encoded by human germline antibody segments, such as V and / or J segments.L For example, in some such embodiments, V H Area and / or V L The framework region sequences contained within the region differ by no more than 10 amino acids, such as no more than 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acids, compared to the framework region sequences encoded by human germline antibody segments.

[0226] B. Immunoconjugates In some embodiments, the antibody is an immunoconjugate or portion thereof in which the antibody is conjugated to one or more heterologous molecules, such as, but not limited to, a cytotoxic agent or an imaging agent. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, such as nucleases; antibiotics; and toxins, such as small molecule toxins or enzymatically active toxins. In some embodiments, the antibody is conjugated to one or more cytotoxic agents, such as a chemotherapeutic agent or drug, a growth inhibitory agent, a toxin (e.g., a protein toxin, an enzymatically active toxin of bacterial, fungal, plant, or animal origin, or a fragment thereof), or a radioactive isotope.

[0227] Some immunoconjugates include those in which the antibody is coupled to, but not limited to, a maytansinoid (see U.S. Pat. Nos. 5,208,020, 5,416,064, and European Patent No. EP 0 425 235). B1); auristatins, such as the monomethyl auristatin drug moieties DE and DF (MMAE and MMAF) (see U.S. Pat. Nos. 5,635,483, 5,780,588, and 7,498,298); dolastatins; calicheamicin or its derivatives [U.S. Pat. Nos. 5,712,374, 5,714,586, 5,739,116, 5,767,285, 5,770,701, 5,770,710, 5,773,001, and 5,877,296; Hinman et al., Cancer Res. 53:3336-3342 (1993); and Lode et al., Cancer Res. 58:2925-2928 (1998)]; anthracyclines such as daunomycin or doxorubicin [Kratz et al., Current Med. Chem. 13:477-523 (2006); Jeffrey et al., Bioorganic & Med. Chem. Letters 16:358-362 (2006); Torgov et al., Bioconj. Chem. 16:717-721 (2005); Nagy et al., Proc. Natl. Acad. Sci. USA 97:829-834 (2000); Dubowchik et al., Bioorg. & Med. Chem. Letters 12: 1529-1532 (2002); King et al., J. Med. Chem. 45:4336-4343 (2002); and U.S. Pat. No. 630,579]; methotrexate; vindesine; taxanes such as docetaxel, paclitaxel, larotaxel, tesetaxel, and ortataxel; trichothecenes; and antibody drug conjugates (ADCs) conjugated to one or more drugs, including CC1065.

[0228] Also included among the immunoconjugates are antibodies conjugated to enzymatically active toxins or fragments thereof, including, but not limited to, diphtheria A chain, nonbinding active fragments of diphtheria toxin, exotoxin A chain (from Pseudomonas aeruginosa), ricin A chain, abrin A chain, modeccin A chain, alphasarcin, Aleurites fordii protein, dianthin protein, pokeweed protein (PAPI, PAPII, and PAP-S), momordica charantia inhibitor, curcin, crotin, Saponaria officinalis inhibitor, gelonin, mitogenin, restrictocin, phenomycin, enomycin, and the trichothecenes.

[0229] Additionally, in some immunoconjugates, antibodies are conjugated to radioactive atoms to form radioconjugates. Exemplary radioisotopes include At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re 188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu.

[0230] Conjugates of antibodies and cytotoxic agents can be made using any of a number of known protein coupling agents, e.g., linkers (see Vitetta et al., Science 238:1098 (1987), WO94 / 11026). The linker may be a "cleavable linker" that facilitates release of the cytotoxic agent into cells, such as an acid-labile linker, a peptidase-sensitive linker, a photolabile linker, a dimethyl linker, and a disulfide-containing linker (Chari et al., Cancer Res. 52:127-131 (1992), U.S. Pat. No. 5,208,020).

[0231] C. Exemplary Features In some embodiments, the provided antibodies have one or more specific functional characteristics, such as binding properties that include binding to a specific epitope or exhibiting low or reduced binding to a related but non-specific antigen. In some embodiments, the provided antibodies can bind to an epitope that is similar to or overlaps with the epitope of another antibody, such as a reference antibody, and / or can exhibit a specific binding affinity. In some embodiments, the provided antibodies can bind to an epitope that is different from the epitope of the other antibody, for example, binding to a conformational epitope.

[0232] In some embodiments, the provided antibodies or antigen-binding fragments thereof specifically bind to B-cell activating factor receptor (BAFF-R). In some of any of the embodiments provided herein, BAFF-R refers to human BAFF-R. The observation that an antibody or other binding molecule binds to BAFF-R or specifically binds to BAFF-R does not necessarily mean that it binds to BAFF-R from any species. For example, in some embodiments, the characteristic of binding to BAFF-R, e.g., the ability to specifically bind to BAFF-R and / or the ability to compete with a reference antibody for binding to BAFF-R and / or the ability to bind with a particular affinity or compete to a particular degree, in some embodiments refers to this ability with respect to human BAFF-R, and the antibody may not have this characteristic with respect to BAFF-R of another species, such as mouse. In some embodiments, the antibody binds to human BAFF-R and binds to BAFF-R of another species, such as rhesus monkeys or cynomolgus monkeys. In some embodiments, the antibody or antigen-binding fragment thereof binds to human BAFF-R and does not bind to BAFF-R of another species, such as mouse. In some embodiments, the antibody binds to human BAFF-R and to BAFF-R of another species, such as mouse.

[0233] In some embodiments, an antibody, such as an anti-BAFF-R antibody, e.g., a human antibody, specifically binds to a particular epitope or region of BAFF-R, e.g., typically an extracellular epitope or region. In some embodiments, the antibody or antigen-binding fragment thereof binds to, e.g., specifically binds to, human BAFF-R, e.g., one or more epitopes or regions of human BAFF-R, or allelic variants or splice variants thereof. In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to one or more epitopes within human BAFF-R.

[0234] In some embodiments, the antibody or antigen-binding fragment thereof binds to one or more epitopes of BAFF-R, such as human BAFF-R. In some embodiments, the antibody or antigen-binding fragment thereof binds to a linear epitope of BAFF-R, such as human BAFF-R. In some embodiments, the antibody or antigen-binding fragment thereof binds to one or more conformational epitopes of BAFF-R, such as human BAFF-R.

[0235] In some embodiments, the antibody binds to a non-human BAFF-R, such as a rhesus monkey (Macaca mulatta) or a cynomolgus monkey (Macaca fasicularis). In some aspects, the extracellular binding domain of the non-human BAFF-R is at least 99% identical to the human BAFF-R sequence. In some embodiments, the antibody binds to a non-human BAFF-R, such as a monkey, rabbit, rat, mouse, or other species' BAFF-R. In some embodiments, the antibody binds to a mouse (Mus musculus) BAFF-R, such as an epitope or region of mouse BAFF-R. In some embodiments, the antibody binds to human BAFF-R and to a mouse BAFF-R. In some of any of the provided embodiments, the antibody or antigen-binding fragment thereof does not bind, does not cross-react, or binds to a lower degree, level, extent, or affinity of a non-human BAFF-R.

[0236] In some embodiments, the antibodies provided can bind to BAFF-R, such as human BAFF-R, with at least a certain affinity as measured by any of a number of known methods. In some embodiments, affinity can be measured using the equilibrium dissociation constant (K D In some embodiments, affinity is represented by EC 50 It is expressed by:

[0237] Binding affinity, equilibrium dissociation constant (K D ), equilibrium association constant (K A ), E.C. 50 , on-rate (association rate constant; k on or k a ;Unit 1 / Ms or M -1 s -1 ) and the dissociation rate (off-rate) (dissociation rate constant; k off or k d ;unit 1 / s or s -1 A variety of assays are known for assessing the binding affinity of a binding molecule (e.g., an antibody or fragment thereof) to a particular ligand (e.g., an antigen such as BAFF-R). The binding affinity of a binding molecule (e.g., an antibody or antigen-binding fragment thereof) to an antigen, e.g., BAFF-R, such as human BAFF-R or cynomolgus monkey BAFF-R or mouse BAFF-R, can be determined, for example, using any of a number of well-known binding assays. For example, in some embodiments, a BIAcore™ instrument may be used to determine the binding kinetics and binding constants of a complex between two proteins (e.g., an antibody or fragment thereof and an antigen such as BAFF-R) using surface plasmon resonance (SPR) analysis (see, e.g., Scatchard et al., Ann. NY Acad. Sci. 51:660, 1949; Wilson, Science 295:2103, 2002; Wolff et al., Cancer Res. 53:2560, 1993; and U.S. Pat. Nos. 5,283,173, 5,468,614, or equivalents).

[0238] SPR measures the change in molecular concentration on the sensor surface as molecules bind to or dissociate from the surface. The change in SPR signal is directly proportional to the change in mass concentration near the surface, thereby allowing the measurement of the binding kinetics between two molecules. The dissociation rate constant (k off Or k d ), association rate constant (k on Or k a ), and / or the equilibrium dissociation constant (K D ) and / or the equilibrium association constant (K A ) can be determined by monitoring the change in refractive index with respect to time as buffer passes over the chip. Other suitable assays for measuring binding of one protein to another include, for example, immunoassays such as enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA), or determining binding by monitoring changes in the spectroscopic or optical properties of the protein via fluorescence, UV absorbance, circular dichroism, or nuclear magnetic resonance (NMR). Other exemplary assays include, but are not limited to, Western blot, ELISA, analytical ultracentrifugation, spectroscopy, flow cytometry, sequencing, gene reporter assays, flow cytometry, and other methods for detecting binding of expressed nucleic acids or proteins.

[0239] In some embodiments, the binding molecule, e.g., an antibody or fragment thereof, is 10 5 M -1 or greater affinity or K A [i.e., unit 1 / M or M -1 The equilibrium association constant for a specific binding interaction is given by the on-rate [k on or k a ] vs. dissociation rate (off-rate) [k off or k d In some embodiments, the peptide binding molecule binds, e.g., specifically binds, to an antigen, e.g., BAFF-R, or an epitope therein, at a ratio equal to 10 5 M -1(In this association reaction, the on-rate [k on ] vs. dissociation rate (off-rate) [k off ]) affinity or K A (i.e., units 1 / M or M -1 In some embodiments, the binding molecule, e.g., antibody or antigen-binding fragment thereof, binds, e.g., specifically binds, to an antigen, e.g., an epitope of human BAFF-R, with an affinity constant greater than 10 (the equilibrium association constant of the specific binding interaction). 6 M -1 ~10 10 M -1 or about 10 6 M -1 ~about 10 10 M -1 , e.g., 10 6 M -1 ~10 9 M -1 Or about 10 6 M -1 ~about 10 9 M -1 , or 10 6 M -1 ~10 8 M -1 Or about 10 6 M -1 ~about 10 8 M -1 Affinity or K in the range A In some embodiments, the binding affinity can be classified as high affinity or low affinity. For example, in some cases, a binding molecule, such as an antibody or antigen-binding fragment thereof, that exhibits high affinity binding to a particular epitope has a binding affinity of at least 10 7 M -1 Or about 10 7 M -1 , at least 10 8 M -1 Or about 10 8 M -1 , at least 10 9 M -1 Or about 10 9 M -1 , at least 10 10 M -1 Or about 1010 M -1 , at least 10 11 M -1 Or about 10 11 M -1 , at least 10 12 M -1 Or about 10 12 M -1 , or at least 10 13 M -1 Or about 10 13 M -1 K A In some cases, binding molecules that exhibit low affinity binding, such as antibodies or antigen-binding fragments thereof, interact with such epitopes at up to 10 7 M -1 , up to 10 6 M -1 , up to 10 5 M -1 K A Shows.

[0240] Alternatively, affinity may be expressed in units of M (e.g., 10 -5 M~10 -13 Equilibrium dissociation constant (K M ) of a specific binding interaction D In some embodiments, the antibody or fragment thereof may be defined as 10 -5 K below M D (i.e., the equilibrium dissociation constant of a particular binding interaction in units M; assuming a bimolecular interaction, this association reaction has an off-rate [k off or k d ] vs. binding rate (on-rate) [k on or k a The equilibrium dissociation constant K D is 10 -5 M~10 -13 M, e.g., 10 -7 M~10 -11 M, 10 -7 M~10 -10 M, 10 -7 M~10 -9 M, 10 -8 M~10 -10 M, or 10 -9M~10 -10 M may be in the range.

[0241] Association rate (on-rate e) [association rate constant; k on or k a ;Unit 1 / Ms or M -1 s -1 ) and the dissociation rate (off-rate) (dissociation rate constant; k off or k d ;unit 1 / s or s -1 ] can be determined using any of the known assay methods, such as surface plasmon resonance (SPR), or other methods described herein for measuring binding of one protein to another.

[0242] In some embodiments, the binding affinity (EC 50 ) and / or the equilibrium dissociation constant (K D ) is 0.1 nM to 500 nM or about 0.1 nM to about 500 nM, 0.1 nM to 100 nM or about 0.1 nM to about 100 nM, 0.1 nM to 50 nM or about 0.1 nM to about 50 nM, 0.1 nM to 10 nM or about 0.1 nM to about 10 nM, 0.1 nM to 1 nM or about 0.1 nM to about 1 nM, 1 nM to 500 nM or about 1 nM to about 500 nM, 1 nM to 100 nM or about 1 nM to about 100 nM, 1 nM to 50 nM or In certain embodiments, the binding affinity (EC) of an antibody to BAFF-R, such as human BAFF-R, is about 1 nM to about 50 nM, 1 nM to 10 nM or about 1 nM to about 10 nM, 10 nM to 500 nM or about 10 nM to about 500 nM, 10 nM to 100 nM or about 10 nM to about 100 nM, 10 nM to 50 nM or about 10 nM to about 50 nM, 50 nM to 500 nM or about 50 nM to about 500 nM, 50 nM to 100 nM or about 50 nM to about 100 nM, or 100 nM to 500 nM or about 100 nM to about 500 nM. 50 ) and / or the equilibrium dissociation constant (K D) is 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM, or about this value, or less, or about this value, or a range as defined by any of the foregoing. In some embodiments, the antibody binds to BAFF-R, such as human BAFF-R, with sub-nanomolar binding affinity, e.g., less than 1 nM or about 1 nM, such as less than or about 0.9 nM, 0.8 nM, 0.7 nM, 0.6 nM, 0.5 nM, 0.4 nM, 0.3 nM, 0.2 nM, or 0.1 nM. In some embodiments, the binding affinity (EC 50 ) and / or the equilibrium dissociation constant, K D is 0.01 nM to about 1 μM, 0.1 nM to 1 μM, 1 nM to 1 μM, 1 nM to 500 nM, 1 nM to 100 nM, 1 nM to 50 nM, 1 nM to 10 nM, 10 nM to 500 nM, 10 nM to 100 nM, 10 nM to 50 nM, 50 nM to 500 nM, 50 nM to 100 nM, or 100 nM to 500 nM, or approximately this value. In certain embodiments, the binding affinity (EC 50 ) and / or the equilibrium dissociation constant, K D is or is about or less than 1 μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM or 1 nM or less, or is a range defined by any of the foregoing.

[0243] In some embodiments, the EC of a binding molecule to BAFF-R, such as an anti-BAFF-R antibody or fragment thereof. 50and / or K D In certain embodiments, the EC of a molecule that binds to BAFF-R, such as human BAFF-R, for example, an anti-BAFF-R antibody or a fragment thereof, is 10 nM to 90 nM or about 10 nM to about 90 nM, 20 nM to 80 nM or about 20 nM to about 80 nM, 30 nM to 70 nM or about 30 nM to about 70 nM, 40 nM to 60 nM or about 40 nM to about 60 nM, or 40 nM to 50 nM or about 40 nM to about 50 nM. 50 and / or K D In certain embodiments, the EC2 of a binding molecule to BAFF-R, such as human BAFF-R, e.g., an anti-BAFF-R antibody or fragment thereof, is 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, or 100 nM, or is approximately this value, or a range defined by any of the foregoing. 50 and / or K D In certain embodiments, the EC2 of a binding molecule to BAFF-R, such as human BAFF-R, e.g., an anti-BAFF-R antibody or fragment thereof, is 10 nM, 20 nM, 30 nM, 40 nM, 50 nM, 60 nM, 70 nM, 80 nM, 90 nM, or 100 nM, or is approximately this value, or a range defined by any of the foregoing. 50 and / or K D is at or about 40 nM, 41 nM, 42 nM, 43 nM, 44 nM or 45 nM, or a range defined by any of the foregoing.

[0244] In some embodiments, provided binding molecules, e.g., anti-BAFF-R antibodies or antigen-binding fragments thereof, or receptors containing such antibodies or antigen-binding fragments, have a fast off-rate (dissociation rate constant; k off or k d ;unit 1 / s or s -1 In some embodiments, the provided binding molecules have an off-rate (k off or k d ) is 1×10- 5 s -1 ~1×10-2 s -1 or about 1 x 10 -5 s -1 ~Approx. 1×10 -2 s -1 , e.g., 5 x 10 -5 s -1 ~9×10 -3 s -1 or about 5 x 10 -5 s -1 ~Approx. 9×10 -3 s -1 , 1×10 -4 s -1 ~8×10 -3 s -1 or about 1 x 10 -4 s -1 ~Approx. 8×10 -3 s -1 , 5×10 -4 s -1 ~7×10 -3 s -1 or about 5 x 10 -4 s -1 ~Approx. 7×10 -3 s -1 , 1×10 -3 s -1 ~6×10 -3 s -1 or about 1 x 10 -3 s -1 ~Approx. 6×10 -3 s -1 , and 4 × 10 -3 s -1 ~6×10 -3 s -1 Or about 4 x 10 -3 s -1 ~Approx. 6×10 -3 s -1 In some embodiments, the off-rate (k off or k d ) is at least 1 × 10 -5 s -1 , 5×0 -5 s -1 , 1×10 -4 s -1 , 5×10 -4 s -1 , 1×10 -3 s -1, 5×10 -3 s -1 Or 1 x 10 -2 s -1 In some embodiments, the off-rate (k off or k d ) is at least 6×10 -4 s -1 , 7×10 -4 s -1 , 8×10 -4 s -1 , 9×10 -4 s -1 , 1×10 -3 s -1 , 2 × 10 -3 s -1 , 3×10 -3 s -1 , 4×10 -3 s -1 , 5×10 -3 s -1 , 6×10 -3 s -1 , 7×10 -3 s -1 , 8×10 -3 s -1 , 9×10 -3 s -1 Or 1 x 10 -2 s -1 In some embodiments, the off-rate k of the provided binding molecule is off or k d ) is at least 4 × 10 -3 s -1 , 5×10 -3 s -1 Or 6 x 10 -3 s -1or about this value, or in a range defined by any of the foregoing. In some embodiments, a provided binding molecule, e.g., an anti-BAFF-R antibody or antigen-binding fragment thereof, or a receptor containing such an antibody or antigen-binding fragment, has an off-rate that is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold faster, or at least about 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold faster, than the off-rate of a reference anti-BAFF-R antibody or antigen-binding fragment thereof, or a receptor containing such an antibody or antigen-binding fragment.

[0245] In some embodiments, the binding affinities of binding molecules, such as anti-BAFF-R antibodies, to different antigens, e.g., BAFF-R from different species, can be compared to determine species cross-reactivity. For example, species cross-reactivity can be classified as high cross-reactivity or low cross-reactivity. In some embodiments, the equilibrium dissociation constants, K, of different antigens, e.g., BAFF-R from different species, such as human, cynomolgus monkey, or mouse, can be determined. D In some embodiments, the species cross-reactivity of an anti-BAFF-R antibody may be high, e.g., the anti-BAFF-R antibody binds to human BAFF-R and species variant BAFF-R to a similar extent, e.g., the K of human BAFF-R. D and species variant BAFF-R K D is 1 or about 1. In some embodiments, the anti-BAFF-R antibody may have low species cross-reactivity, e.g., an anti-BAFF-R antibody has high affinity for human BAFF-R but low affinity for species variant BAFF-R, or vice versa. For example, the K D and human BAFF-R K Dis greater than 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500, 1000, 2000 or more, the anti-BAFF-R antibody has low species cross-reactivity. The degree of species cross-reactivity can be compared to the species cross-reactivity of a known antibody, such as a reference antibody.

[0246] In some embodiments, the provided antibodies or antigen-binding fragments thereof bind to human BAFF-R and non-human BAFF-R to a similar extent. For example, in some embodiments, the provided antibodies or antigen-binding fragments thereof bind to human BAFF-R or its allelic variants or splice variants with a particular equilibrium dissociation constant (K D ) and have a K similar to, or approximately the same as, or less than 2-fold different from, or less than 5-fold different from, non-human BAFF-R, such as cynomolgus monkey BAFF-R. D Combine with.

[0247] For example, in some embodiments, the provided antibodies or antigen-binding fragments thereof have a K for human BAFF-R of about, less than, or less than about 1 μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less. D and binds to cynomolgus monkey BAFF-R with a K of about 1 μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less, or less than or about this value. DIn some embodiments, the provided antibodies or antigen-binding fragments thereof bind to mouse BAFF-R protein with a K of about or less than or about 1 μM, 500 nM, 100 nM, 50 nM, 40 nM, 30 nM, 25 nM, 20 nM, 19 nM, 18 nM, 17 nM, 16 nM, 15 nM, 14 nM, 13 nM, 12 nM, 11 nM, 10 nM, 9 nM, 8 nM, 7 nM, 6 nM, 5 nM, 4 nM, 3 nM, 2 nM, or 1 nM or less. D In some embodiments, the provided antibodies or antigen-binding fragments thereof bind with high affinity to human BAFF-R, cynomolgus monkey BAFF-R, and mouse BAFF-R. In some embodiments, the provided antibodies or antigen-binding fragments thereof bind with high affinity to human BAFF-R and cynomolgus monkey BAFF-R, and with low affinity to mouse BAFF-R. In some embodiments, the provided antibodies or antigen-binding fragments thereof bind with high affinity to human BAFF-R and BAFF-R from other species, or other variants of the BAFF-R protein.

[0248] In some embodiments, the total binding capacity (R) is measured using specific surface plasmon resonance (SPR) conditions. max ) is used to determine the binding or binding ability of a provided antibody or antigen-binding fragment thereof to an antigen, e.g., BAFF-R, such as human BAFF-R. In an SPR analysis, the "ligand" is an immobilized target molecule on the sensor surface, e.g., BAFF-R, and the "analyte" is a test molecule, e.g., an antibody, that binds to the "ligand." For example, the "analyte" can be either a provided antibody or its antigen-binding fragment that binds to BAFF-R. For a particular ligand and analyte pair in SPR, R max can be determined assuming a 1:1 binding stoichiometry model under certain conditions. In some embodiments, the binding capacity (R max ) can be determined using the following formula: R max(RU) = (molecular weight of analyte) / (molecular weight of ligand) × immobilized ligand level (RU). In certain embodiments of SPR conditions, the R of binding between any of the provided antibodies or antigen-binding fragments thereof and BAFF-R, such as human BAFF-R or cynomolgus monkey BAFF-R, is max is at least 50 resonance units (RU) or at least about 50 RU, for example, about 25 RU, 20 RU, 15 RU, 10 RU, 5 RU, or 1 RU.

[0249] In some embodiments, the properties or characteristics of the provided antibodies are described in comparison with the properties observed with another antibody, e.g., a reference antibody. In some embodiments, the reference antibody is a non-human anti-BAFF-R antibody, such as a rabbit or chimeric or humanized anti-BAFF-R antibody. In some embodiments, the provided antibodies contain heavy and light chain CDRs that differ from the CDRs present in the reference antibody or antibody. Some of the provided antibodies compete for binding to and / or bind to the same or overlapping epitope of BAFF-R as bound by the reference antibody or antibody, but nevertheless contain different CDRs, e.g., different heavy and / or light chain CDR1, CDR2, and CDR3.

[0250] In some embodiments, the antibody has an affinity that is about the same as or lower than the affinity of the corresponding form of the reference antibody (e.g., the EC 50 or K D EC less than or equal to about 1.5 times, or less than or equal to about 2 times, or less than or equal to about 3 times, and / or less than or equal to about 10 times 50 or K D In some embodiments, the antibody has an affinity that is about the same as or lower than the affinity of the corresponding form of the reference antibody (e.g., the EC 50 or K Dat least 1.5 times greater or about 1.5 times greater, at least 2 times greater or about 2 times greater, at least 3 times greater or about 3 times greater, at least 5 times greater or about 5 times greater, at least 10 times greater or about 10 times greater, at least 20 times greater or about 20 times greater, at least 25 times greater or about 25 times greater, at least 30 times greater or about 30 times greater, at least 40 times greater or about 40 times greater, at least 50 times greater or about 50 times greater, or at least 100 times greater or about 100 times greater 50 or K D In some embodiments, the antibody has an affinity that is about the same as or lower than the affinity of the corresponding form of the reference antibody (1.5, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 25, 30, 40, 50, or 100 times lower than the affinity of the reference antibody, or an affinity of approximately this magnitude).

[0251] In some embodiments, the antibody has an affinity that is greater than the affinity of the corresponding form of the reference antibody (e.g., the EC 50 Or K D Lower EC 50 Or K D , or the EC of the corresponding form of the reference antibody 50 Or K D EC of 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 40, 1 / 50, 1 / 60, 1 / 70, 1 / 80, 1 / 90, 1 / 100, 1 / 150, 1 / 200, 1 / 250 50 Or K D , or an EC of approximately this size 50 Or K D ).

[0252] In some embodiments, the antibody exhibits binding preference for BAFF-R-expressing cells compared to BAFF-R-negative cells, e.g., specific cells known to express BAFF-R and / or described herein, as well as cells known not to express BAFF-R. In some embodiments, binding preference is observed when a significantly greater degree of binding to BAFF-R-expressing cells is measured compared to non-expressing cells or cells expressing a related but different antigen. In some embodiments, a significantly greater degree of binding is measured compared to non-BAFF-R-expressing cells or cells expressing a related but different antigen, e.g., mean fluorescence intensity and / or dissociation constant or EC2 in a flow cytometry-based assay. 50 The fold change in the detected extent of binding to BAFF-R-expressing cells, as measured by, is at least, or at least about, 1.5, 2, 3, 4, 5, 6 or more, and / or is as great as, about the same, at least as great, or at least about as great, or greater than the fold change observed for the corresponding form of the reference antibody. In some cases, the total observed extent of binding to BAFF-R or BAFF-R-expressing cells is about the same, at least as great, or greater than that observed for the corresponding form of the reference antibody.

[0253] In some embodiments, the affinity is the same, or about the same, or substantially the same as the affinity of the corresponding form of a reference antibody, such as a rabbit BAFF-R antibody, hi some embodiments, the affinity is at least 80, 85, 90, 95, or 99%, or at least about 80, 85, 90, 95, or 99%, or the same, as the affinity of the corresponding form of the reference antibody.

[0254] In some embodiments, the antibody specifically binds to an epitope of BAFF-R that overlaps with the epitope of BAFF-R bound by the reference antibody. In some aspects, some of these antibodies bind to the same or similar epitope as the reference antibody. In some embodiments, the antibody binds to the same or similar epitope, or an epitope within the same region as the reference antibody or an epitope containing residues within the same region of BAFF-R as the reference antibody. In some embodiments, the antibody inhibits binding to BAFF-R, such as human BAFF-R, and / or competes with the reference antibody for binding to BAFF-R, such as human BAFF-R.

[0255] Competitive inhibition assays are known and include ELISA-based, flow cytometry-based, and RIA-based assays. In some aspects, competitive inhibition assays are performed by incorporating an excess of one of the antibodies in unlabeled form and assessing its ability to block the binding of another antibody labeled with a detectable marker, so that the degree of binding and its reduction can be assessed by detecting the label or marker. In some embodiments, adding an excess of a provided antibody, for example, 1-, 2-, 5-, 10-, 50-, or 100-fold excess, compared to the amount or concentration of a reference antibody inhibits binding to an antigen by the reference antibody (or vice versa). In some embodiments, binding inhibition is at least 50%, and in some embodiments, at least 75%, 90%, or 99%. In some aspects, competitive inhibition is measured in a competitive binding assay (see, e.g., Junghans et al., Cancer Res. 1990:50:1495-1502). A competitive assay can be used to identify antibodies that compete with any of the antibodies described herein. Assays to map the epitope bound by an antibody and a reference antibody are also available and known.

[0256] The anti-BAFF-R antibodies provided herein can be identified, screened, or characterized for their physical / chemical properties and / or biological activity by various known assays. In one embodiment, the antibodies are tested for their antigen-binding activity by known methods, such as, for example, ELISA, Western blot, and / or flow cytometry assays (including cell-based binding assays), which evaluate the binding of the antibody (e.g., conjugated or tagged with a fluorescent marker) to cells expressing a target antigen, e.g., BAFF-R, in some cases compared to results using cells that do not express the target antigen, e.g., BAFF-R. Binding affinity is expressed as K D , K. A or EC 50 It can be measured as:

[0257] D. Mutants In certain embodiments, the antibody contains one or more amino acid variations, e.g., substitutions, deletions, insertions, and / or mutations, compared to the antibody sequences described herein. Exemplary variations include those designed to improve the binding affinity and / or other biological properties of the antibody. Amino acid sequence variants of the antibody can be prepared by introducing appropriate modifications into the nucleotide sequence encoding the antibody or by peptide synthesis. Such modifications include, for example, deletions, insertions, and / or substitutions of residues within the amino acid sequence of the antibody. Any combination of deletions, insertions, and substitutions can be made to achieve the final construct, provided that the final construct possesses the desired characteristics, e.g., antigen binding.

[0258] In certain embodiments, the antibody contains one or more amino acid substitutions, for example, compared to the antibody sequences described herein and / or compared to sequences in a natural repertoire, e.g., a human repertoire. Substitution mutagenesis sites of interest include the CDRs and FRs. Amino acid substitutions are introduced into the antibody of interest, and the products can be screened for desired activity, e.g., retention / improvement of antigen binding, reduced immunogenicity, improved half-life, and / or improved effector function, such as the ability to improve antibody-dependent cellular cytotoxicity (ADCC) or complement-dependent cytotoxicity (CDC).

[0259] In some embodiments, one or more residues within a CDR of a parent antibody (e.g., a humanized or human antibody) are substituted. In some embodiments, substitutions are made to return a sequence or position within a sequence to a germline sequence, such as an antibody sequence found in the germline (e.g., human germline), e.g., to reduce the potential for immunogenicity, e.g., upon administration to a human subject.

[0260] In some embodiments, the changes are made in "hotspot" residues of the CDRs that are encoded by codons that undergo high frequency of mutation during somatic maturation (see, e.g., Chowdhury, Methods Mol. Biol. 207:179-196 (2008)), and / or in residues that contact the antigen, and the resulting mutant V H or V LThe resulting antibodies are tested for binding affinity. Affinity maturation by construction and reselection from a secondary library is described, for example, by Hoogenboom et al. in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, (2001)). In some affinity maturation embodiments, diversity is introduced into the various genes selected for maturation by any of a variety of methods (e.g., error-prone PCR, chain shuffling, or oligonucleotide-directed mutagenesis). A secondary library is then created. The library is then screened to identify any antibody variants with the desired affinity. Another method for introducing diversity involves a CDR-specific approach, in which several CDR residues (e.g., 4-6 residues at a time) are randomized. CDR residues involved in antigen binding can be specifically identified using, for example, alanine scanning mutagenesis or modeling. CDR-H3 and CDR-L3 in particular are often targeted.

[0261] In certain embodiments, substitutions, insertions, or deletions may occur within one or more CDRs, as long as such changes do not substantially reduce the antibody's ability to bind to the antigen. For example, conservative changes (e.g., conservative substitutions provided herein) that do not substantially reduce binding affinity may be made in the CDRs. Such changes may, for example, be outside the antigen-contacting residues of the CDRs. The mutant V provided above may be H and V L In certain embodiments of the sequences, each CDR is either unaltered or contains no more than 1, 2, or 3 amino acid substitutions.

[0262] Amino acid sequence insertions include amino- and / or carboxyl-terminal fusions ranging in length from one residue to polypeptides containing hundreds or more residues, as well as intrasequence insertions of single or multiple amino acid residues. An example of a terminal insertion is an antibody with an N-terminal methionyl residue. Other insertional variants of antibody molecules include fusion of the antibody to an enzyme or polypeptide at the N- or C-terminus, which increases the serum half-life of the antibody.

[0263] II. Recombinant Receptors (e.g., Chimeric Antigen Receptors) In some aspects, BAFF-R-binding agents, such as recombinant receptors or chimeric antigen receptors (CARs), are provided, which comprise an extracellular binding domain that binds to BAFF-R. In some embodiments, the extracellular binding domain is a bispecific binding domain that binds to BAFF-R and CD19. The provided recombinant receptors generally contain an extracellular binding domain and an intracellular signaling domain. Among the provided receptors are recombinant receptors in which the extracellular binding domain is composed of an antibody or antigen-binding fragment thereof, such as an anti-BAFF-R antibody or an anti-BAFF-R antibody and an anti-CD19 antibody. Such receptors include chimeric antigen receptors containing such antibodies. In some embodiments, the recombinant receptor, such as a CAR, contains an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain. In some embodiments, the extracellular binding domain of the recombinant receptor, such as a CAR, targets BAFF-R. In some embodiments, the extracellular binding domain of the recombinant receptor, such as a CAR, targets both BAFF-R and CD19. In some embodiments, the recombinant receptor, such as a CAR, also contains a spacer domain (e.g., a hinge domain) separating the extracellular binding domain from the transmembrane domain.

[0264] In some embodiments, the extracellular binding domain of any of the provided recombinant receptors, such as CARs, comprises a BAFF-R binding domain. In some embodiments, the BAFF-R binding domain comprises a cell surface protein containing an antibody (e.g., an antigen-binding antibody fragment) and / or other binding peptide that specifically binds to BAFF-R (e.g., human BAFF-R protein). In some aspects, the binding domain binds to the extracellular portion of BAFF-R. In some aspects, the BAFF-R binding domain binds to the extracellular portion of BAFF-R. In some examples, the recombinant receptor is one that contains a chimeric antigen receptor, for example, an anti-BAFF-R antibody or antigen-binding fragment thereof.

[0265] Also provided herein are recombinant receptors, such as chimeric antigen receptors (CARs), whose extracellular binding domains bind to both BAFF-R and CD19. In some embodiments, the extracellular binding domain comprises a BAFF-R binding domain that binds to BAFF-R and a CD19 binding domain that binds to CD19. The BAFF-R binding domain comprises a cell surface protein containing an antibody (e.g., an antigen-binding antibody fragment) and / or other binding peptide that specifically binds to BAFF-R (e.g., human BAFF-R protein). The CD19 binding domain comprises a cell surface protein containing an antibody (e.g., an antigen-binding antibody fragment) and / or other binding peptide that specifically binds to CD19 (e.g., human CD19). In some aspects, the binding domain binds to the extracellular portion of BAFF-R. In some aspects, the BAFF-R binding domain binds to the extracellular portion of BAFF-R. In some aspects, the binding domain binds to the extracellular portion of CD19. In some aspects, the CD19 binding domain binds to the extracellular portion of CD19.

[0266] Also provided herein are polynucleotides encoding any of the provided recombinant receptors, e.g., any of the provided CARs.

[0267] In some embodiments, some of the provided polynucleotides encode recombinant receptors, such as CAR, that specifically bind to BAFF-R. The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) or RNA constructs, for example, constructs that can be introduced into cells for the expression of the encoded recombinant BAFF-R binding domain. Thus, also provided herein are engineered cells that contain any of the provided BAFF-R targeting binding receptors. Exemplary engineered cells and methods for preparing them are described in Section III. Also provided herein are compositions, products, and uses of any of the engineered cells.

[0268] In some embodiments, some of the provided polynucleotides encode recombinant receptors, such as CARs, that specifically bind to BAFF-R and CD19 (BAFF-R / CD19). The provided polynucleotides can be incorporated into constructs, such as deoxyribonucleic acid (DNA) or RNA constructs, for example, constructs that can be introduced into cells for expression of the encoded recombinant BAFF-R / CD19 binding domain. Thus, also provided herein are engineered cells containing any of the provided BAFF-R / CD19 bispecific binding receptors. Exemplary engineered cells and methods for preparing them are described in Section III. Also provided herein are compositions, products, and uses of any of the engineered cells.

[0269] Also provided are cells expressing the recombinant receptor and their uses in adoptive cell therapy, eg, in treating diseases and disorders associated with expression of BAFF-R, CD19, or both.

[0270] A. Extracellular Binding Domain 1.BAFF-R binding domain In some embodiments, the extracellular binding domain of a provided recombinant receptor, such as a CAR, includes, is, or comprises an anti-BAFF-R antibody. Thus, a chimeric receptor, e.g., a CAR, typically includes a BAFF-R binding domain, such as an antigen-binding fragment, domain, or portion, or one or more antibody variable regions and / or antibody molecules, such as those described herein, in the extracellular portion of the CAR.

[0271] In some embodiments, the extracellular binding domain comprises a BAFF-R binding domain. In some embodiments, the BAFF-R binding domain comprises an anti-BAFF-R antibody or an antigen-binding fragment thereof. In some embodiments, the BAFF-R binding domain comprises a heavy chain variable (V H ) region and the light chain variable (V L ) area.

[0272] In some embodiments, the CAR comprises the heavy chain variable (V H ) region and / or light chain variable (V L In some embodiments, the BAFF-R binding domain comprises an antibody comprising the (V H ) area and (V L ) regions of the BAFF-R binding domain are connected by a linker. H ) area and (V L ) region comprises an scFv antibody fragment. In some embodiments, the provided BAFF-R-binding CAR contains an antibody, such as an anti-BAFF-R antibody or antigen-binding fragment thereof, that confers BAFF-R-binding properties to the provided CAR. In some embodiments, the CAR comprises a variable heavy chain (V) derived from an antibody described in Section I. H ) and / or variable light chain (V L ) region.

[0273] In some embodiments, the antibody, e.g., anti-BAFF-R antibody or antigen-binding fragment, comprises a heavy and / or light chain variable (V H Or VL In some embodiments, an anti-BAFF-R antibody, e.g., an antigen-binding fragment, comprises a V region sequence containing the described CDR-H1, CDR-H2, and / or CDR-H3. H In some embodiments, an anti-BAFF-R antibody, e.g., an antigen-binding fragment, comprises a V domain sequence containing the described CDR-L1, CDR-L2, and / or CDR-L3. L In some embodiments, the anti-BAFF-R antibody, e.g., antigen-binding fragment, comprises a V domain sequence containing the described CDR-H1, CDR-H2, and / or CDR-H3. H V containing the region sequence and containing the CDR-L1, CDR-L2 and / or CDR-L3 as described L In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. H It has an area.

[0274] In some embodiments, the antibody or antigen-binding fragment in the provided CAR is a single-chain antibody fragment, such as a single-chain variable fragment (scFv) or a diabody or a single-domain antibody (sdAb). H In some embodiments, the antibody or antigen-binding fragment is a single domain antibody comprising only the heavy chain variable (V H ) region and the light chain variable (V L In some embodiments, the single-chain antibody fragment (e.g., scFv) is an scFv comprising a heavy chain variable (V H ) region and the light chain variable (V LThe linker comprises one or more linkers connecting two antibody domains or regions, such as the α- and β-domains. The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker. Some linkers are rich in glycine and serine, and / or in some cases, threonine. In some embodiments, the linker further comprises charged residues, such as lysine and / or glutamic acid, which may improve solubility. In some embodiments, the linker further comprises one or more prolines.

[0275] Thus, the provided CARs can be used in combination with single-chain antibody fragments such as scFvs and diabodies, particularly V H Area and V L In some embodiments, the BAFF-R scFvs provided herein comprise an anti-BAFF-R antibody comprising a human single-chain antibody fragment that typically comprises a linker(s) connecting two antibody domains or regions, such as a nucleotide sequence (SEQ ID NO: 11-15). In some embodiments, the BAFF-R scFvs provided herein comprise the amino acid sequence set forth in SEQ ID NO: 11-15 or have an amino acid sequence having at least or about 90%, 91%, or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 11-15.

[0276] The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker such as one rich in glycine and serine. In some embodiments, the BAFF-R binding domain is V H Area and V L In some embodiments, the BAFF-R binding domain comprises a V H Area and V L One of the regions, the linker, and V H Area and V Land the other of the regions, in that order from N-terminus to C-terminus. In some embodiments, the linker is set forth in SEQ ID NO: 58. Thus, in some embodiments, the BAFF-R binding domain comprises V H Area and V L one of the regions, a linker shown in SEQ ID NO: 58, and V H Area and V L The other of the regions is included in that order from N-terminus to C-terminus.

[0277] In some aspects, a linker rich in glycine and serine (and / or threonine) comprises at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of such amino acid(s). In some embodiments, the linker comprises at least 50%, 55%, 60%, 70%, or 75% or approximately this percentage of glycine, serine, and / or threonine. In some embodiments, the linker is substantially entirely composed of glycine, serine, and / or threonine. Linkers are generally about 5 to about 50 amino acids in length, typically 10 or about 10 to 30 or about 30 amino acids in length, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids in length, and in some instances, 10 to 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS, SEQ ID NO: 60), e.g., 2, 3, 4, and 5 repeats of such a sequence. Exemplary linkers include those having or consisting of the sequence set forth in SEQ ID NO: 58 (GGGGSGGGGSGGGGS). Further exemplary linkers include those having or consisting of the sequences set forth in SEQ ID NO: 59 (GSTSGSGKPGSGEGSTKG), SEQ ID NO: 61 (GGGGSGGGGS), and SEQ ID NO: 62 (GGGGSGGGGSGGGGSGGGGS).

[0278] Thus, in some embodiments, provided embodiments include single chain antibody fragments, e.g., scFvs, comprising one or more of the foregoing linkers, such as glycine / serine-rich linkers, including linkers with repeats of GGGS (SEQ ID NO: 60), such as the linkers set forth in SEQ ID NOs: 58, 61 or 62.

[0279] 2. Bispecific BAFF-R / CD19 binding domain In some embodiments, the extracellular binding domain of the provided recombinant receptor, such as a CAR, includes, is, or comprises an anti-BAFF-R antibody and an anti-CD19 antibody. Thus, a chimeric receptor, e.g., a CAR, typically comprises a BAFF-R binding domain and a CD19 binding domain, such as an antigen-binding fragment, domain, or portion, or one or more antibody variable regions and / or antibody molecules, such as those described herein, in the extracellular portion of the CAR.

[0280] In some embodiments, the extracellular binding domain comprises a BAFF-R binding domain and a CD19 binding domain. In some embodiments, the BAFF-R binding domain comprises an anti-BAFF-R antibody or an antigen-binding fragment thereof. In some embodiments, the CD19 binding domain comprises an anti-CD19 antibody or an antigen-binding fragment thereof. In some embodiments, the BAFF-R binding domain comprises a heavy chain variable (V H ) region and the light chain variable (V L In some embodiments, the CD19 binding domain comprises a heavy chain variable (V H ) region and the light chain variable (V L ) area.

[0281] a. BAFF-R binding domain In some embodiments, the CAR comprises the heavy chain variable (V H ) region and / or light chain variable (V L In some embodiments, the BAFF-R binding domain comprises an antibody comprising the (V H) area and (V L ) regions of the BAFF-R binding domain are connected by a linker. H ) area and (V L ) region comprises an scFv antibody fragment. In some embodiments, the provided BAFF-R binding CAR contains an antibody, such as an anti-BAFF-R antibody or antigen-binding fragment thereof, that confers BAFF-R binding properties to the provided CAR. In some embodiments, the CAR comprises a variable heavy (V) region derived from an antibody described in Section I. H ) and / or variable light (V L ) region.

[0282] In some embodiments, the antibody, e.g., anti-BAFF-R antibody or antigen-binding fragment, comprises a heavy and / or light chain variable (V H Or V L In some embodiments, an anti-BAFF-R antibody, e.g., an antigen-binding fragment, comprises a V region sequence containing the described CDR-H1, CDR-H2, and / or CDR-H3. H In some embodiments, an anti-BAFF-R antibody, e.g., an antigen-binding fragment, comprises a V domain sequence containing the described CDR-L1, CDR-L2, and / or CDR-L3. L In some embodiments, the anti-BAFF-R antibody, e.g., antigen-binding fragment, comprises a V domain sequence containing the described CDR-H1, CDR-H2, and / or CDR-H3. H V containing the region sequence and containing the CDR-L1, CDR-L2 and / or CDR-L3 as described LIn some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. In some embodiments, the antibody or antibody fragment in the provided CAR contains a V region sequence of any of the antibodies described in Section I. H It has an area.

[0283] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 1. H ) region, or V shown in SEQ ID NO: 1 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0284] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 3. H ) region, or V shown in SEQ ID NO:3 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence HThe antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0285] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 5. H ) region, or V shown in SEQ ID NO:5 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0286] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 7. H ) region, or V shown in SEQ ID NO: 7 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0287] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 9. H ) region, or V shown in SEQ ID NO: 9 Hor about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0288] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to Kabat numbering. H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to Chothia numbering. H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to AbM numbering.

[0289] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 16, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 17, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 18. H In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 16, 17, and 18, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 16, 17, and 18. H Includes the area.

[0290] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V HThe region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is V shown in SEQ ID NO: 1. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO: 1. In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO: 1. H Includes the area.

[0291] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 22, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 23, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 24. H In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 22, 23, and 24, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 22, 23, and 24. H Includes the area.

[0292] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is shown in SEQ ID NO: 3. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:3. H Includes the area.

[0293] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 28, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 29, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 30. H In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 28, 29, and 30, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 28, 29, and 30. H Includes the area.

[0294] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is V shown in SEQ ID NO: 5. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:5. H Includes the area.

[0295] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 22, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 32, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 24. H In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 22, 32, and 24, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 22, 32, and 24. H Includes the area.

[0296] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is shown in SEQ ID NO: 7. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:7. H Includes the area.

[0297] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 35, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 36, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 37. H In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 35, 36, and 37, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 35, 36, and 37. H Includes the area.

[0298] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is shown in SEQ ID NO: 9. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:9. H Includes the area.

[0299] In some embodiments, V H The antibody or antibody fragment in the provided CAR comprising the region further comprises a light chain or a sufficient antigen-binding portion thereof. For example, in some embodiments, the antibody or antigen-binding fragment thereof comprises a V H Area and V L Area, or V H Area and V L In such an embodiment, the V H The domain sequence is the V H In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0300] In some embodiments, the CARs provided herein are selected from the group consisting of the V H For example, in some embodiments, the CAR comprises an antibody, such as an anti-BAFF-R antibody or antigen-binding fragment thereof, containing either the V or V region, and the V region or a sufficient antigen-binding portion thereof. H domain and variable light chain (V L ) area, or V H Area and V L In such embodiments, the V H The domain sequence is the V HIn some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region. In some embodiments, the antibody is a V antibody, as described in Section I. L It has an area.

[0301] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO:2. L ) region, or V shown in SEQ ID NO:2 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0302] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 4. L ) region, or V shown in SEQ ID NO: 4 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0303] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 6. L) region, or V shown in SEQ ID NO:6 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0304] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 8. L ) region, or V shown in SEQ ID NO: 8 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0305] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 10. L ) region, or V shown in SEQ ID NO: 10 L or about 99% sequence identity with the amino acid sequence of the V region, or LV having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0306] In some embodiments, the V of the antibody or antigen-binding fragment thereof L The V region comprises CDR-L1, CDR-L2 and / or CDR-L3 according to Kabat numbering. L The V region comprises CDR-L1, CDR-L2 and / or CDR-L3 according to Chothia numbering. L The regions include CDR-L1, CDR-L2 and / or CDR-L3 according to AbM numbering.

[0307] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 19, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 20, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 21. L In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 19, 20, and 21, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 19, 20, and 21. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO:2. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0308] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 25, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 27. LIn some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 25, 26, and 27, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 25, 26, and 27. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO:4. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0309] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 31, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 27. L In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 31, 26, and 27, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 31, 26, and 27. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO:6. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0310] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 33, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 26, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 34. LIn some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 33, 26, and 34, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 33, 26, and 34. L In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO:8. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0311] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 38, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 39, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 40. L In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 38, 39, and 40, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 38, 39, and 40. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region as set forth in SEQ ID NO: 10. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0312] Among the CARs provided herein, an antibody, such as an anti-BAFF-R antibody or antibody fragment in the provided CAR, has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:1. H V region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:2. L There is a CAR that contains the region.

[0313] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO: 1 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 2. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0314] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 1 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 2. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V LThe regions comprise the amino acid sequences set forth in SEQ ID NOs: 1 and 2, respectively, or have at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0315] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences shown in SEQ ID NOs: 1 and 2, respectively.

[0316] Among the CARs provided herein, an antibody, such as an anti-BAFF-R antibody or antibody fragment in the provided CAR has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:3. H V region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:4. L There is a CAR that contains the region.

[0317] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:3 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 4. LThe amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0318] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 3 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 4. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V L The region comprises the amino acid sequence set forth in SEQ ID NOs: 3 and 4, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0319] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences shown in SEQ ID NOs: 3 and 4, respectively.

[0320] Among the CARs provided herein, an antibody, such as an anti-BAFF-R antibody or antibody fragment in the provided CAR has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:5. Hand V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:6. L There is a CAR that contains the region.

[0321] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:5 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 6. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0322] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 5 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 6. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V L The region comprises the amino acid sequence set forth in SEQ ID NOs: 5 and 6, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0323] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences shown in SEQ ID NOs: 5 and 6, respectively.

[0324] Among the CARs provided herein, an antibody, such as an anti-BAFF-R antibody or antibody fragment in the provided CAR, has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:7. H V region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:8. L There is a CAR that contains the region.

[0325] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:7 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 8. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0326] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 7 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 8. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V LThe region comprises the amino acid sequence set forth in SEQ ID NOs: 7 and 8, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0327] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences shown in SEQ ID NOs: 7 and 8, respectively.

[0328] Among the CARs provided herein, an antibody, such as an anti-BAFF-R antibody or antibody fragment in the provided CAR has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:9. H and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 10. L There is a CAR that contains the region.

[0329] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:9 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 10. LThe amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0330] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 9 and is a V region of the antibody or antigen-binding fragment thereof. L The V region comprises the amino acid sequence set forth in SEQ ID NO: 10. In some embodiments, the V region of the antibody or antigen-binding fragment thereof H Area and V L The region comprises the amino acid sequence set forth in SEQ ID NOs: 9 and 10, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the above V H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0331] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 9 and 10, respectively.

[0332] In some embodiments, the antibody or antigen-binding fragment in the provided CAR is based on a single-chain antibody fragment, such as a single-chain variable fragment (scFv) or a diabody or a single-domain antibody (sdAb). H In some embodiments, the antibody or antigen-binding fragment is a single domain antibody comprising only the heavy chain variable (V H ) region and the light chain variable (V L In some embodiments, the single-chain antibody fragment (e.g., scFv) is an scFv comprising a heavy chain variable (V H ) region and the light chain variable (V LThe linker comprises one or more linkers connecting two antibody domains or regions, such as the α- and β-domains. The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker. Some linkers are rich in glycine and serine, and / or in some cases, threonine. In some embodiments, the linker further comprises charged residues, such as lysine and / or glutamic acid, which may improve solubility. In some embodiments, the linker further comprises one or more prolines.

[0333] Thus, the provided CARs are single-chain antibody fragments based on scFvs and diabodies, in particular V H Area and V L The provided CARs include anti-BAFF-R antibodies comprising human single-chain antibody fragments, which typically include a linker(s) connecting two antibody domains or regions, such as the V region. The provided CARs are also suitable for scFv and diabody-based single-chain antibody fragments, particularly V H Area and V L The present invention includes anti-CD19 antibodies comprising human single-chain antibody fragments that typically contain a linker(s) connecting two antibody domains or regions, such as a region.

[0334] The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker such as one rich in glycine and serine. In some embodiments, the BAFF-R binding domain is V H Area and V L In some embodiments, the BAFF-R binding domain comprises a V H Area and V L One of the regions, the linker, and V H Area and V L and the other of the regions, in that order from N-terminus to C-terminus. In some embodiments, the linker is set forth in SEQ ID NO: 58. Thus, in some embodiments, the BAFF-R binding domain comprises V H Area and V L one of the regions, a linker shown in SEQ ID NO: 58, and V H Area and VL The other of the regions is included in that order from N-terminus to C-terminus.

[0335] In some aspects, a linker rich in glycine and serine (and / or threonine) comprises at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of such amino acid(s). In some embodiments, the linker comprises at least 50%, 55%, 60%, 70%, or 75% or approximately this percentage of glycine, serine, and / or threonine. In some embodiments, the linker is substantially entirely composed of glycine, serine, and / or threonine. Linkers are generally about 5 to about 50 amino acids in length, typically 10 or about 10 to 30 or about 30 amino acids in length, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 amino acids in length, and in some instances, 10 to 25 amino acids in length. Exemplary linkers include linkers having various numbers of repeats of the sequence GGGGS (4GS, SEQ ID NO: 60), e.g., 2, 3, 4, and 5 repeats of such a sequence. Exemplary linkers include those having or consisting of the sequence set forth in SEQ ID NO: 58 (GGGGSGGGGSGGGGS). Further exemplary linkers include those having or consisting of the sequences set forth in SEQ ID NO: 59 (GSTSGSGKPGSGEGSTKG), SEQ ID NO: 61 (GGGGSGGGGS), and SEQ ID NO: 62 (GGGGSGGGGSGGGGSGGGGS).

[0336] Thus, in some embodiments, provided embodiments include single chain antibody fragments, e.g., V of scFvs, comprising one or more of the foregoing linkers, such as glycine / serine-rich linkers, including linkers with GGGS (SEQ ID NO: 60) repeats, such as the linkers set forth in SEQ ID NOs: 58, 61 or 62. H and V L Includes.

[0337] In some embodiments, the CAR comprises a loop format. In some embodiments, the V of the CD19 binding domain H or V L The V region of the BAFF-R binding domain is separated by a linker. H or V L In some embodiments, the V region of the CD19 binding domain is H and V L One of the regions is connected to the V of the CD19-binding domain by a linker. H and V L In some embodiments, the V of the BAFF-R binding domain is connected to another V of the BAFF-R binding domain. H and V L One of the regions is connected to the V of the BAFF-R binding domain by a linker. H and V L In some embodiments, the linker is set forth in SEQ ID NO: 58. In some embodiments, the linker is set forth in SEQ ID NO: 59. In some embodiments, the linker is set forth in SEQ ID NO: 60. In some embodiments, the linker is set forth in SEQ ID NO: 61. In some embodiments, the linker is set forth in SEQ ID NO: 62.

[0338] In some embodiments, the V of the CD19 binding domain H The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 62. L In some embodiments, the V region of the CD19 binding domain is H The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 60. L In some embodiments, the V region of the CD19 binding domain is H The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 61. L In some embodiments, the V region of the CD19 binding domain is H The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 62. H In some embodiments, the V region of the CD19 binding domain is HThe region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 60. H In some embodiments, the V region of the CD19 binding domain is H The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 61. H is connected to the area.

[0339] In some embodiments, the V of the CD19 binding domain L The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 62. L In some embodiments, the V region of the CD19 binding domain is L The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 60. L In some embodiments, the V region of the CD19 binding domain is L The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 61. L In some embodiments, the V region of the CD19 binding domain is L The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 62. H In some embodiments, the V region of the CD19 binding domain is L The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 60. H In some embodiments, the V region of the CD19 binding domain is L The region is connected to the V of the BAFF-R binding domain by a linker shown in SEQ ID NO: 61. H is connected to the area.

[0340] Thus, in some embodiments, provided embodiments include single chain antibody fragments, e.g., scFv V fragments, comprising one or more of the foregoing linkers, such as glycine / serine-rich linkers, including linkers with GGGGS (SEQ ID NO: 60) repeats, such as the linkers set forth in SEQ ID NOs: 58, 61 or 62. H and V LIn some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 58. In some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 60. In some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 61. In some embodiments, the linker comprises the sequence set forth in SEQ ID NO: 62.

[0341] In some embodiments, V H The region is V L In some embodiments, the V H The region is V L In certain embodiments, the fragment may be carboxy-terminal to the V H A region or a portion thereof followed by a linker, followed by V L In other embodiments, the fragment may be followed by a region or portion thereof. L A region or a portion thereof followed by a linker, followed by V H The region or part thereof may follow.

[0342] In some embodiments, the CAR comprises a linear format. Thus, in some embodiments, the CAR comprises the V of the anti-BAFF-R scFv. H and V L , as well as anti-CD19 scFv V H and V L In some embodiments, the V of the anti-BAFF-R scFv H and V L and V of anti-CD19 scFv H and V L are connected by a linker. In some embodiments, the linker is set forth in SEQ ID NO: 58. In some embodiments, the linker is set forth in SEQ ID NO: 60. In some embodiments, the linker is set forth in SEQ ID NO: 61. In some embodiments, the linker is set forth in SEQ ID NO: 62. In some embodiments, the V of the anti-BAFF-R scFv is H Area and V L The V regions are connected by a linker set forth in SEQ ID NO: 58. In some embodiments, the V of the anti-CD19 scFv HArea and V L The regions are connected by a linker shown in SEQ ID NO:59.

[0343] In some embodiments, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NOs: 11-15, or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NOs: 11-15. In some aspects, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 11 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 11. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 11. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:11. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 12 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 12. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 12.In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 12.

[0344] In some aspects, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 13 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 13. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 14 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 14. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 14. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 14.In some aspects, the BAFF-R scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 15 or has an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 15. In some aspects, the scFv provided herein comprises the amino acid sequence set forth in SEQ ID NO: 15. In some aspects, the scFvs provided herein comprise an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO: 15.

[0345] Among the provided CARs, the BAFF-R binding domain is a V comprising the sequence set forth in SEQ ID NO: 1. H a region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:1; H V containing the region and comprising the sequence shown in SEQ ID NO:2 L a region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:2; LIn some embodiments, the BAFF-R binding domain of the provided CAR comprises a V region having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 16, 17, and 18, respectively. H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 19, 20 and 21, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 1, L The region comprises the sequence shown in SEQ ID NO:2.

[0346] Among the provided CARs, the BAFF-R binding domain is a V comprising the sequence set forth in SEQ ID NO: 3. H a region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:3; H V containing the region and comprising the sequence shown in SEQ ID NO:4 L a region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:4; L In some embodiments, the BAFF-R binding domain of the provided CAR comprises a V region having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 22, 23, and 24, respectively. H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 25, 26 and 27, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 3, LThe region comprises the sequence shown in SEQ ID NO:4.

[0347] Among the provided CARs, the BAFF-R binding domain is a V comprising the sequence set forth in SEQ ID NO:5. H a region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:5; H V containing the region and comprising the sequence shown in SEQ ID NO:6 L a region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:6; L In some embodiments, the BAFF-R binding domain of the provided CAR comprises a V region having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 28, 29, and 30, respectively. H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 31, 26 and 27, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 5, L The region comprises the sequence shown in SEQ ID NO:6.

[0348] Among the provided CARs, the BAFF-R binding domain is a V comprising the sequence set forth in SEQ ID NO: 7. Ha region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:7; H V containing the region and comprising the sequence shown in SEQ ID NO:8 L a region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:8; L In some embodiments, the BAFF-R binding domain of the provided CAR comprises a V domain having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 22, 32, and 24, respectively. H and a V region having CDRL1, CDRL2, and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 33, 26, and 34, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 7, L The region comprises the sequence shown in SEQ ID NO:8.

[0349] Among the provided CARs, the BAFF-R binding domain is a V comprising the sequence set forth in SEQ ID NO: 9. H a region, or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO:9; H V containing the region and comprising the sequence shown in SEQ ID NO: 10 La region or a V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% identity to SEQ ID NO: 10; L In some embodiments, the BAFF-R binding domain of the provided CAR comprises a V region having CDRH1, CDRH2, and CDRH3 comprising the amino acid sequences of SEQ ID NOs: 35, 36, and 37, respectively. H and a V region having CDRL1, CDRL2 and CDRL3 comprising the amino acid sequences of SEQ ID NOs: 38, 39 and 40, respectively. L In some embodiments, the V H The region comprises the sequence shown in SEQ ID NO: 9, L The region comprises the sequence shown in SEQ ID NO:10.

[0350] Among the antibodies, e.g., antigen-binding fragments, in the provided CARs are human antibodies. In some embodiments of the provided human anti-BAFF-R antibodies, e.g., antigen-binding fragments, the human antibody comprises a V segment that includes a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain V segment, a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain D segment, and / or a portion having at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to an amino acid sequence encoded by a germline nucleotide human heavy chain J segment. HV segments containing a region and / or a portion having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence encoded by a germline nucleotide human kappa or lambda chain V segment and / or a portion having at least 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence encoded by a germline nucleotide human kappa or lambda chain J segment. L In some embodiments, the V H The portions of the regions correspond to CDR-H1, CDR-H2 and / or CDR-H3. H The portions of the regions correspond to framework region 1 (FR1), FR2, FR2, and / or FR4. L The portions of the regions correspond to CDR-L1, CDR-L2 and / or CDR-L3. L The portions of the regions correspond to FR1, FR2, FR2 and / or FR4.

[0351] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-H1 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-H1 region in a sequence encoded by a germline nucleotide human heavy chain V segment. For example, a human antibody, in some embodiments, contains a CDR-H1 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-H1 region in a sequence encoded by a germline nucleotide human heavy chain V segment.

[0352] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-H2 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-H2 region in a sequence encoded by a germline nucleotide human heavy chain V segment. For example, a human antibody, in some embodiments, contains a CDR-H2 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-H2 region in a sequence encoded by a germline nucleotide human heavy chain V segment.

[0353] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-H3 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-H3 region in a sequence encoded by a germline nucleotide human heavy chain V, D, and J segment. For example, a human antibody, in some embodiments, contains a CDR-H3 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-H3 region in a sequence encoded by a germline nucleotide human heavy chain V, D, and J segment.

[0354] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-L1 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-L1 region in a sequence encoded by a germline nucleotide human light chain V segment. For example, a human antibody, in some embodiments, contains a CDR-L1 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-L1 region in a sequence encoded by a germline nucleotide human light chain V segment.

[0355] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-L2 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-L2 region in a sequence encoded by a germline nucleotide human light chain V segment. For example, a human antibody, in some embodiments, contains a CDR-L2 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-L2 region in a sequence encoded by a germline nucleotide human light chain V segment.

[0356] In some embodiments, a human antibody, e.g., an antigen-binding fragment, contains a CDR-L3 that has at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to the amino acid sequence of the corresponding CDR-L3 region in a sequence encoded by a germline nucleotide human light chain V and J segment. For example, in some embodiments, a human antibody contains a CDR-L3 that has a sequence that is 100% identical or has no more than 1, 2, or 3 amino acid differences compared to the corresponding CDR-L3 region in a sequence encoded by a germline nucleotide human light chain V and J segment.

[0357] In some embodiments, human antibodies, e.g., antigen-binding fragments, contain framework regions that contain human germline gene segment sequences. For example, in some embodiments, human antibodies contain V and / or J segments in which the framework regions, e.g., FR1, FR2, FR3, and FR4, have at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to framework regions encoded by human germline antibody segments, such as V and / or J segments. H In some embodiments, a human antibody comprises a V segment, in which the framework regions, e.g., FR1, FR2, FR3, and FR4, have at least 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to framework regions encoded by human germline antibody segments, such as V and / or J segments.L For example, in some such embodiments, V H Area and / or V L The framework region sequences contained within the region differ by no more than 10 amino acids, such as no more than 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acids, compared to the framework region sequences encoded by human germline antibody segments.

[0358] b. CD19 binding domain In some embodiments, the CAR comprises the heavy chain variable (V H ) region and / or light chain variable (V L In some embodiments, the CD19 binding domain comprises an antibody comprising the (V H ) area and (V L ) regions of the CD19 binding domain are connected by an intradomain linker. H ) area and (V L ) region comprises an scFv antibody fragment. In some embodiments, the provided CD19-binding CARs contain an antibody, such as an anti-CD19 antibody or antigen-binding fragment thereof, that confers CD19-binding properties to the provided CAR.

[0359] In some embodiments, the antibody, e.g., anti-CD19 antibody or antigen-binding fragment, comprises a heavy and / or light chain variable (V H Or V L In some embodiments, the anti-CD19 antibody, e.g., antigen-binding fragment, contains a V region sequence, VH ... H In some embodiments, the anti-CD19 antibody, e.g., antigen-binding fragment, comprises a V domain sequence containing the CDR-L1, CDR-L2, and / or CDR-L3 described above. L In some embodiments, the anti-CD19 antibody, e.g., antigen-binding fragment, comprises a V domain sequence containing the described CDR-H1, CDR-H2, and / or CDR-H3.H V containing the region sequence and containing the CDR-L1, CDR-L2 and / or CDR-L3 as described L Also, some antibodies have sequences that are at least or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% identical to such sequences.

[0360] In some embodiments, the VH and VL regions of the anti-CD19 antibody in the provided CAR are the VH and VL sequences of a CAR T-cell therapy that targets CD19. Exemplary CAR T-cell therapies that target CD19 include the FDA-approved products BREYANZI® (lisocabtagene maraleucel), TECARTUS™ (brexucabtagene autoleucel), KYMRIAH™ (tisagenlecleucel), and YESCARTA™ (axicabtagene cycloleucel). Clinical trials, including NCT02644655, NCT03744676, NCT01087294, NCT03366350, NCT03790891, NCT03497533, NCT04007029, NCT03960840, NCT04049383, NCT04094766, NCT03366324, NCT02546739, NCT034483 These include those investigated or under investigation in NCT03467256, NCT03488160, NCT04012879, NCT03016377, NCT03468153, NCT03483688, NCT03398967, NCT03229876, NCT03455972, NCT03423706, NCT03497533, and NCT04002401.

[0361] In some embodiments, V Hand V L are derived from antibodies or antibody fragments specific for CD19. In some embodiments, the antibodies or antibody fragments that bind to CD19 are mouse-derived antibodies such as FMC63 and SJ25CJ. In some embodiments, exemplary antibodies or antibody fragments include human anti-CD19 antibodies such as those described in U.S. Patent Publication Nos. WO2014 / 031687, US2016 / 0152723, and WO2016 / 033570 (the contents of each of which are incorporated by reference in their entirety).

[0362] In some embodiments, the antigen-binding domain is a V H and / or V L In some embodiments, the scFv and / or V H The domain is derived from FMC63. FMC63 generally refers to a murine monoclonal IgG1 antibody raised against Nalm-1 and 16 cells expressing CD19 of human origin (Ling, NR et al. (1987). Leucocyte typing III. 302). The FMC63 antibody comprises the sequences of CDRH1 and H2 set forth in SEQ ID NOs: 43 and 44, respectively, CDRH3 set forth in SEQ ID NO: 45 or 46, CDRL1 set forth in SEQ ID NO: 47, CDRL2 set forth in SEQ ID NO: 48 or 49, and CDRL3 set forth in SEQ ID NO: 50 or 51. The FMC63 antibody comprises a heavy chain variable region (VH) comprising the amino acid sequence of SEQ ID NO: 41. H ) and a light chain variable region (V) comprising the amino acid sequence of SEQ ID NO: 42 L In some embodiments, the scFv comprises a variable light chain containing the CDRL1 sequence of SEQ ID NO: 47, the CDRL2 sequence of SEQ ID NO: 48, and the CDRL3 sequence of SEQ ID NO: 50, and / or a variable heavy chain containing the CDRH1 sequence of SEQ ID NO: 43, the CDRH2 sequence of SEQ ID NO: 44, and the CDRH3 sequence of SEQ ID NO: 45. In some embodiments, the scFv comprises the variable heavy chain region of FMC63 set forth in SEQ ID NO: 41 and the variable light chain region of FMC63 set forth in SEQ ID NO: 42.

[0363] In some embodiments, the anti-CD19 binding domain of the CAR is the V of the antigen binding domain of the anti-CD19 CAR of BREYANZI® (lysocbutagen malaleucel). H Array and V L Contains arrays.

[0364] In some embodiments, the anti-CD19 binding domain of the CAR is the V of the antigen binding domain of the anti-CD19 CAR of TECARTUS™ (brexcavtagene outleucel). H Array and V L Contains arrays.

[0365] In some embodiments, the anti-CD19 binding domain of the CAR is the V of the antigen binding domain of the anti-CD19 CAR of KYMRIAH™ (tisagenlecleucel). H Array and V L Contains arrays.

[0366] In some embodiments, the anti-CD19 binding domain of the CAR is the V of the antigen binding domain of the anti-CD19 CAR of YESCARTA™ (axicabtagene cycloleucel). H Array and V L Contains arrays.

[0367] In some embodiments, the anti-CD19 antigen binding domain of the provided CARs is V from SJ25C1. H and / or V L SJ25C1 refers to a mouse monoclonal IgG1 antibody produced against Nalm-1 and 16 cells expressing CD19 of human origin (Ling, NR et al. (1987). Leucocyte typing III. 302). The SJ25C1 antibody comprises the sequences of CDRH1, H2, and H3 shown in SEQ ID NOs: 124-126, respectively, and DRL1, L2, and L3 shown in SEQ ID NOs: 121-123, respectively. The SJ25C1 antibody comprises a heavy chain variable region (V) comprising the amino acid sequence of SEQ ID NO: 127. H ) and a light chain variable region (VL In some embodiments, the scFv comprises a variable light chain containing the CDRL1 sequence of SEQ ID NO: 121, the CDRL2 sequence of SEQ ID NO: 122, and the CDRL3 sequence of SEQ ID NO: 123, and / or a variable heavy chain containing the CDRH1 sequence of SEQ ID NO: 124, the CDRH2 sequence of SEQ ID NO: 125, and the CDRH3 sequence of SEQ ID NO: 126. In some embodiments, the scFv comprises the variable heavy chain region of SJ25C1 set forth in SEQ ID NO: 127 and the variable light chain region of SJ25C1 set forth in SEQ ID NO: 128.

[0368] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 41. H ) region, or V shown in SEQ ID NO: 41 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H The antibody or antigen-binding antibody fragment thereof comprises an antibody having the region.

[0369] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 63. H ) region, or V shown in SEQ ID NO: 63 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence HThe antibody or antigen-binding antibody fragment thereof comprises an antibody having the region.

[0370] In some embodiments, the CAR comprises a heavy chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 64. H ) region, or V shown in SEQ ID NO: 64 H or about 99% sequence identity with the amino acid sequence of the V region, or H V having an amino acid sequence containing CDR-H1, CDR-H2, and / or CDR-H3 present in the sequence H The antibody or antigen-binding antibody fragment thereof comprises an antibody having the region.

[0371] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to Kabat numbering. H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to Chothia numbering. H The regions include CDR-H1, CDR-H2 and / or CDR-H3 according to AbM numbering.

[0372] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 43, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 44, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 45 or 46. HIn some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 43, 44, and 45, respectively, or set forth in SEQ ID NOs: 43, 44, and 46, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 43, 44, and 45. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 43, 44, and 46. H In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO:41. H The amino acid sequences of CDR-H1, CDR-H2 and CDR-H3 are contained within the region amino acid sequence.

[0373] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is represented by SEQ ID NO: 41. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:41. H Includes the area.

[0374] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 75, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 76, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 77. H In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 75, 76, and 77, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 75, 76, and 77. H In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO: 63. H The amino acid sequences of CDR-H1, CDR-H2 and CDR-H3 are contained within the region amino acid sequence.

[0375] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is represented by SEQ ID NO: 63. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:63. H Includes the area.

[0376] In some embodiments, the CAR comprises a variable heavy chain (VH1) comprising a CDR-H1 comprising the amino acid sequence set forth in SEQ ID NO: 75, a CDR-H2 comprising the amino acid sequence set forth in SEQ ID NO: 76, and a CDR-H3 comprising the amino acid sequence set forth in SEQ ID NO: 77. H In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-H1, CDR-H2, and CDR-H3 comprising the amino acid sequences set forth in SEQ ID NOs: 75, 76, and 77, respectively. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NOs: 75, 76, and 77. H In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO: 64. H The amino acid sequences of CDR-H1, CDR-H2 and CDR-H3 are contained within the region amino acid sequence.

[0377] In some embodiments of the antibodies or antigen-binding fragments thereof provided herein, V H The region includes any of the CDR-H1, CDR-H2 and CDR-H3 described, and is represented by SEQ ID NO: 64. H In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising the amino acid sequence set forth in SEQ ID NO:64. H Includes the area.

[0378] In some embodiments, V HThe antibody or antibody fragment in the provided CAR comprising the region further comprises a light chain or a sufficient antigen-binding portion thereof. For example, in some embodiments, the antibody or antigen-binding fragment thereof comprises a V H Area and V L Area, or V H Area and V L In such an embodiment, the V H The domain sequence is the V H In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0379] In some embodiments, the CARs provided herein are selected from the group consisting of the V H For example, in some embodiments, the CAR comprises an antibody, such as an anti-CD19 antibody or antigen-binding fragment thereof, containing either the V or VL region, and the V or VL region, or a sufficient antigen-binding portion thereof. H domain and variable light chain (V L ) area, or V H Area and V L In such embodiments, the V H The domain sequence is the V H In some such embodiments, the antibody is an antigen-binding fragment, such as a Fab or scFv. In some such embodiments, the antibody is a full-length antibody that also contains a constant region.

[0380] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 42. L ) region, or V shown in SEQ ID NO: 42 Lor about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0381] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 65. L ) region, or V shown in SEQ ID NO: 65 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0382] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 66. L ) region, or V shown in SEQ ID NO: 66 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence LThe antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0383] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 67. L ) region, or V shown in SEQ ID NO: 67 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0384] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 68. L ) region, or V shown in SEQ ID NO: 68 L or about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0385] In some embodiments, the CAR comprises a light chain variable (V) having the amino acid sequence set forth in SEQ ID NO: 69. L ) region, or V shown in SEQ ID NO: 69 Lor about 99% sequence identity with the amino acid sequence of the V region, or L V having an amino acid sequence containing CDR-L1, CDR-L2, and / or CDR-L3 present in the sequence L The antibody or antigen-binding fragment thereof comprises an antibody having a region.

[0386] In some embodiments, the V of the antibody or antigen-binding fragment thereof L The V region comprises CDR-L1, CDR-L2 and / or CDR-L3 according to Kabat numbering. L The V region comprises CDR-L1, CDR-L2 and / or CDR-L3 according to Chothia numbering. L The regions include CDR-L1, CDR-L2 and / or CDR-L3 according to AbM numbering.

[0387] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 47, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 48 or 49, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 50 or 51. L In some embodiments, the antibody or antigen-binding fragment thereof comprises a V region comprising CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOs: 47, 48, and 50, respectively; set forth in SEQ ID NOs: 47, 49, and 50, respectively; set forth in SEQ ID NOs: 47, 48, and 51, respectively; or set forth in SEQ ID NOs: 47, 49, and 51, respectively. L Includes the area.

[0388] In some embodiments, the antibody or antigen-binding fragment thereof comprises the VL Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0389] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 78, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 79, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 80. L In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOs: 78, 79, and 80, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO: 65. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0390] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 81, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 82, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 83. L In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOs: 81, 82, and 83, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO: 66. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0391] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 85, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 86. LIn some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOs: 84, 85, and 86, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO:67. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0392] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 84, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 85, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 87. L In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOs: 84, 85, and 87, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO:68. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0393] In some embodiments, the CAR comprises a variable light chain (VLCD) comprising a CDR-L1 comprising the amino acid sequence set forth in SEQ ID NO: 88, a CDR-L2 comprising the amino acid sequence set forth in SEQ ID NO: 89, and a CDR-L3 comprising the amino acid sequence set forth in SEQ ID NO: 90. L In some embodiments, the antibody or antigen-binding fragment thereof comprises an antibody or antigen-binding fragment thereof having a V region comprising CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences set forth in SEQ ID NOs: 88, 89, and 90, respectively. L In some embodiments, the antibody or antigen-binding fragment thereof comprises the V region set forth in SEQ ID NO:69. L Each of the CDR-L1, CDR-L2, and CDR-L3 regions contains an amino acid sequence.

[0394] Among the CARs provided herein, an antibody, such as an anti-CD19 antibody or antibody fragment in the provided CAR has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:41. H and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:42. L There is a CAR that contains the region.

[0395] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO: 41 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 42. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0396] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 41 and is a V region of the antibody or antigen-binding fragment thereof. L In some embodiments, the V region of the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 42. H Area and V LThe region comprises the amino acid sequence set forth in SEQ ID NOs: 41 and 42, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0397] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 41 and 42, respectively.

[0398] Among the CARs provided herein, an antibody, such as an anti-CD19 antibody or antibody fragment in the provided CAR has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:63. H and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:65. L There is a CAR that contains the region.

[0399] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:63 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are set forth in SEQ ID NO: 65. LThe amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0400] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 63 and is a V region of the antibody or antigen-binding fragment thereof. L In some embodiments, the V region of the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 65. H Area and V L The region comprises the amino acid sequence set forth in SEQ ID NOs: 63 and 65, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the above V H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0401] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 63 and 65, respectively.

[0402] Among the CARs provided herein, an antibody, such as an anti-CD19 antibody or antibody fragment in the provided CAR has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:63. Hand V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:66. L There is a CAR that contains the region.

[0403] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:63 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are shown in SEQ ID NO: 66. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0404] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 63 and is a V region of the antibody or antigen-binding fragment thereof. L In some embodiments, the V region of the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 66. H Area and V L The region comprises the amino acid sequence set forth in SEQ ID NOs: 63 and 66, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0405] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V LThe regions comprise the amino acid sequences set forth in SEQ ID NOs: 63 and 66, respectively.

[0406] Among the CARs provided herein, an antibody, such as an anti-CD19 antibody or antibody fragment in the provided CAR, has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:64. H and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:67. L There is a CAR that contains the region.

[0407] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:64 H The amino acid sequence of CDR-H1, CDR-H2, and CDR-H3 contained in the V region amino acid sequence is shown in SEQ ID NO: 67. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0408] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 64 and is a V region of the antibody or antigen-binding fragment thereof. L In some embodiments, the V region of the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 67. H Area and V LThe region comprises the amino acid sequence set forth in SEQ ID NOs: 64 and 67, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0409] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 64 and 67, respectively.

[0410] Among the CARs provided herein, an antibody, such as an anti-CD19 antibody or antibody fragment in the provided CAR, has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:64. H V region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:68. L There is a CAR that contains the region.

[0411] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:64 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are set forth in SEQ ID NO: 68. LThe amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0412] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 64 and is a V region of the antibody or antigen-binding fragment thereof. L In some embodiments, the V region of the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 68. H Area and V L The region comprises the amino acid sequence set forth in SEQ ID NOs: 64 and 68, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0413] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V L The regions comprise the amino acid sequences set forth in SEQ ID NOs: 64 and 68, respectively.

[0414] Among the CARs provided herein, an antibody, such as an anti-CD19 antibody or antibody fragment in the provided CAR, has at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:64. HV region amino acid sequences, and V comprising an amino acid sequence having at least or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:69. L There is a CAR that contains the region.

[0415] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region is V shown in SEQ ID NO:64 H The amino acid sequences of CDR-H1, CDR-H2, and CDR-H3 contained within the V region amino acid sequence are set forth in SEQ ID NO: 69. L The amino acid sequences of CDR-L1, CDR-L2 and CDR-L3 are contained within the amino acid sequences of CDR-L1, CDR-L2 and CDR-L3, respectively.

[0416] In some embodiments, the V of the antibody or antigen-binding fragment thereof H The region comprises the amino acid sequence set forth in SEQ ID NO: 64 and is a V region of the antibody or antigen-binding fragment thereof. L In some embodiments, the V region of the antibody or antigen-binding fragment thereof comprises the amino acid sequence set forth in SEQ ID NO: 69. H Area and V L The region comprises the amino acid sequence set forth in SEQ ID NOs: 64 and 69, respectively, or has at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity with any of the V sequences described above. H and V L The present invention includes any antibody or antigen-binding fragment thereof having at least 90% sequence identity with any of the following:

[0417] For example, the V of an antibody or antigen-binding fragment thereof provided herein H Area and V LThe regions comprise the amino acid sequences set forth in SEQ ID NOs: 64 and 69, respectively.

[0418] In some embodiments, the antibody or antigen-binding fragment in the provided CAR is a single-chain antibody fragment, such as a single-chain variable fragment (scFv) or a diabody or a single-domain antibody (sdAb). H In some embodiments, the antibody or antigen-binding fragment is a single domain antibody comprising only the heavy chain variable (V H ) region and the light chain variable (V L In some embodiments, the single-chain antibody fragment is based on an scFv comprising a heavy chain variable (V H ) region and the light chain variable (V L The linker comprises one or more linkers connecting two antibody domains or regions, such as the α- and β-domains. The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker. Some linkers are rich in glycine and serine, and / or in some cases, threonine. In some embodiments, the linker further comprises charged residues, such as lysine and / or glutamic acid, which may improve solubility. In some embodiments, the linker further comprises one or more prolines.

[0419] Thus, the provided CARs can be used in combination with single-chain antibody fragments such as scFvs and diabodies, particularly V H Area and V L The present invention also includes an anti-CD19 antibody comprising a human single-chain antibody fragment that typically includes a linker(s) connecting two antibody domains or regions, such as a V domain. The linker is typically a peptide linker, e.g., a flexible and / or soluble peptide linker, such as one rich in glycine and serine. In some embodiments, the CD19-binding domain is a V H Area and V L In some embodiments, the CD19 binding domain comprises a V H Area and V L One of the regions, the linker, and V H Area and VL and the other of the regions, in that order from N-terminus to C-terminus. In some embodiments, the linker is set forth in SEQ ID NO: 59. Thus, in some embodiments, the CD19-binding domain comprises V H Area and V L one of the regions, a linker shown in SEQ ID NO: 59, and V H Area and V L The other of the regions is included in that order from N-terminus to C-terminus.

[0420] In some aspects, a linker rich in glycine and serine (and / or threonine) comprises at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% of such amino acid(s). In some embodiments, the linker comprises at least 50%, 55%, 60%, 70%, or 75% or approximately this percentage of glycine, serine, and / or threonine. In some embodiments, the linker is substantially entirely co...

Claims

1. A bispecific chimeric antigen receptor (CAR) comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is Heavy chain variable (V Ｈ ) region and the light chain variable (V Ｌ a B-cell activating factor receptor (BAFF-R) binding domain that binds to BAFF-R, comprising a BAFF-R-binding domain; V Ｈ Region and V Ｌ a CD19-binding domain that binds to CD19, comprising a region and the extracellular binding domain comprises (i) V of the BAFF-R binding domain Ｈ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｌ region, (ii) V of the BAFF-R binding domain Ｌ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｈ region, (iii) V of the BAFF-R binding domain Ｈ Region V of the CD19 binding domain Ｈ Region V of the CD19 binding domain Ｌ region, and V of the BAFF-R binding domain Ｌ Area, or (iv) V of the BAFF-R binding domain Ｌ Region V of the CD19 binding domain Ｈ Region V of the CD19 binding domain Ｌ region, and V of the BAFF-R binding domain Ｈ region, in this order from the amino terminus to the carboxy terminus.

2. The extracellular binding domain is V of the BAFF-R binding domain. Ｌ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｈ The bispecific CAR of claim 1, comprising the regions in this order from the amino terminus to the carboxy terminus.

3. The extracellular binding domain is V of the BAFF-R binding domain. Ｈ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｌ The bispecific CAR of claim 1, comprising the regions in this order from the amino terminus to the carboxy terminus.

4. (i) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

1. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO:2; (ii) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

3. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each having the sequence contained within SEQ ID NO:4; (iii) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each having the sequence contained within SEQ ID NO:

5. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO:6; (iv) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

7. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each comprising the sequence contained within SEQ ID NO:8; or (v) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

9. Ｌ the regions comprising CDR-L1, CDR-L2, and CDR-L3, each comprising the sequence contained within SEQ ID NO: 10; The bispecific CAR according to any one of claims 1 to 3.

5. The bispecific CAR of any one of claims 1 to 4, wherein each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition.

6. A bispecific CAR comprising an extracellular binding domain, a transmembrane domain, a spacer, and an intracellular signaling domain, wherein the extracellular binding domain is Heavy chain variable (V Ｈ ) region and the light chain variable (V Ｌ a B-cell activating factor receptor (BAFF-R) binding domain that binds to BAFF-R, comprising a BAFF-R-binding domain; V Ｈ Region and V Ｌ a CD19-binding domain that binds to CD19, comprising a region (i) the V of the BAFF-R binding domain; Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

1. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO:2; (ii) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

3. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO:4; (iii) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

5. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each of which comprises the sequence contained within SEQ ID NO:6; (iv) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

7. Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3, each comprising the sequence contained within SEQ ID NO:8; or (v) V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

9. Ｌ the regions comprising CDR-L1, CDR-L2, and CDR-L3, each comprising the sequence contained within SEQ ID NO: 10; Bispecific CAR.

7. 7. The bispecific CAR of claim 6, wherein each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition.

8. (i) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 16, 17 and 18, respectively, and the V of the BAFF-R binding domain Ｌ the region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 19, 20 and 21, respectively; (ii) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 22, 23 and 24, respectively, and the V of the BAFF-R binding domain Ｌ the regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 25, 26 and 27, respectively; (iii) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 28, 29 and 30, respectively, and the V of the BAFF-R binding domain Ｌ the regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 31, 26 and 27, respectively; (iv) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 22, 32 and 24, respectively, and the V of the BAFF-R binding domain Ｌ the regions comprise the CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 33, 26 and 34, respectively; or (v) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 35, 36 and 37, respectively, and the V of the BAFF-R binding domain Ｌ The region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 38, 39 and 40, respectively; The bispecific CAR according to any one of claims 1 to 7.

9. A bispecific CAR comprising an extracellular binding domain, a transmembrane domain, a spacer, and an intracellular signaling domain, wherein the extracellular binding domain is Heavy chain variable (V Ｈ ) region and the light chain variable (V Ｌ a B-cell activating factor receptor (BAFF-R) binding domain that binds to BAFF-R, comprising a BAFF-R-binding domain; V Ｈ Region and V Ｌ a CD19-binding domain that binds to CD19, comprising a region Including, (i) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 16, 17 and 18, respectively, and the V of the BAFF-R binding domain Ｌ the region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 19, 20 and 21, respectively; (ii) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 22, 23 and 24, respectively, and the V of the BAFF-R binding domain Ｌ the regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 25, 26 and 27, respectively; (iii) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 28, 29 and 30, respectively, and the V of the BAFF-R binding domain Ｌ the regions comprise the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 31, 26 and 27, respectively; (iv) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 22, 32 and 24, respectively, and the V of the BAFF-R binding domain Ｌ the regions comprise the CDR-L1, CDR-L2 and CDR-L3 sequences set forth in SEQ ID NOs: 33, 26 and 34, respectively; or (v) V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 35, 36 and 37, respectively, and the V of the BAFF-R binding domain Ｌ The region comprises the sequences of CDR-L1, CDR-L2 and CDR-L3 set forth in SEQ ID NOs: 38, 39 and 40, respectively; Bispecific CAR.

10. The extracellular binding domain is (i) V of the BAFF-R binding domain Ｈ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｌ region, (ii) V of the BAFF-R binding domain Ｌ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｈ region, (iii) V of the BAFF-R binding domain Ｈ Region V of the CD19 binding domain Ｈ Region V of the CD19 binding domain Ｌ region, and V of the BAFF-R binding domain Ｌ region, (iv) V of the BAFF-R binding domain Ｌ Region V of the CD19 binding domain Ｈ Region V of the CD19 binding domain Ｌ region, and V of the BAFF-R binding domain Ｈ region, (v) V of the CD19 binding domain Ｌ Region V of the BAFF-R binding domain Ｈ Region V of the BAFF-R binding domain Ｌ region, and V of the CD19 binding domain Ｈ region, (vi) V of the CD19-binding domain Ｈ Region V of the BAFF-R binding domain Ｈ Region V of the BAFF-R binding domain Ｌ region, and V of the CD19 binding domain Ｌ region, (vii) V of the CD19-binding domain Ｌ Region V of the CD19 binding domain Ｈ Region V of the BAFF-R binding domain Ｈ region, and V of the BAFF-R binding domain Ｌ region, (viii) V of the CD19-binding domain Ｌ Region V of the CD19 binding domain Ｈ Region V of the BAFF-R binding domain Ｌ region, and V of the BAFF-R binding domain Ｈ region, (ix) V of the CD19-binding domain Ｈ Region V of the CD19 binding domain Ｌ Region V of the BAFF-R binding domain Ｈ region, and V of the BAFF-R binding domain Ｌ region, (x) V of the CD19 binding domain Ｈ Region V of the CD19 binding domain Ｌ Region V of the BAFF-R binding domain Ｌ region, and V of the BAFF-R binding domain Ｈ region, (xi) V of the BAFF-R binding domain Ｌ Region V of the BAFF-R binding domain Ｈ Region V of the CD19 binding domain Ｈ region, and V of the CD19 binding domain Ｌ region, (xii) V of the BAFF-R binding domain Ｌ Region V of the BAFF-R binding domain Ｈ Region V of the CD19 binding domain Ｌ region, and V of the CD19 binding domain Ｈ region, (xiii) V of the BAFF-R binding domain Ｈ Region V of the BAFF-R binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the CD19 binding domain Ｌ region, (xiv) V of the BAFF-R binding domain Ｈ Region V of the BAFF-R binding domain Ｌ Region V of the CD19 binding domain Ｌ region, and V of the CD19 binding domain Ｈ region, (xv) V of the CD19-binding domain Ｌ Region V of the BAFF-R binding domain Ｌ Region V of the BAFF-R binding domain Ｈ region, and V of the CD19 binding domain Ｈ Area, or (xvi) V of the CD19-binding domain Ｈ Region V of the BAFF-R binding domain Ｌ Region V of the BAFF-R binding domain Ｈ region, and V of the CD19 binding domain Ｌ region, The bispecific CAR according to claims 6 to 9, comprising:

11. (i) V of the BAFF-R binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO: 1 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and Ｌ the region comprises the sequence set forth in SEQ ID NO:2 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:2; (ii) V of the BAFF-R binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO:3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:3, and Ｌ the region comprises the sequence set forth in SEQ ID NO:4 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:4; (iii) V of the BAFF-R binding domain Ｈ a region comprising the sequence set forth in SEQ ID NO:5 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:5, Ｌ the region comprises the sequence set forth in SEQ ID NO:6 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:6; (iv) V of the BAFF-R binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO:7 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:7, and Ｌ the region comprises the sequence set forth in SEQ ID NO:8 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:8; or (v) V of the BAFF-R binding domain Ｈ The region comprises the sequence set forth in SEQ ID NO:9 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:9, and Ｌ the region comprises the sequence set forth in SEQ ID NO: 10 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 10; The bispecific CAR according to any one of claims 1 to 10.

12. (i) V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 1, and the V Ｌ the region comprises the sequence set forth in SEQ ID NO:2; (ii) V of the BAFF-R binding domain Ｈ comprises the sequence shown in SEQ ID NO: 3, and the V of the BAFF-R binding domain Ｌ the region comprises the sequence set forth in SEQ ID NO:4; (iii) V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 5, and the V Ｌ The region comprises the sequence set forth in SEQ ID NO:6, or (iv) V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 7, and the V Ｌ the region comprises the sequence set forth in SEQ ID NO:8, or (v) V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 9, and the V Ｌ The region comprises the sequence set forth in SEQ ID NO: 10; The bispecific CAR according to any one of claims 1 to 11.

13. The extracellular binding domain is V of the BAFF-R binding domain. Ｈ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 1 to 12, comprising the region from the amino terminus to the carboxy terminus.

14. The extracellular binding domain is V of the BAFF-R binding domain. Ｌ Region V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ region, and V of the BAFF-R binding domain Ｈ The bispecific CAR according to any one of claims 1 to 12, comprising the region from the amino terminus to the carboxy terminus.

15. The extracellular binding domain is V of the CD19 binding domain Ｌ Region V of the BAFF-R binding domain Ｈ Region V of the BAFF-R binding domain Ｌ region, and V of the CD19 binding domain Ｈ The bispecific CAR according to any one of claims 6 to 12, comprising the region from the amino terminus to the carboxy terminus.

16. The extracellular binding domain is V of the CD19 binding domain Ｈ Region V of the BAFF-R binding domain Ｈ Region V of the BAFF-R binding domain Ｌ region, and V of the CD19 binding domain Ｌ The bispecific CAR according to any one of claims 6 to 12, comprising the region from the amino terminus to the carboxy terminus.

17. The extracellular binding domain is V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ Region V of the BAFF-R binding domain Ｈ region, and V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 6 to 12, comprising the region from the amino terminus to the carboxy terminus.

18. The extracellular binding domain is V of the CD19 binding domain Ｌ Region V of the CD19 binding domain Ｈ Region V of the BAFF-R binding domain Ｌ region, and V of the BAFF-R binding domain Ｈ The bispecific CAR according to any one of claims 6 to 12, comprising the region from the amino terminus to the carboxy terminus.

19. V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 22, 23 and 24, respectively, and the V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 1 to 18, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 sequences shown in SEQ ID NOs: 25, 26 and 27, respectively.

20. V of the BAFF-R binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO:3 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:3, and Ｌ The bispecific CAR according to any of claims 1 to 19, wherein the region comprises the sequence shown in SEQ ID NO: 4 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:

4.

21. V of the BAFF-R binding domain Ｈ comprises the sequence shown in SEQ ID NO: 3, and the V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 1 to 20, wherein the region comprises the sequence shown in SEQ ID NO:

4.

22. V of the BAFF-R binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO:5 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:5, and Ｌ The bispecific CAR according to any of claims 1 to 18, wherein the region comprises the sequence shown in SEQ ID NO: 6 or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:

6.

23. V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 28, 29 and 30, respectively, and the V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 1 to 18 and 22, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 sequences shown in SEQ ID NOs: 31, 26 and 27, respectively.

24. V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 5, and the V Ｌ The bispecific CAR according to any one of claims 1 to 18, 22, and 23, wherein the region comprises the sequence shown in SEQ ID NO:

6.

25. V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 16, 17 and 18, respectively, and the V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 1 to 18, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 sequences shown in SEQ ID NOs: 19, 20 and 21, respectively.

26. V of the BAFF-R binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO: 1 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 1, and Ｌ The bispecific CAR according to any of claims 1 to 18 and 25, wherein the region comprises a sequence as set forth in SEQ ID NO: 2 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:

2.

27. V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 1, and the V Ｌ The bispecific CAR according to any one of claims 1 to 18, 25, and 26, wherein the region comprises the sequence shown in SEQ ID NO:

2.

28. V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences shown in SEQ ID NOs: 22, 32 and 24, respectively, and the V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 1 to 18, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 sequences shown in SEQ ID NOs: 33, 26 and 34, respectively.

29. V of the BAFF-R binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO:7 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:7, and Ｌ The bispecific CAR according to any of claims 1 to 18 and 28, wherein the region comprises a sequence as set forth in SEQ ID NO: 8, or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:

8.

30. V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 7, and the V Ｌ The bispecific CAR according to any one of claims 1 to 18, 28, and 29, wherein the region comprises the sequence shown in SEQ ID NO:

8.

31. V of the BAFF-R binding domain Ｈ The region comprises the CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 35, 36 and 37, respectively, and the V of the BAFF-R binding domain Ｌ The bispecific CAR according to any one of claims 1 to 18, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 sequences shown in SEQ ID NOs: 38, 39 and 40, respectively.

32. V of the BAFF-R binding domain Ｈ The region comprises the sequence set forth in SEQ ID NO:9 or a sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:9, and Ｌ The bispecific CAR according to any of claims 1 to 18 and 31, wherein the region comprises the sequence shown in SEQ ID NO: 10, or a sequence that is at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:

10.

33. V of the BAFF-R binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 9, and the V Ｌ The bispecific CAR according to any one of claims 1 to 18, 31, and 32, wherein the region comprises the sequence shown in SEQ ID NO:

10.

34. V of the BAFF-R binding domain Ｈ The V region of the BAFF-R binding domain is connected to the V region of the BAFF-R binding domain via an intradomain linker. Ｌ The bispecific CAR according to any one of claims 1 to 33, which is connected to a region.

35. The VH region of the CD19 binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO: 41, and the VH region of the CD19 binding domain comprises CDR-H1, CDR-H2, and CDR-H3, each of which comprises the sequence contained within SEQ ID NO:

41. Ｌ 35. The bispecific CAR of any one of claims 1 to 34, wherein the regions comprise CDR-L1, CDR-L2, and CDR-L3, each comprising a sequence contained within SEQ ID NO:

42.

36. 36. The bispecific CAR of claim 35, wherein each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition.

37. V of the CD-19 binding domain Ｈ The regions comprise the CDR-H1, CDR-H2 and CDR-H3 sequences set forth in SEQ ID NOs: 41, 44 and 46, respectively, and the V of the CD19 binding domain Ｌ The bispecific CAR according to any one of claims 1 to 36, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 sequences shown in SEQ ID NOs: 47, 49 and 51, respectively.

38. (i) V of the CD19-binding domain Ｈ the region comprises the sequence set forth in SEQ ID NO:41 or a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:41; (ii) V of the CD19-binding domain Ｌ the region comprises the sequence set forth in SEQ ID NO:42 or a sequence that is at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO:42; The bispecific CAR according to any one of claims 1 to 37.

39. V of the CD19 binding domain Ｈ The region comprises the sequence shown in SEQ ID NO: 41, and the V Ｌ The bispecific CAR according to any one of claims 1 to 38, wherein the region comprises the sequence shown in SEQ ID NO:

42.

40. A bispecific CAR comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is Heavy chain variable (V Ｈ ) region and the light chain variable (V Ｌ a B-cell activating factor receptor (BAFF-R) binding domain that binds to BAFF-R, comprising a BAFF-R-binding domain; V Ｈ Region and V Ｌ a CD19-binding domain that binds to CD19, comprising a region Including, The extracellular binding domain is V of the BAFF-R binding domain comprising the sequence shown in SEQ ID NO: 3 Ｈ region, V of the CD-19 binding domain comprising the sequence set forth in SEQ ID NO:42 Ｌ region, V of the CD19 binding domain comprising the sequence set forth in SEQ ID NO:41 Ｈ region, and the V region of the BAFF-R binding domain comprising the sequence set forth in SEQ ID NO:4 Ｌ region in this order from the amino terminus to the carboxy terminus.

41. A bispecific CAR comprising an extracellular binding domain, a spacer, a transmembrane domain, and an intracellular signaling domain, wherein the extracellular binding domain is V Ｈ and V Ｌ a BAFF-R binding domain comprising: V Ｈ and V Ｌ a CD19 binding domain comprising Including, The extracellular binding domain is V of the BAFF-R binding domain comprising the sequence shown in SEQ ID NO: 6 Ｌ region, V of the CD-19 binding domain comprising the sequence set forth in SEQ ID NO:42 Ｌ region, V of the CD19 binding domain comprising the sequence set forth in SEQ ID NO:41 Ｈ region, and the V region of the BAFF-R binding domain comprising the sequence set forth in SEQ ID NO:5 Ｈ region in this order from the amino terminus to the carboxy terminus.

42. V of the CD-19 binding domain Ｈ The V region of the CD-19 binding domain is connected to the V region of the CD-19 binding domain via an intradomain linker. Ｌ The bispecific CAR according to any one of claims 1 to 41, wherein the bispecific CAR is connected to a region.

43. 43. The bispecific CAR of claim 34 or claim 42, wherein the intradomain linker is a flexible linker.

44. The bispecific CAR of any of claims 34, 42, and 43, wherein the intradomain linker is 5 to 25 amino acids in length.

45. The bispecific CAR according to any one of claims 34 and 42 to 44, wherein the intradomain linker is 12 to 18 amino acids in length.

46. The bispecific CAR according to any one of claims 34 and 42 to 45, wherein the intradomain linker comprises the sequence shown in SEQ ID NO:

58.

47. The bispecific CAR according to any one of claims 34 and 42 to 45, wherein the intradomain linker comprises the sequence shown in SEQ ID NO:

59.

48. The bispecific CAR according to any of claims 1 to 47, wherein the VH region or VL region of the BAFF-R-binding domain is connected to the VH region or VL region of the CD19-binding domain via an interdomain linker.

49. (i) V of the BAFF-R binding domain Ｈ The V region of the CD19 binding domain is connected to the V region of the CD19 binding domain by an interdomain linker. Ｌ Is it connected to an area? (i) V of the BAFF-R binding domain Ｈ The V region of the CD19 binding domain is connected to the V region of the CD19 binding domain by an interdomain linker. Ｈ Is it connected to an area? (iii) V of the BAFF-R binding domain Ｌ The V region of the CD19 binding domain is connected to the V region of the CD19 binding domain by an interdomain linker. Ｌ connected to the area, or (iv) V of the BAFF-R binding domain Ｌ The V region of the CD19 binding domain is connected to the V region of the CD19 binding domain by an interdomain linker. Ｈ connected to the area, The bispecific CAR according to any one of claims 1 to 48.

50. 50. The bispecific CAR of claim 48 or claim 49, wherein the interdomain linker is a flexible peptide linker.

51. The bispecific CAR according to any of claims 48 to 50, wherein the interdomain linker has a length of 5 to 25 amino acids (inclusive of the length of 5 amino acids and the length of 25 amino acids).

52. The bispecific CAR according to any of claims 48 to 51, wherein the interdomain linker has a length of 5 to 15 amino acids (inclusive of a length of 5 amino acids and a length of 15 amino acids).

53. The bispecific CAR according to any one of claims 34 and 48 to 52, wherein the interdomain linker is a G4S linker (SEQ ID NO: 60), a G4S2 linker (SEQ ID NO: 61), or a (G4S)4 linker (SEQ ID NO: 62).

54. The bispecific CAR according to any one of claims 48 to 53, wherein the interdomain linker is set forth in SEQ ID NO:

60.

55. The bispecific CAR according to any one of claims 48 to 54, wherein the interdomain linker is set forth in SEQ ID NO:

61.

56. The bispecific CAR according to any one of claims 1 to 55, wherein the spacer is sandwiched between the extracellular binding domain and the transmembrane domain.

57. The bispecific CAR of any one of claims 1 to 56, wherein the spacer comprises a hinge region sequence.

58. The bispecific CAR according to any one of claims 1 to 57, wherein the spacer comprises a hinge region of an immunoglobulin or a variant thereof.

59. 53. The bispecific CAR of claim 52, wherein the immunoglobulin hinge region is an IgG4 hinge region, optionally a human IgG4 hinge region, or a variant thereof.

60. The bispecific CAR according to any one of claims 1 to 59, wherein the spacer comprises a mutant IgG4 hinge region comprising a substitution of amino acids CPSC to CPPC compared to a wild-type IgG4 hinge region.

61. 61. The bispecific CAR of any one of claims 1 to 60, wherein the spacer is 15 or less than about 15 amino acids in length.

62. The bispecific CAR of any one of claims 1 to 61, wherein the spacer is 12 to 15 amino acids in length.

63. 63. The bispecific CAR of any one of claims 1 to 62, wherein the spacer comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 52, optionally wherein the spacer has the sequence shown in SEQ ID NO:

52.

64. The bispecific CAR of any one of claims 1 to 60, wherein the spacer is 200 to 250 amino acids in length, or 220 to 240 amino acids in length.

65. 65. The bispecific CAR of any one of claims 1 to 60 and 64, wherein the spacer comprises a hinge region of an immunoglobulin, a CH2 region of an immunoglobulin or a chimeric CH2 region of two different immunoglobulins, and a CH3 region of an immunoglobulin.

66. 66. The bispecific CAR of claim 65, wherein the spacer comprises an IgG4 hinge region or a variant thereof, a chimeric CH2 region comprising a portion of an IgG4 CH2 and a portion of an IgG2 CH2 (IgG2 / 4 CH2 region), and an IgG4 CH3 region.

67. 67. The bispecific CAR of any one of claims 1 to 62 and 64 to 66, wherein the spacer comprises an amino acid sequence having at least or about 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identity to SEQ ID NO: 53, optionally wherein the spacer has the sequence shown in SEQ ID NO:

53.

68. 68. The bispecific CAR of any one of claims 1 to 67, wherein the transmembrane domain comprises a transmembrane domain derived from CD28, suitably human CD28.

69. 69. The bispecific CAR according to any one of claims 1 to 68, wherein the transmembrane domain is or comprises SEQ ID NO: 55 or an amino acid sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:

55.

70. The bispecific CAR according to any one of claims 1 to 69, wherein the transmembrane domain is set forth in SEQ ID NO:

55.

71. The bispecific CAR according to any one of claims 1 to 70, wherein the intracellular signaling domain comprises an intracellular signaling domain capable of inducing a primary activation signal in a T cell.

72. 72. The bispecific CAR of claim 71 , wherein the intracellular signaling domain is a domain derived from a T cell receptor (TCR) component and / or comprises an immunoreceptor tyrosine-based activation motif (ITAM).

73. 73. The bispecific CAR of claim 71 or claim 72, wherein the intracellular signalling domain is the cytoplasmic signalling domain of the CD3-zeta (CD3ζ) chain, optionally the human CD3ζ chain.

74. The bispecific CAR according to any one of claims 71 to 73, wherein the intracellular signalling domain comprises the sequence set forth in SEQ ID NO: 57, or an amino acid sequence having at least or about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:

57.

75. The bispecific CAR according to any one of claims 71 to 74, wherein the intracellular signaling domain is set forth in SEQ ID NO:

57.

76. The bispecific CAR of any one of claims 71 to 75, wherein the intracellular signaling region further comprises a costimulatory signaling region.

77. 77. The bispecific CAR of claim 76, wherein the costimulatory signaling region is between the transmembrane region and the intracellular signaling domain.

78. 78. The bispecific CAR of claim 76 or claim 77, wherein the costimulatory signaling region comprises the intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

79. The bispecific CAR of any one of claims 76 to 78, wherein the costimulatory signalling region comprises the intracellular signalling domain of 4-1BB, optionally human 4-1BB.

80. The bispecific CAR according to any of claims 76 to 79, wherein the costimulatory signaling region comprises the sequence set forth in SEQ ID NO: 56, or an amino acid sequence having at least or approximately 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% sequence identity to SEQ ID NO:

56.

81. The bispecific CAR according to any of claims 76 to 80, wherein the costimulatory signaling region is set forth in SEQ ID NO:

56.

82. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:94, or an amino acid sequence that has at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

94.

83. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:95, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

95.

84. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:96, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

96.

85. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:97, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

97.

86. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:98, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

98.

87. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO:99, or an amino acid sequence that has at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

99.

88. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 100, or an amino acid sequence that has at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97%, or about 97%, 98%, or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

100.

89. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 101, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

101.

90. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 102, or an amino acid sequence that has at least or about 85%, 86%, or about 86%, 87%, or about 87%, 88%, or about 88%, 89%, or about 89%, 90%, or about 90%, 91%, or about 91%, 92%, or about 92%, 93%, or about 93%, 94%, or about 94%, 95%, or about 95%, 96%, or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

102.

91. A bispecific CAR comprising the amino acid sequence set forth in SEQ ID NO: 103, or an amino acid sequence that has at least or about 85%, 86% or about 86%, 87% or about 87%, 88% or about 88%, 89% or about 89%, 90% or about 90%, 91% or about 91%, 92% or about 92%, 93% or about 93%, 94% or about 94%, 95% or about 95%, 96% or about 96%, 97% or about 97%, 98% or about 98%, or 99% or about 99% sequence identity to the amino acid sequence set forth in SEQ ID NO:

103.

92. The bispecific CAR according to any one of claims 1 to 91, wherein binding of the BAFF-R domain to BAFF in the presence of soluble BAFF is reduced by 10% or less compared to binding in the absence of soluble BAFF.

93. The bispecific CAR according to any one of claims 1, 3 to 13, 19 to 21, 35 to 40, 42 to 45, 47 to 54, and 56 to 92, wherein binding of the CD19 domain to CD19 in the presence of FMC63 scFv is reduced by 30% or less compared to binding in the absence of FMC63 scFv.

94. A polynucleotide encoding the bispecific CAR of any one of claims 1 to 93.

95. 95. The polynucleotide of claim 94, which is optimized by splice site elimination.

96. 96. The polynucleotide of either claim 94 or claim 95, which is codon-optimized for expression in a human cell.

97. A vector comprising the polynucleotide of any one of claims 94 to 96.

98. 98. The vector of claim 97, which is a viral vector.

99. 99. The vector of claim 98, wherein the viral vector is a retroviral vector (e.g., a lentiviral vector).

100. A cell comprising the bispecific CAR of any one of claims 1 to 93.

101. A cell comprising the polynucleotide of any one of claims 94 to 96 or the vector of any one of claims 97 to 99.

102. 102. The cell of claim 100 or 101, which is an immune cell.

103. The cell according to any one of claims 100 to 102, which is a lymphocyte.

104. The cell according to any one of claims 100 to 103, which is a NK cell or a T cell.

105. The cell of any one of claims 100 to 104, which is a T cell.

106. The cell of any one of claims 100 to 105, wherein the T cell is a CD4+ T cell or a CD8+ T cell.

107. The cell of any one of claims 100 to 106, which is a primary cell.

108. The cell according to any one of claims 100 to 107, which exhibits cytotoxic activity against CD19+ cells, BAFF-R+ cells, and CD19+ / BAFF-R+ cells.

109. A composition comprising a plurality of cells according to any one of claims 100 to 108.

110. 110. The composition of claim 109, further comprising a pharmaceutically acceptable excipient.

111. 111. The composition of claim 109 or 110, comprising CD4+ T cells and CD8+ T cells.

112. 112. The composition of claim 111, wherein the ratio of CD4+ T cells to CD8+ T cells is 1:3 to 3:1 or about 1:3 to 3:1, optionally 1:2 to 2:1 or about 1:2 to 2:1, optionally 1:1 or about 1:

1.

113. 113. The composition of any one of claims 109-112, wherein greater than or about 90%, greater than or about 95%, or greater than or about 95%, or greater than or about 98% of the cells in the composition are CD3+ T cells.

114. The composition of any one of claims 109-113, wherein at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of cells in the composition express the CAR.

115. 115. The composition of any one of claims 109-114, wherein among a plurality of cells in the composition expressing the bispecific CAR, at or about 10%, 9% or about 9%, 8% or about 8%, 7% or about 7%, 5% or about 5%, 4% or about 4%, 3% or about 3%, 2% or about 2%, or less than 1% or about 1% of the plurality of cells exhibit tonic signaling and / or antigen-independent activity or signaling.

116. Approximately 1.0×10 ７ Bispecific CAR-expressing T cells ~1.2 x 10 ９ Bispecific CAR-expressing T cells, approximately 1.0 x 10 ７ Bispecific CAR-expressing T cells -6.5 x 10 ８ Bispecific CAR-expressing T cells, approximately 1.5 x 10 ７ Bispecific CAR-expressing T cells -6.5 x 10 ８ Bispecific CAR-expressing T cells, approximately 1.5 x 10 ７ Bispecific CAR-expressing T cells ~6.0 x 10 ８ Bispecific CAR-expressing T cells, approximately 2.5 x 10 ７ Bispecific CAR-expressing T cells ~6.0 x 10 ８ Bispecific CAR-expressing T cells, approximately 5.0 x 10 ７ Bispecific CAR-expressing T cells ~6.0 x 10 ８ Bispecific CAR-expressing T cells, approximately 1.25 x 10 ７ Bispecific CAR-expressing T cells ~1.2 x 10 ９ Bispecific CAR-expressing T cells, approximately 1.5 x 10 ７ Bispecific CAR-expressing T cells ~1.2 x 10 ９ Bispecific CAR-expressing T cells, approximately 5.0 x 10 ７ Bispecific CAR-expressing T cells - 4.5 x 10 ８ bispecific CAR-expressing T cells, or about 1.5 x 10 ８ Bispecific CAR-expressing T cells ~3.0 x 10 ８ The composition of any one of claims 109 to 115, comprising bispecific CAR-expressing T cells (each inclusive).

117. 1.5 x 10 ７ Or about 1.5 x 10 ７ , 2.5 × 10 ７ Or about 2.5 x 10 ７ , 5.0 × 10 ７ Or about 5.0 x 10 ７ , 7.5 × 10 ７ Or about 7.5 x 10 ７ , 1.5 × 10 ８ Or about 1.5 x 10 ８ , 2.25 × 10 ８ Or about 2.25 x 10 ８ , 3.0 × 10 ８ Or about 3.0 x 10 ８ , 4.5 × 10 ８ Or about 4.5 x 10 ８ , 6.0 × 10 ８ Or about 6.0 x 10 ８ , 8.0 × 10 ８ Or about 8.0 x 10 ８ , or 1.2 × 10 ９ Or about 1.2 x 10 ９ The composition of any one of claims 109 to 116, comprising a bispecific CAR-expressing T cell of

118. 116. A method of treating a disease or disorder in a subject, comprising administering to a subject in need thereof a cell according to any one of claims 100-108 or a composition according to any one of claims 107-115.

119. 97. A method of treatment, comprising administering to a subject having a disease or disorder the bispecific CAR of any of claims 1 to 93, the polynucleotide of any one of claims 94 to 96, or the vector of any one of claims 97 to 99.

120. 120. The method of claim 118 or claim 119, wherein the disease or disorder is cancer or an autoimmune disease.

121. 121. The method of claim 120, wherein the disease or disorder is cancer.

122. 122. The method of claim 120 or 121, wherein the cancer is a BAFF-R-expressing cancer, a CD19-expressing cancer, or a BAFF-R- and CD19-expressing cancer.

123. The method of any one of claims 120 to 122, wherein the cancer is lymphoma or leukemia.

124. 124. The method of claim 123, wherein the lymphoma is large B-cell lymphoma.

125. 124. The method of claim 123, wherein the lymphoma is non-Hodgkin's lymphoma.

126. 121. The method of claim 120, wherein the disease or disorder is an autoimmune disease.

127. A cell according to any of claims 100 to 108 or a composition according to any of claims 109 to 117 for use in treating a disease or disorder.

128. 118. Use of a cell according to any one of claims 100 to 108 or a composition according to any one of claims 109 to 117 for the manufacture of a medicament for treating a disease or disorder.

129. Use of a cell according to any one of claims 100 to 108 or a composition according to any one of claims 109 to 117 for the treatment of a disease or disorder.

130. 100. The bispecific CAR of any one of claims 1 to 93, the polynucleotide of any one of claims 94 to 96, or the vector of any one of claims 97 to 99 for use in treating a disease or disorder.

131. Use of the bispecific CAR of any of claims 1 to 93, the polynucleotide of any of claims 94 to 96, or the vector of any of claims 97 to 99 for the manufacture of a medicament for treating a disease or disorder.

132. Use of the bispecific CAR of any one of claims 1 to 93, the polynucleotide of any one of claims 94 to 96, or the vector of any one of claims 97 to 99 for the treatment of a disease or disorder.

133. 128. The use according to claim 126 or claim 127, wherein the disease or disorder is cancer or an autoimmune disease.

134. 134. The use of claim 133, wherein the disease or disorder is cancer.

135. The use of claim 133 or 134, wherein the cancer is a BAFF-R-expressing cancer, a CD19-expressing cancer, or a BAFF-R- and CD19-expressing cancer.

136. The use according to any one of claims 133 to 135, wherein the cancer is lymphoma or leukemia.

137. 137. The use of claim 136, wherein the lymphoma is large B-cell lymphoma.

138. 137. The use of claim 136, wherein the lymphoma is non-Hodgkin's lymphoma.

139. 134. The use of claim 133, wherein the disease or disorder is an autoimmune disease.

140. 130. The use of claim 128 or claim 129, wherein the disease or disorder is cancer or an autoimmune disease.

141. 141. The use of claim 140, wherein the disease or disorder is cancer.

142. The use of claim 140 or 141, wherein the cancer is a BAFF-R-expressing cancer, a CD19-expressing cancer, or a BAFF-R- and CD19-expressing cancer.

143. The use according to any one of claims 140 to 142, wherein the cancer is lymphoma or leukemia.

144. 144. The use of claim 143, wherein the lymphoma is large B-cell lymphoma.

145. 144. The use of claim 143, wherein the lymphoma is non-Hodgkin's lymphoma.

146. 141. The use of claim 140, wherein the disease or disorder is an autoimmune disease.

147. 146. A kit comprising a bispecific CAR according to any one of claims 1 to 93, a polynucleotide according to any one of claims 94 to 96, a vector according to any one of claims 97 to 99, a cell according to any one of claims 100 to 108, or a composition according to any one of claims 109 to 117, and instructions for use, optionally the instructions are for administering the bispecific CAR, cell or composition in accordance with the method for use, cell, composition, bispecific CAR, polynucleotide or vector, or use according to any one of claims 128 to 146.

148. An article of manufacture comprising the bispecific CAR of any one of claims 1 to 93, the polynucleotide of any one of claims 94 to 96, the vector of any one of claims 97 to 99, the cell of any one of claims 100 to 108, or the composition of any one of claims 109 to 117, or the kit of claim 147.

149. Heavy chain variable region (V Ｈ ) and the light chain variable region (V Ｌ and (iii) a B-cell activating factor receptor (BAFF-R)-binding antibody or antigen-binding portion thereof, comprising: (i) V Ｈ comprises CDR-H1, CDR-H2, and CDR-H3, each having the sequence contained within SEQ ID NO: 1; Ｌ the region comprises light chain complementarity determining region 1 (CDR-L1), light chain complementarity determining region 2 (CDR-L2) and light chain complementarity determining region 3 (CDR-L3) contained within SEQ ID NO:2; (ii) V Ｈ The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 3, and V Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:4; (iii) V Ｈ The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO:5, and V Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:6; (iv) V Ｈ The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 7, Ｌ the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:8; or (v) V Ｈ comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO:9, and V Ｌ The region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO: 10; An antibody or antigen-binding portion thereof.

150. V Ｈ comprises CDR-H1, CDR-H2, and CDR-H3, each having the sequence contained within SEQ ID NO: 1; Ｌ 150. The antibody or antigen-binding portion thereof of claim 149, comprising CDR-L1, CDR-L2, and CDR-L3, each having the sequence contained within SEQ ID NO:

2.

151. V Ｈ comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO:3, and V Ｌ 151. The antibody or antigen-binding portion thereof of claim 150, comprising CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:

4.

152. V Ｈ The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO:5, and V Ｌ The antibody or antigen-binding fragment thereof of claim 150, wherein the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:

6.

153. V Ｈ The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 7, Ｌ The antibody or antigen-binding fragment thereof of claim 150, wherein the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:

8.

154. V Ｈ The region comprises CDR-H1, CDR-H2, and CDR-H3 contained within SEQ ID NO: 9, and V Ｌ The antibody or antigen-binding fragment thereof of claim 150, wherein the region comprises CDR-L1, CDR-L2, and CDR-L3 contained within SEQ ID NO:

10.

155. 155. The antibody or antigen-binding portion thereof of any one of claims 150 to 154, wherein each CDR is defined according to the Kabat definition, the Chothia definition, a combination of the Kabat and Chothia definitions, the AbM definition, or the contact definition.

156. about 10 －7 M ~ about 10 －11 K of M Ｄ 155. The antibody or antigen-binding portion thereof of any one of claims 149 to 154, which binds to BAFF-R at

157. V Ｈ and V Ｌ An antibody or antigen-binding portion thereof that specifically binds to BAFF-R, comprising: (i) V Ｈ comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 16, 17 and 18, respectively; Ｌ comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 19, 20 and 21, respectively; (ii) V Ｈ comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 22, 23 and 24, respectively; Ｌ comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 25, 26 and 27, respectively; (iii) V Ｈ comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 28, 29 and 30, respectively; Ｌ the regions comprise CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 31, 26 and 27, respectively; (iv) V Ｈ comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 22, 32 and 24, respectively; Ｌ comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 33, 26 and 34, respectively; or (v) V Ｈ comprises CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 35, 36 and 37, respectively; Ｌ comprises CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 38, 39 and 40, respectively; An antibody or antigen-binding portion thereof.

158. V Ｈ the regions include CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 16, 17 and 18, respectively; Ｌ 158. The antibody or antigen-binding fragment thereof of any of claims 149, 150, and 157, wherein the regions comprise CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 19, 20, and 21, respectively.

159. V Ｈ the regions include CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 22, 23 and 24, respectively; Ｌ 158. An antibody or antigen-binding fragment thereof according to any one of claims 149, 151 and 157, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 25, 26 and 27, respectively.

160. V Ｈ the regions include CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 28, 29 and 30, respectively; Ｌ An antibody or antigen-binding fragment thereof according to any of claims 149, 152, and 157, wherein the regions comprise CDR-L1, CDR-L2, and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 31, 26, and 27, respectively.

161. V Ｈ the regions include CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 22, 32 and 24, respectively; Ｌ An antibody or antigen-binding fragment thereof according to any of claims 149, 153 and 157, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 33, 26 and 34, respectively.

162. V Ｈ the regions include CDR-H1, CDR-H2 and CDR-H3 comprising the sequences set forth in SEQ ID NOs: 35, 36 and 37, respectively; Ｌ An antibody or antigen-binding fragment thereof according to any of claims 149, 154 and 157, wherein the regions comprise CDR-L1, CDR-L2 and CDR-L3 comprising the sequences set forth in SEQ ID NOs: 38, 39 and 40, respectively.

163. (i) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 1, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:2, (ii) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:3, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:4, (iii) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:5, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:6, (iv) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:7, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 8; or (v) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 9, Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 10; An antibody or antigen-binding portion thereof according to claim 149 or claim 157.

164. V Ｈ and V Ｌ An antibody or antigen-binding portion thereof that specifically binds to BAFF-R, comprising: (i) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 1, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:2, (ii) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:3, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:4, (iii) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:5, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:6, (iv) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:7, and V Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 8; or (v) V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 9, Ｌ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 10; An antibody or antigen-binding portion thereof.

165. V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 1, and V Ｌ 165. The antibody or antigen-binding portion thereof of any of claims 149, 150, 157, 158, 160, and 164, wherein the antibody or antigen-binding portion thereof is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or approximately this percentage identity to SEQ ID NO:

2.

166. V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:3, and V Ｌ 165. The antibody or antigen-binding portion thereof of any of claims 149, 151, 157, 159, 163, and 164, wherein the antibody or antigen-binding portion thereof is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:4 or approximately this percentage.

167. V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:5, and V Ｌ 165. The antibody or antigen-binding portion thereof of any of claims 149, 152, 157, 160, 163, and 164, wherein the antibody or antigen-binding portion thereof is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO:6 or approximately this percentage.

168. V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO:7, and V Ｌ 165. The antibody or antigen-binding portion thereof of any of claims 149, 153, 157, 161, 163, and 164, wherein the antibody or antigen-binding portion thereof is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 8 or approximately this percentage.

169. V Ｈ is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% or about this percentage identity to SEQ ID NO: 9, Ｌ 165. The antibody or antigen-binding portion thereof of any of claims 149, 154, 157, 162, 163, and 164, wherein the antibody or antigen-binding portion thereof is or comprises an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity to SEQ ID NO: 10 or approximately this percentage.

170. (i) V Ｈ and V Ｌ are or contain the sequences set forth in SEQ ID NOs: 1 and 2, respectively; (ii) V Ｈ and V Ｌ are or contain the sequences set forth in SEQ ID NOs: 3 and 4, respectively; (iii) V Ｈ and V Ｌ are or comprise the sequences set forth in SEQ ID NOs: 5 and 6, respectively; (iv) V Ｈ and V Ｌ are or comprise the sequences set forth in SEQ ID NOs: 7 and 8, respectively; or (v) V Ｈ and V Ｌ are or comprise the sequences set forth in SEQ ID NOs: 9 and 10, respectively; An antibody or antigen-binding portion thereof according to any one of claims 149, 157, 163, and 164.

171. V Ｈ and V Ｌ An antibody or antigen-binding portion thereof that specifically binds to BAFF-R, comprising: (i) V Ｈ and V Ｌ are or contain the sequences set forth in SEQ ID NOs: 1 and 2, respectively; (ii) V Ｈ and V Ｌ are or contain the sequences set forth in SEQ ID NOs: 3 and 4, respectively; (iii) V Ｈ and V Ｌ are or comprise the sequences set forth in SEQ ID NOs: 5 and 6, respectively; (iv) V Ｈ and V Ｌ are or comprise the sequences set forth in SEQ ID NOs: 7 and 8, respectively; or (v) V Ｈ and V Ｌ are or comprise the sequences set forth in SEQ ID NOs: 9 and 10, respectively; An antibody or antigen-binding portion thereof.

172. V Ｈ and V Ｌ 172. An antibody or antigen-binding portion thereof according to any one of claims 149, 150, 157, 158, 163, 164, 165, 170, and 171, wherein:

173. V Ｈ and V Ｌ 172. An antibody or antigen-binding portion thereof according to any one of claims 149, 151, 157, 159, 163, 164, 166, 170, and 171, wherein said antibody or antigen-binding portion is or comprises the sequence set forth in SEQ ID NOs: 3 and 4, respectively.

174. V Ｈ and V Ｌ 172. An antibody or antigen-binding portion thereof according to any one of claims 149, 152, 157, 160, 163, 164, 167, 170, and 171, wherein said antibody or antigen-binding portion is or comprises the sequence set forth in SEQ ID NOs: 5 and 6, respectively.

175. V Ｈ and V Ｌ 172. An antibody or antigen-binding portion thereof according to any one of claims 149, 153, 157, 161, 163, 164, 168, 170, and 171, wherein: is or comprises the sequence set forth in SEQ ID NOs: 7 and 8, respectively.

176. V Ｈ and V Ｌ 172. An antibody or antigen-binding portion thereof according to any one of claims 149, 154, 157, 162, 163, 164, 169, 170, and 171, wherein: is or comprises the sequence set forth in SEQ ID NOs: 9 and 10, respectively.

177. 177. An antibody or antigen-binding portion thereof according to any one of claims 149 to 176, which is a full-length antibody.

178. 177. The antibody or antigen-binding portion thereof of any one of claims 149 to 176, which is an antigen-binding fragment.

179. 179. The antibody or antigen-binding portion thereof of any of claims 149-178, wherein the anti-BAFF-R antibody or antigen-binding portion thereof is recombinant.

180. V Ｈ and V Ｌ 180. The antibody or antigen-binding portion thereof of any of claims 149 to 179, which is human or derived from a human protein.

181. 181. The antibody or antigen-binding portion thereof of any of claims 149-176 and 177-180, wherein the antigen-binding portion comprises a single-chain variable fragment (scFv).

182. V Ｈ V Ｌ The antibody or antigen-binding portion thereof of claim 181, which is amino-terminal to

183. V Ｈ V Ｌ The antibody or antigen-binding portion thereof of claim 181, which is carboxy-terminal to

184. V Ｈ and V Ｌ An antibody or antigen-binding portion thereof according to any one of claims 179 to 181, wherein said

185. The antibody or antigen-binding portion thereof of claim 184, wherein the flexible linker comprises the sequence set forth in SEQ ID NO:

58.

186. 186. The antibody or antigen-binding portion thereof of any of claims 179 to 185, wherein the antigen-binding portion is or comprises the sequence set forth in SEQ ID NO: 11, 12, 13, 14, or 15, or an amino acid sequence having at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% or about this percentage sequence identity to SEQ ID NO: 11, 12, 13, 14, or 15.

187. 186. An antibody or antigen-binding portion thereof according to any of claims 179 to 185, wherein the antigen-binding portion is or comprises the sequence shown in SEQ ID NO:

11.

188. 186. The antibody or antigen-binding portion thereof of any of claims 179 to 185, wherein the antigen-binding portion is or comprises the sequence shown in SEQ ID NO:

12.

189. 186. The antibody or antigen-binding portion thereof of any of claims 179 to 185, wherein the antigen-binding portion is or comprises the sequence shown in SEQ ID NO:

13.

190. 186. The antibody or antigen-binding portion thereof of any of claims 179 to 185, wherein the antigen-binding portion is or comprises the sequence shown in SEQ ID NO:

14.

191. 186. The antibody or antigen-binding portion thereof of any of claims 179 to 185, wherein the antigen-binding portion is or comprises the sequence shown in SEQ ID NO:

15.

192. 192. The antibody or antigen-binding portion thereof of any of claims 149-191, wherein the anti-BAFF-R antibody or antigen-binding portion thereof specifically binds to human B-cell activating factor receptor (BAFF-R) protein.

193. 193. The antibody or antigen-binding portion thereof of claim 192, wherein the human BAFF-R protein comprises the amino acid sequence set forth in SEQ ID NO:

120.

194. 194. A pharmaceutical composition comprising the antibody or antigen-binding portion thereof of any of claims 149-193 and a pharmaceutical carrier.

195. A chimeric antigen receptor (CAR) comprising an extracellular binding domain, a transmembrane domain, and an intracellular signaling domain, comprising the antibody or antigen-binding portion thereof according to any one of claims 149 to 193.

196. The CAR of claim 195, wherein the intracellular signaling domain comprises an intracellular signaling domain capable of inducing a primary activation signal in a T cell.

197. The CAR of claim 195 or 196, wherein the intracellular signaling domain is a domain derived from a T cell receptor (TCR) component and / or comprises an immunoreceptor tyrosine-based activation motif (ITAM).

198. The CAR of any one of claims 195 to 197, wherein the intracellular signaling domain is the cytoplasmic signaling domain of the CD3-zeta (CD3ζ) chain, suitably the human CD3ζ chain.

199. The CAR of any one of claims 195 to 198, wherein the intracellular signaling region further comprises a costimulatory signaling region.

200. The CAR of claim 199, wherein the costimulatory signaling region is located between the transmembrane region and the intracellular signaling domain.

201. The CAR of claim 199 or claim 200, wherein the costimulatory signaling region comprises the intracellular signaling domain of a T cell costimulatory molecule or a signaling portion thereof.

202. The CAR of any one of claims 199 to 201, wherein the costimulatory signaling region comprises the intracellular signaling domain of 4-1BB, optionally human 4-1BB.

203. 194. A conjugate comprising the antibody or antigen-binding portion thereof of any of claims 149-193 and a heterologous molecule or moiety.

204. 204. The conjugate of claim 203, wherein the heterologous molecule or moiety is a therapeutic moiety.

205. A nucleic acid encoding the antibody or antigen-binding portion thereof of any of claims 149 to 193.

206. A polynucleotide comprising the nucleic acid of claim 205.

207. A polynucleotide comprising a nucleic acid encoding the conjugate of claim 203 or claim 204.

208. 208. The polynucleotide of claim 206 or claim 207, which is optimized by splice site elimination.

209. 209. The polynucleotide of any one of claims 206 to 208, which is codon-optimized for expression in a human cell.

210. An expression vector comprising the nucleic acid of claim 205.

211. A vector comprising the polynucleotide of any one of claims 206 to 209.

212. The vector of claim 211, which is a viral vector.

213. The vector of claim 212, wherein the viral vector is a retroviral vector or a lentiviral vector.

214. A cell comprising the antibody or antigen-binding portion thereof according to any one of claims 149 to 193, the CAR according to any one of claims 195 to 202, or the conjugate according to claim 203 or claim 204.

215. A cell comprising a polynucleotide according to any one of claims 206 to 209 or a vector according to any one of claims 210 to 213.

216. The cell of claim 215, which is an immune cell.

217. 217. The cell of claim 215 or claim 216, which is a lymphocyte.

218. The cell of any one of claims 215 to 217, which is a NK cell or a T cell.

219. The cell of any one of claims 215 to 218, which is a T cell, and the T cell is a CD4+ T cell or a CD8+ T cell.

220. 220. The cell of any one of claims 214 to 219, which is a primary cell obtained from a subject.

221. A composition comprising a cell according to any one of claims 214 to 220.

222. A composition comprising the antibody or antigen-binding portion thereof according to any one of claims 149 to 193, the CAR according to any one of claims 195 to 202, or the conjugate according to claim 203 or claim 204.

223. 214. The composition of claim 212 or claim 213, further comprising a pharmaceutically acceptable excipient.

224. 223. The composition of claim 221 or claim 222, comprising CD4+ and CD8+ T cells, wherein the ratio of CD4+ T cells to CD8+ T cells is 1:3 to 3:1 or about 1:3 to 3:1, optionally 1:2 to 2:1 or about 1:2 to 2:1, optionally 1:1 or about 1:

1.

225. 216. A method for producing an antibody or antigen-binding portion thereof that specifically binds to BAFF-R, the method comprising culturing the host cell of claim 215 under suitable conditions and obtaining the product expressed by the host cell.

226. 202. A method for preparing a BAFF-R targeting drug, an anti-BAFF-R antibody drug conjugate (ADC), a multifunctional anti-BAFF-R antibody, a reagent for diagnosing a tumor expressing BAFF-R, or an anti-BAFF-R chimeric antigen receptor (CAR)-modified immune cell, comprising providing an antibody or antigen-binding portion thereof according to any of claims 149-193, and incorporating said antibody or antigen-binding portion thereof into the BAFF-R targeting drug, anti-BAFF-R ADC, multifunctional anti-BAFF-R antibody, a reagent for diagnosing a tumor expressing BAFF-R, or an anti-BAFF-R chimeric antigen receptor (CAR)-modified immune cell.

227. 22. A method of treatment comprising administering a cell according to any one of claims 214 to 220 or a composition according to any one of claims 221 to 224 to a subject having a disease or disorder associated with BAFF-R.

228. 226. The cell of any one of claims 214 to 220 or the composition of any one of claims 221 to 224 for use in treating a disease or disorder associated with BAFF-R.

229. Use of a cell according to any one of claims 214 to 220 or a composition according to any one of claims 221 to 224 for the manufacture of a medicament for treating a disease or disorder associated with BAFF-R.

230. Use of a cell according to any one of claims 214 to 220 or a composition according to any one of claims 221 to 224 for the treatment of a disease or disorder associated with BAFF-R.

231. 209. A method of treatment comprising administering to a subject having a disease or disorder associated with BAFF-R an antibody or antigen-binding portion thereof according to any of claims 149 to 193, a pharmaceutical composition according to claim 194, a CAR according to any one of claims 195 to 1202, a conjugate according to claim 203 or claim 204, a nucleic acid according to claim 205, a polynucleotide according to any one of claims 206 to 209, or a vector according to any one of claims 210 to 213.

232. 216. An anti-BAFF-R antibody or an antigen-binding portion thereof according to any of claims 149 to 193, a pharmaceutical composition according to claim 194, a CAR according to any one of claims 195 to 202, a conjugate according to claim 203 or claim 204, a nucleic acid according to claim 205, a polynucleotide according to any one of claims 206 to 209, or a vector according to any one of claims 210 to 213, for use in treating a disease or disorder associated with BAFF-R.

233. Use of the anti-BAFF-R antibody or antigen-binding portion thereof according to any one of claims 149 to 193, the pharmaceutical composition according to claim 194, the CAR according to any one of claims 195 to 202, the conjugate according to claim 203 or claim 204, the nucleic acid according to claim 205, the polynucleotide according to any one of claims 206 to 209, or the vector according to any one of claims 210 to 213, for the manufacture of a medicament for treating a disease or disorder associated with BAFF-R.

234. Use of the antibody or antigen-binding portion thereof according to any one of claims 149 to 193, the pharmaceutical composition according to claim 194, the CAR according to any one of claims 195 to 202, the conjugate according to claim 203 or claim 204, the nucleic acid according to claim 205, the polynucleotide according to any one of claims 206 to 209, or the vector according to any one of claims 210 to 213 for the treatment of a disease or disorder associated with BAFF-R.

235. 235. The method, cell, composition, antibody or antigen-binding portion thereof, conjugate, polynucleotide, or vector, or use for use according to any of claims 225 to 234, wherein the disease or disorder associated with BAFF-R is cancer.

236. 236. The method, cell, composition, antibody or antigen-binding portion thereof, conjugate, polynucleotide, or vector, or use for use according to claim 235, wherein the cancer is a BAFF-R-expressing cancer.

237. 236. A kit comprising an antibody or antigen binding portion thereof according to any of claims 149 to 193, a pharmaceutical composition according to claim 194, a CAR according to any of claims 195 to 202, a conjugate according to claim 203 or claim 204, a nucleic acid according to claim 205, a polynucleotide according to any of claims 206 to 209, or a vector according to any of claims 210 to 213, a cell according to any of claims 214 to 220, or a composition according to any of claims 221 to 224, and instructions for use, optionally wherein the instructions are for administering the antibody or antigen binding portion thereof, conjugate, cell or composition in accordance with the method for use, cell, composition, antibody or antigen binding portion thereof, conjugate, polynucleotide or vector, or use as appropriate according to any of claims 225 to 236.

238. 237. An article of manufacture comprising the antibody or antigen-binding portion thereof of any one of claims 149 to 193, the pharmaceutical composition of claim 194, the CAR of any one of claims 195 to 202, the conjugate of claim 203 or claim 204, the nucleic acid of claim 205, the polynucleotide of any one of claims 206 to 209, or the vector of any one of claims 210 to 213, the cell of any one of claims 214 to 220, the composition of any one of claims 221 to 224, or the kit of claim 237.

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