Antibodies targeting baffr and uses thereof

Abstract

The present invention provides an anti-BAFFR antibody or an antigen-binding fragment thereof, a nucleic acid molecule encoding the antibody or an antigen-binding fragment thereof, a carrier containing the nucleic acid molecule, a host cell containing the nucleic acid molecule or the carrier, an antibody conjugate containing the antibody molecule, a chimeric antigen receptor, a pharmaceutical composition and a cassette, and their use in the preparation of a medicament for treating cancer or an autoimmune disease.

Description

Technical Field

[0001] This disclosure pertains to the field of biomedical technology. Specifically, this disclosure relates to anti-BAFFR antibodies or antigen-binding fragments thereof, nucleic acid molecules encoding said antibodies or antigen-binding fragments thereof, carriers containing said nucleic acid molecules, host cells containing said nucleic acid molecules or carriers, antibody conjugates containing said antibody molecules, chimeric antigen receptors, pharmaceutical compositions, kits or combination products, and their use in the preparation of medicaments for treating cancer or autoimmune diseases, and methods of treating diseases using the aforementioned products. Background Technology

[0002] B cells are a crucial component of the human immune system, but their abnormal proliferation can lead to various diseases, such as autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, systemic lupus erythematosus, connective tissue diseases, Sjögren's syndrome, cold agglutinin disease, antisynthetic enzyme syndrome, idiopathic pulmonary fibrosis, multiple sclerosis, lupus nephritis, lymphadenopathy, non-Hodgkin's lymphoma, rheumatoid arthritis, and B-cell chronic lymphocytic leukemia. These diseases characterized by abnormal B cell proliferation commonly exhibit high expression of BAFF (also known as CD257, TNFSF13B, BLyS) and BAFF receptor (BAFFR) (also known as TNFRSF13C, BROMIX, CD268, CVID4). BAFF is a cytokine that regulates B lymphocyte survival and maturation, belonging to the tumor necrosis factor (TNF) family, and regulates B cell survival, proliferation, development, and differentiation. BAFF exerts its functions by binding to three different receptors (BAFFR, TACI, and BCMA), including promoting B cell differentiation and maturation, class switching, enhancing humoral immune responses, and participating in T cell activation. The BAFF / BAFFR pathway is primarily responsible for the survival and maturation of immature B cells, the BAFF / BCMA pathway is primarily responsible for plasma cell maturation, and the BAFF / TACI pathway is primarily responsible for T cell-independent antibody responses and B cell class switching. Several drugs targeting BAFF have been used to treat the aforementioned diseases, but response rates are low and there is a risk of infection. Compared to blocking all three BAFF receptor pathways, blocking only BAFF / BAFFR specifically reduces the survival of abnormally proliferating B cells and has a higher safety profile.

[0003] Furthermore, BAFFR is expressed at almost all developmental stages of B cells except plasma cells, proto-B cells, and pre-B cells, and its expression abundance is higher than that of CD20. However, it is not expressed in bone marrow stem cells from which B cells originate. After the overproliferated B cells are cleared, the number of B cells can return to normal after a period of drug withdrawal, further demonstrating that this target blocking mechanism has a high safety profile.

[0004] BAFFR, encoded by the TNFRSF13C gene, consists of an extracellular, transmembrane, and intracellular region. The extracellular region is relatively short, containing only 78 amino acids. Unlike other TNFR members, BAFFR has only one CRD (cysteine ​​enrichment domain), containing four cysteine ​​residues, which binds to BAFF in a trimer form. Upon binding to BAFFR, BAFF triggers non-canonical NF-κB2 pathway activation. This pathway activates kinase NIK, which in turn activates the IKKα homodimer. Activated IKKα phosphorylates RelB-p100; under ubiquitination degradation conditions, the p100 precursor degrades to active p52. The RelB-p52 heterodimer enters the nucleus, regulating the activation of NF-κB2-related target genes and inhibiting apoptosis gene expression. Furthermore, the binding of BAFF to BAFFR also induces a PI3K-dependent signaling cascade. Downstream of PI3K, AKT / mTOR induces metabolic reprogramming in B cells, leading to increased cell adaptation and survival.

[0005] Several drugs targeting BAFF have been used to treat diseases related to abnormal B-cell proliferation, but response rates are low and there is a risk of infection. Meanwhile, some inhibitors that directly target B cells, such as CD20 and CD19, suffer from high relapse rates and limited clinical efficacy due to issues such as antigen loss. Therefore, the existing drugs for treating diseases related to abnormal B-cell proliferation still do not meet clinical needs. Summary of the Invention

[0006] The purpose of this application is to provide an antibody or antigen-binding fragment thereof that targets BAFFR to inhibit the abnormal proliferation of B cells in various diseases, while improving the safety of treatment.

[0007] In one aspect, this application provides an anti-BAFFR antibody or an antigen-binding fragment thereof, comprising:

[0008] HCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12;

[0009] HCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 128 (KIX1PX2SGYTDFNQKFKD, where X1=N or E; X2=S or A), SEQ ID NO: 8, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 128 and SEQ ID NO: 8;

[0010] HCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13; and / or

[0011] LCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14;

[0012] LCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 5;

[0013] LCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15.

[0014] In some embodiments, this application provides an anti-BAFFR antibody or its antigen-binding fragment, comprising:

[0015] HCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12;

[0016] HCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 8, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 2, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 8;

[0017] HCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13; and / or

[0018] LCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14;

[0019] LCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 5;

[0020] LCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15.

[0021] In another aspect, this application relates to nucleic acid molecules comprising a nucleotide sequence encoding the aforementioned anti-BAFFR antibody or an antigen-binding fragment thereof.

[0022] In another aspect, this application relates to vectors containing the aforementioned nucleic acid molecules.

[0023] In another aspect, this application relates to host cells containing the aforementioned nucleic acid molecules or vectors.

[0024] In another aspect, this application relates to a method for producing the above-described anti-BAFFR antibody or its antigen-binding fragment.

[0025] In another aspect, this application relates to antibody conjugates comprising the aforementioned anti-BAFFR antibody or its antigen-binding fragment.

[0026] In another aspect, this application relates to a chimeric antigen receptor (CAR) comprising the aforementioned anti-BAFFR antibody or its antigen-binding fragment.

[0027] In another aspect, this application relates to pharmaceutical compositions comprising: the above-described anti-BAFFR antibody or its antigen-binding fragment, or the above-described antibody conjugate, chimeric antigen receptor, and optionally pharmaceutically acceptable excipients.

[0028] In another aspect, this application relates to kits or combination products comprising the aforementioned anti-BAFFR antibody or its antigen-binding fragment, the aforementioned antibody-drug conjugate, chimeric antigen receptor, or pharmaceutical composition.

[0029] The antibody or its antigen-binding fragment described in this application interferes with, reduces or inhibits the binding of BAFF to BAFFR, and eliminates B cells in vitro and in vivo.

[0030] In another aspect, this application relates to the use of the aforementioned anti-BAFFR antibody or its antigen-binding fragment, antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, kit, or combination product in the preparation of a BAFFR inhibitor. Alternatively, this application relates to the use of the aforementioned anti-BAFFR antibody or its antigen-binding fragment, antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, kit, or combination product as a BAFFR inhibitor. Alternatively, this application relates to a method of inhibiting BAFFR, comprising administering the aforementioned anti-BAFFR antibody or its antigen-binding fragment, antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, kit, or combination product to a subject in need. Alternatively, the method for inhibiting BAFFR described in this application uses the antibody or its antigen-binding fragment to inhibit, for example, the function of antagonizing BAFFR, thereby delaying, preventing, preventing the onset of, or inhibiting the development of symptoms or conditions associated with the presence of BAFF and / or BAFFR, such as treating pathogenic conditions mediated by BAFFR or treatable by killing or eliminating B cells; for example, autoimmune diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) or B-cell tumors such as lymphoma, leukemia, or myeloma. Therefore, such antibodies or antigen-binding fragments can be used prophylactically, preventively, or as part of a treatment method.

[0031] In another aspect, this application relates to the use of the aforementioned anti-BAFFR antibody or its antigen-binding fragment, antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, kit, or combination product in the preparation of a medicament for the prevention or treatment of cancer or an autoimmune disease. Alternatively, this application relates to the use of the aforementioned anti-BAFFR antibody or its antigen-binding fragment, antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, kit, or combination product as a medicament for cancer or an autoimmune disease. Alternatively, this application relates to a method of treating cancer or an autoimmune disease, comprising administering the aforementioned anti-BAFFR antibody or its antigen-binding fragment, antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, kit, or combination product to a subject in need.

[0032] This application also relates to methods for detecting antigens, such as methods for detecting antigens in a sample (e.g., a biological sample).

[0033] This application relates to a method of specifically reducing the survival of abnormally proliferating B cells by blocking the BAFF / BAFFR pathway, with improved safety. This application can be applied to immunotherapy for cancer or autoimmune diseases. Preferably, the cancer includes diseases involving abnormal B cell proliferation, and the autoimmune diseases include autoimmune diseases mediated by abnormal B cell proliferation or abnormal antibody secretion. Attached Figure Description

[0034] Figure 1 The SDS-PAGE detection results of the chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 in Example 5 are shown.

[0035] Figure 2 The graph shows the activity results of chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 binding to 293T-BAFFR, as detected by FACS.

[0036] Figure 3 The graph shows the results of the chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 blocking the binding of human BAFF to 293T-BAFFR, as detected by FACS.

[0037] Figure 4 The graph shows the activity results of chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 binding to Raji cells, as detected by FACS.

[0038] Figure 5The graph shows the results of the chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 blocking the binding of human BAFF to Raji cells, as detected by FACS.

[0039] Figure 6 The graph shows the results of the chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 blocking the binding of human BAFF to SU-DHL-4 cells, as detected by FACS.

[0040] Figure 7 The SDS-PAGE detection results of the humanized antibodies hu55E11V1-hIgG1~hu55E11V10-hIgG1 in Example 7 are shown.

[0041] Figure 8 The graph shows the binding activity results of humanized antibodies hu55E11V1-hIgG1~hu55E11V10-hIgG1 with recombinant human BAFFR protein, which were detected by ELISA.

[0042] Figure 9 The graph shows the binding activity results of humanized antibodies hu55E11V1-hIgG1~hu55E11V10-hIgG1 with monkey BAFFR recombinant protein, which were detected by ELISA.

[0043] Figure 10 The graph shows the binding activity of humanized antibodies hu55E11V1-hIgG1~hu55E11V10-hIgG1 with Raji cells, which was detected by FACS.

[0044] Figure 11 The graph shows the results of the humanized antibodies hu55E11V1-hIgG1~hu55E11V10-hIgG1 blocking the binding activity of human BAFF to Raji cells, which were detected by FACS.

[0045] Figure 12 The results of ADCC activity assays for humanized antibodies hu55E11V2-hIgG1, hu55E11V4-hIgG1, and hu55E11V5-hIgG1 using Jurkat-NFAT-Luc2-CD16a-V158 as effector cells are shown.

[0046] Figure 13The results of ADCC activity assays for humanized antibodies hu55E11V2-hIgG1 and hu55E11V4-hIgG1 using PBMCs as effector cells are shown.

[0047] Figures 14A-14B The tumor growth inhibitory effect of the humanized antibody hu55E11V4KOF in a mouse model of subcutaneous heterotopic transplantation of human lymphoma Raji cells was demonstrated.

[0048] Figure 15 The activity results of the modified antibodies hu55E11V4YPYKOF, hu55E11V4YTEKOF, hu55E11V4LSKOF, hu55E11V4YTEFFKOF, and hu55E11V4DQVKOF with 293T-BAFFR are shown, and the results were detected by FACS.

[0049] Figure 16 The results of the modified antibodies hu55E11V4YPYKOF, hu55E11V4YTEKOF, hu55E11V4LSKOF, hu55E11V4YTEFFKOF, and hu55E11V4DQVKOF blocking the binding of human BAFF to 293T-BAFFR are shown, and the results were detected by FACS.

[0050] Figure 17 The results of ADCC activity assays mediated by the modified antibodies hu55E11V4YPYKOF, hu55E11V4YTEKOF, hu55E11V4LSKOF, hu55E11V4YTEFFKOF, and hu55E11V4DQVKOF are shown. Detailed Implementation

[0051] Next, the technical solution of this application will be described in more detail through exemplary embodiments, but the scope of protection of this application is not limited thereto.

[0052] Anti-BAFFR antibody or its antigen-binding fragment

[0053] This application provides an anti-BAFFR antibody or its antigen-binding fragment, which can specifically bind to BAFFR; the anti-BAFFR antibody or its antigen-binding fragment provided in this application can block the binding of BAFF to BAFFR by specifically binding to BAFFR.

[0054] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application includes three complementarity-determining regions (CDRs) from the heavy chain variable region, namely HCDR1, HCDR2 and HCDR3, and / or three complementarity-determining regions (CDRs) from the light chain variable region, namely LCDR1, LCDR2 and LCDR3.

[0055] In some embodiments, HCDR1 comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 1, 7 or 12; or HCDR1 comprises an amino acid sequence having one, two or three amino acid changes (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 1, 7 or 12.

[0056] In some embodiments, HCDR2 comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 128 (KIX1PX2SGYTDFNQKFKD; where X1=N or E; X2=S or A) or SEQ ID NO: 8; or HCDR2 comprises an amino acid sequence having one, two, or three amino acid changes (e.g., substitution, deletion, addition, or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequences shown in SEQ ID NO: 128 or 8.

[0057] In some embodiments, HCDR2 comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 2, 126, 127 or 8; or HCDR2 comprises an amino acid sequence having one, two or three amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 2, 126, 127 or 8.

[0058] In some embodiments, HCDR3 comprises, or is composed of, the amino acid sequence of SEQ ID NO: 3, 9 or 13; or HCDR3 comprises an amino acid sequence having one, two or three amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence of SEQ ID NO: 3, 9 or 13.

[0059] In some embodiments, LCDR1 comprises, or is composed of, the amino acid sequence of SEQ ID NO: 4, 10 or 14; or LCDR1 comprises an amino acid sequence having one, two or three amino acid changes (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence of SEQ ID NO: 4, 10 or 14.

[0060] In some embodiments, LCDR2 comprises or is composed of the amino acid sequence of SEQ ID NO: 5; or LCDR2 comprises an amino acid sequence having one, two, or three amino acid changes (e.g., substitution, deletion, addition, or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence of SEQ ID NO: 5.

[0061] In some embodiments, LCDR3 comprises, or is composed of, the amino acid sequence of SEQ ID NO: 6, 11 or 15; or LCDR3 comprises an amino acid sequence having one, two or three amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence of SEQ ID NO: 6, 11 or 15.

[0062] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0063] HCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12, and an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) sequence identity with SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12;

[0064] HCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 128, SEQ ID NO: 8, and an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) sequence identity with SEQ ID NO: 128 and SEQ ID NO: 8;

[0065] HCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13, and an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) sequence identity with SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13; and / or

[0066] LCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14, and an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) sequence identity with SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14;

[0067] LCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, and an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) sequence identity with SEQ ID NO: 5;

[0068] LCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15, and an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) sequence identity with SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15.

[0069] In some embodiments, the isolated anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0070] HCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12;

[0071] HCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 2, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 8, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 2, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 8;

[0072] HCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13; and / or

[0073] LCDR1 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14;

[0074] LCDR2 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 5;

[0075] LCDR3 having an amino acid sequence selected from the group consisting of: SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15, and an amino acid sequence having at least 80% sequence identity with SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15.

[0076] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application includes:

[0077] (1) HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1, HCDR2 having the amino acid sequence of SEQ ID NO: 128 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 128, HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3, and / or LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4, LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5, and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6;

[0078] (2) HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1, HCDR2 having the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 2, HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3, and / or LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4, LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5, and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6;

[0079] (3) HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1, HCDR2 having the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 126, HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3, and / or LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4, LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5, and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6;

[0080] (4) HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1, HCDR2 having the amino acid sequence of SEQ ID NO: 127 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 127, HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3, and / or LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4, LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5, and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6;

[0081] (5) HCDR1 having the amino acid sequence of SEQ ID NO: 7 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 7; HCDR2 having the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 8; HCDR3 having the amino acid sequence of SEQ ID NO: 9 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 9; and / or LCDR1 having the amino acid sequence of SEQ ID NO: 10 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 10; LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5; and LCDR3 having the amino acid sequence of SEQ ID NO: 11 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 11; or

[0082] (6) HCDR1 having the amino acid sequence of SEQ ID NO: 12 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 12, HCDR2 having the amino acid sequence of SEQ ID NO: 8 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 8, HCDR3 having the amino acid sequence of SEQ ID NO: 13 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 13, and / or LCDR1 having the amino acid sequence of SEQ ID NO: 14 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 14, LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5, and LCDR3 having the amino acid sequence of SEQ ID NO: 15 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 15.

[0083] In a preferred embodiment, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0084] HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1; HCDR2 having the amino acid sequence of SEQ ID NO: 128 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 128; HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3; and / or

[0085] LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4; LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5; and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0086] In a preferred embodiment, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0087] (1) HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1; HCDR2 having the amino acid sequence of SEQ ID NO: 2 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 2; HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3; and / or

[0088] LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4; LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5; and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0089] (2) HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1, HCDR2 having the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 126, HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3, and / or

[0090] LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4; LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5; and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0091] (3) HCDR1 having the amino acid sequence of SEQ ID NO: 1 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 1, HCDR2 having the amino acid sequence of SEQ ID NO: 127 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 127, HCDR3 having the amino acid sequence of SEQ ID NO: 3 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 3, and / or

[0092] LCDR1 having the amino acid sequence of SEQ ID NO: 4 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 4; LCDR2 having the amino acid sequence of SEQ ID NO: 5 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 5; and LCDR3 having the amino acid sequence of SEQ ID NO: 6 or an amino acid sequence having at least 80% sequence identity with the amino acid sequence of SEQ ID NO: 6.

[0093] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0094] HCDR1 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12; HCDR2 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 128, SEQ ID NO: 8; HCDR3 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13; and / or

[0095] LCDR1 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14; LCDR2 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 5; LCDR3 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15.

[0096] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0097] HCDR1 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 7, SEQ ID NO: 12; HCDR2 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 2, SEQ ID NO: 126, SEQ ID NO: 127, SEQ ID NO: 8; HCDR3 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 13; and / or

[0098] LCDR1 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 14; LCDR2 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 5; LCDR3 having an amino acid sequence selected from the group consisting of or consisting of said amino acid sequences: SEQ ID NO: 6, SEQ ID NO: 11, SEQ ID NO: 15.

[0099] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application includes:

[0100] (1) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 128, HCDR3 shown in SEQ ID NO: 3, and / or LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6;

[0101] (2) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, and / or LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6;

[0102] (3) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 126, HCDR3 shown in SEQ ID NO: 3, and / or LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6;

[0103] (4) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 127, HCDR3 shown in SEQ ID NO: 3, and / or LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6;

[0104] (5) HCDR1 shown in SEQ ID NO: 7, HCDR2 shown in SEQ ID NO: 8, HCDR3 shown in SEQ ID NO: 9, and / or LCDR1 shown in SEQ ID NO: 10, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 11; or

[0105] (6) HCDR1 shown in SEQ ID NO: 12, HCDR2 shown in SEQ ID NO: 8, HCDR3 shown in SEQ ID NO: 13, and / or LCDR1 shown in SEQ ID NO: 14, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 15.

[0106] In a preferred embodiment, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0107] HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 128, HCDR3 shown in SEQ ID NO: 3, and / or LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.

[0108] In a preferred embodiment, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0109] (1) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6;

[0110] (2) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 126, HCDR3 shown in SEQ ID NO: 3, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6; or

[0111] (3) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 127, HCDR3 shown in SEQ ID NO: 3, LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6.

[0112] In this document, the heavy chain variable region CDRs (HCDRs) and light chain variable region CDRs (LCDRs) in the anti-BAFFR antibody or its antigen-binding fragment are defined using the Kabat numbering system. Variable regions defined using other numbering systems are also within the scope of protection of this application.

[0113] The scope of the aforementioned CDRs has been defined according to the Kabat numbering rules (see Kabat, et al., Ann. NYAcad. Sci. 190:382-93 (1971); Kabat, et al., Sequences of Proteins of Immunological Interest, Fifth Edition, US Department of Health and Human Services, NIH Publication No. 91-3242 (1991)). However, those skilled in the art will understand that CDR sequences numbered according to one or more of the Chothia numbering rules, the ImMunoGenTics (IMGT) numbering rules, the AbM numbering rules, and the Contact numbering rules (based on the analysis of available complex crystal structures) also fall within the scope of protection of this application.

[0114] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application includes: HCDR1, HCDR2, and HCDR3 of each of SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 39, or SEQ ID NO: 47-56; and / or LCDR1, LCDR2, and LCDR3 of each of SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, or SEQ ID NO: 57-58.

[0115] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application includes:

[0116] (1) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 35, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 36;

[0117] (2) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 47, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0118] (3) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 48, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0119] (4) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 49, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0120] (5) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 50, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0121] (6) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 51, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0122] (7) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 52, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0123] (8) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 53, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0124] (9) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 54, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0125] (10) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 55, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0126] (11) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 56, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0127] (12) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 37, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 38; or

[0128] (13) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 39 and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 40.

[0129] In a preferred embodiment, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0130] (1) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 35, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 36;

[0131] (2) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 47, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0132] (3) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 48, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0133] (4) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 49, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0134] (5) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 50, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0135] (6) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 51, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 57;

[0136] (7) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 52, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0137] (8) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 53, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0138] (9) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 54, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58;

[0139] (10) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 55, and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58; or

[0140] (11) HCDR1, HCDR2 and HCDR3 in SEQ ID NO: 56 and LCDR1, LCDR2 and LCDR3 in SEQ ID NO: 58.

[0141] In a preferred embodiment, the CDR sequence is defined using one or more of the following: Kabat numbering rules, IMGT numbering rules, AbM numbering rules, Chothia numbering rules, and Contact numbering rules.

[0142] The following table provides exemplary CDR sequences defined using the Kabat numbering rule, IMGT numbering rule, Chothia numbering rule, and Contact numbering rule in the variable regions of the heavy and light chains, as shown in SEQ ID NO: 35 and SEQ ID NO: 36, respectively, as illustrated in Table 1 below:

[0143] QVQLQQSGAELARPGASVKMSCKASGYTFTTYPMHWVKQRPGQGLEWIGKINPSSGYTDFNQKFKDRATLTADKSSSTAYMQLSSLTSEDSAVYFCASSYYAMDYWGQGTSVTVSS (SEQ ID NO: 35);

[0144] DIVMSQSPSSLAVSVGEKVTLSCKSSQSLLYSSNQKNYLAWYQQKPGQSPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYIYPTFGGGTKLAIK (SEQ ID NO: 36).

[0145] Table 1. Exemplary CDR sequences under different numbering rules

[0146]

[0147] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment further includes a framework region (FR). In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment includes a heavy chain variable region and / or a light chain variable region, wherein at least a portion of the heavy chain variable region and / or light chain variable region is derived from a murine antibody, a human antibody, a primate-derived antibody, or a mutant thereof.

[0148] For example, the anti-BAFFR antibody or its antigen-binding fragment further includes four frame regions from the heavy chain variable region, namely HFR1, HFR2, HFR3 and HFR4, and / or four frame regions from the light chain variable region, namely LFR1, LFR2, LFR3 and LFR4.

[0149] In some embodiments, HFR1 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 16, 24, 31 or 71; or, HFR1 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid changes (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 16, 24, 31 or 71; or, HFR1 may comprise an amino acid sequence having at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 16, 24, 31 or 71.

[0150] In a preferred embodiment, HFR1 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 16 or 71; or, HFR1 may comprise an amino acid sequence having 1, 2, 3, 4, or 5 amino acid alterations (e.g., substitution, deletion, addition, or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 16 or 71; or, HFR1 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 16 or 71.

[0151] In some embodiments, HFR2 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 17, 25, 72 or 75; or, HFR2 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid changes (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 17, 25, 72 or 75; or, HFR2 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 17, 25, 72 or 75.

[0152] In a preferred embodiment, HFR2 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 17, 72 or 75; or, HFR2 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 17, 72 or 75; or, HFR2 may comprise an amino acid sequence having at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 17, 72 or 75.

[0153] In some embodiments, HFR3 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 18, 26, 32, 73, 76, 77 or 78; or, HFR3 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 18, 26, 32, 73, 76, 77 or 78; or, HFR3 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 18, 26, 32, 73, 76, 77 or 78.

[0154] In a preferred embodiment, HFR3 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 18, 73, 76, 77 or 78; or, HFR3 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 18, 73, 76, 77 or 78; or, HFR3 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 18, 73, 76, 77 or 78.

[0155] In some embodiments, HFR4 comprises, or is composed of, the amino acid sequence shown in SEQ ID NO: 19 or 74; or, HFR4 comprises an amino acid sequence having 1, 2, 3, 4, or 5 amino acid alterations (e.g., substitution, deletion, addition, or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 19 or 74; or HFR4 comprises an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 19 or 74.

[0156] In some embodiments, LFR1 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 20, 27, 33, 79 or 83; or, LFR1 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 20, 27, 33, 79 or 83; or, LFR1 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 20, 27, 33, 79 or 83.

[0157] In a preferred embodiment, LFR1 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 20, 79 or 83; or, LFR1 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 20, 79 or 83; or, LFR1 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 20, 79 or 83.

[0158] In some embodiments, LFR2 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 21, 28, 80 or 84; or, LFR2 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid changes (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 21, 28, 80 or 84; or, LFR2 may comprise an amino acid sequence having at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 21, 28, 80 or 84.

[0159] In a preferred embodiment, LFR2 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 21, 80, or 84; or, LFR2 may comprise an amino acid sequence having 1, 2, 3, 4, or 5 amino acid alterations (e.g., substitution, deletion, addition, or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 21, 80, or 84; or, LFR2 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 21, 80, or 84.

[0160] In some embodiments, LFR3 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 22, 29, 34, 81 or 85; or, LFR3 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 22, 29, 34, 81 or 85; or, LFR3 may comprise an amino acid sequence having at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 22, 29, 34, 81 or 85.

[0161] In a preferred embodiment, LFR3 may comprise, or be composed of, the amino acid sequence shown in SEQ ID NO: 22, 81 or 85; or, LFR3 may comprise an amino acid sequence having 1, 2, 3, 4 or 5 amino acid alterations (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 22, 81 or 85; or, LFR3 may comprise an amino acid sequence having at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 22, 81 or 85.

[0162] In some embodiments, LFR4 comprises or is composed of the amino acid sequence shown in SEQ ID NO: 23, 30 or 82; or, LFR4 comprises an amino acid sequence having 1, 2, 3, 4 or 5 amino acid changes (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 23, 30 or 82; or LFR4 comprises an amino acid sequence having at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 23, 30 or 82.

[0163] In a preferred embodiment, LFR4 comprises or is composed of the amino acid sequence shown in SEQ ID NO: 23 or 82; or, LFR4 comprises an amino acid sequence having 1, 2, 3, 4 or 5 amino acid changes (e.g., substitution, deletion, addition or any combination thereof, preferably amino acid substitution, more preferably conservative substitution) compared to the amino acid sequence shown in SEQ ID NO: 23 or 82; or LFR4 comprises an amino acid sequence having at least 80% (e.g. at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%) identity with the amino acid sequence shown in SEQ ID NO: 23 or 82.

[0164] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application includes a heavy chain variable region (VH) and / or a light chain variable region (VL).

[0165] In some embodiments, the heavy chain variable region (VH) comprises CDR and FR regions. In a preferred embodiment, the heavy chain variable region (VH) comprises CDR and FR regions arranged in the following order from the amino terminus to the carboxyl terminus: HFR1, HCDR1, HFR2, HCDR2, HFR3, HCDR3, and HFR4.

[0166] In some embodiments, the heavy chain variable region (VH) comprises a FR region derived from a human germline heavy chain. In some embodiments, the FR region derived from the human germline heavy chain may include the same amino acid sequence as the human antibody from which it originates, or may include some amino acid changes, for example, no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid change.

[0167] In some embodiments, the heavy chain variable region (VH) includes:

[0168] (1) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 73, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0169] (2) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 76, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; or

[0170] (3) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 77, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; or

[0171] (4) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 78, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; or

[0172] (5) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 16, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 17, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 18, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19; or

[0173] (6) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 24, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 25, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 26, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19; or

[0174] (7) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 31, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 25, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 32, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19.

[0175] In some embodiments, the heavy chain variable region (VH) includes:

[0176] (1) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 73, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0177] (2) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 73, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0178] (3) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 127, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 73, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0179] (4) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 76, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0180] (5) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 76, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0181] (6) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 77, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0182] (7) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 77, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0183] (8) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 127, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 77, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0184] (9) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 78, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0185] (10) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 78, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74;

[0186] (11) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 16, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 17, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 18, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19;

[0187] (12) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 24, HCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 7, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 25, HCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 26, HCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 9, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19; or

[0188] (13) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 31, HCDR1 shown in SEQ ID NO: 12, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 25, HCDR2 shown in SEQ ID NO: 8, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 32, HCDR3 shown in SEQ ID NO: 13, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19.

[0189] In some implementations, the heavy chain variable region (VH):

[0190] (i) An amino acid sequence comprising or consisting of an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37, and 39; or

[0191] (ii) Contains or consists of the amino acid sequence shown by any one of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37 and 39; or

[0192] (iii) An amino acid sequence comprising or consisting of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37, and 39, preferably the amino acid changes not occurring in the CDR region.

[0193] In a preferred embodiment, the heavy chain variable region (VH) is:

[0194] (i) An amino acid sequence comprising or consisting of, having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 35; or

[0195] (ii) Contains or consists of the amino acid sequence shown by any one of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 and 35; or

[0196] (iii) An amino acid sequence comprising or consisting of the amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 35, preferably the amino acid changes not occurring in the CDR region.

[0197] In some embodiments, the light chain variable region (VL) comprises CDR and FR regions. In a preferred embodiment, the light chain variable region (VL) comprises CDR and FR regions arranged in the following order from the amino terminus to the carboxyl terminus: LFR1, LCDR1, LFR2, LCDR2, LFR3, LCDR3, and LFR4.

[0198] In some embodiments, the light chain variable region (VL) comprises a FR region derived from a human germline light chain. In some embodiments, the FR region derived from the human germline light chain may include the same amino acid sequence as the human antibody from which it originates, or may include some amino acid changes, for example, no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid change. In some embodiments, this amino acid change may be present only in the heavy chain FR region, only in the light chain FR region, or simultaneously in both chains.

[0199] In some embodiments, the light chain variable region (VL) comprises:

[0200] (1) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 79, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 80, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 81, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82;

[0201] (2) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 83, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 84, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 85, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82;

[0202] (3) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 20, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 21, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 22, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 23;

[0203] (4) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 27, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 28, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 29, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 30; or

[0204] (5) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 33, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 21, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 34, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 30.

[0205] In some embodiments, the light chain variable region (VL) comprises:

[0206] (1) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 79, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 4, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 80, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 81, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 6, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82;

[0207] (2) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 83, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 4, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 84, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 85, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 6, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82;

[0208] (3) LFR1, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 20; LCDR1, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 21; LCDR2, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5; LFR3, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 22; LCDR3, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 23; and LFR4, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 23.

[0209] (4) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 27, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 10, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 28, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 29, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 11, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 30; or

[0210] (5) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 33, LCDR1 shown in SEQ ID NO: 14, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 21, LCDR2 shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 34, LCDR3 shown in SEQ ID NO: 15, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 30.

[0211] In a preferred embodiment, the light chain variable region (VL) comprises:

[0212] (1) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 79, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 4, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 80, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 81, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 6, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82;

[0213] (2) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 83, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 4, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 84, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 85, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 6, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82; or

[0214] (3) LFR1, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 20, LCDR1 shown in SEQ ID NO: 4, LFR2, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 21, LCDR2 shown in SEQ ID NO: 5, LFR3, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 22, LCDR3 shown in SEQ ID NO: 6, and LFR4 which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 23.

[0215] In some embodiments, the light chain variable region (VL):

[0216] (i) an amino acid sequence comprising or consisting of, having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38, and 40; or

[0217] (ii) Contains or consists of the amino acid sequence shown by any one of SEQ ID NOs: 57, 58, 36, 38 and 40; or

[0218] (iii) An amino acid sequence comprising or consisting of the amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38, and 40, preferably the amino acid changes not occurring in the CDR region.

[0219] In a preferred embodiment, the light chain variable region (VL) is:

[0220] (i) an amino acid sequence comprising or consisting of, having at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 97%, 98%, or 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 57, 58, and 36; or

[0221] (ii) Contains or consists of the amino acid sequence shown by any of SEQ ID NOs: 57, 58 and 36; or

[0222] (iii) An amino acid sequence comprising or consisting of the amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 57, 58, and 36, preferably the amino acid changes do not occur in the CDR region.

[0223] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0224] The amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown by any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37, and 39; containing VH of at least 80%, at least 81%, at least 82%, at least 83%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown by any of SEQ ID NOs: A VH consisting of an amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37, and 39; or an amino acid sequence comprising one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37, and 39, preferably the amino acid changes do not occur in the CDR region; and / or

[0225] A VL having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38, and 40; or a VL comprising or composed of the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38, and 40; or comprising a VL with at least 80%, at least 81%, at least 82%, at least 83%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38, and 40; or a VL comprising a VL with at least 80%, at least 81%, at least 82%, at least 83%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38, and 40; or a VL comprising a VL with at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 96%, at least 97%, at least 98%, or at least 99% identity with the amino acid sequence shown in any of SEQ ID NOs: 57 The amino acid sequence shown in any of 57, 58, 36, 38 and 40 has one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to an amino acid sequence or a VL composed of said amino acid sequence, preferably said amino acid changes do not occur in the CDR region.

[0226] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0227] A VH having at least 80% identity with the amino acid sequence shown by any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 35; a VH comprising or composed of the amino acid sequence shown by any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 35; or a VH comprising or composed of an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown by any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, and 35, preferably the amino acid changes do not occur in the CDR region; and / or

[0228] A VL having at least 80% identity with the amino acid sequence shown in any of SEQ ID NOs: 57, 58 and 36; a VL comprising the amino acid sequence shown in any of SEQ ID NOs: 57, 58 and 36 or composed of said amino acid sequence; or a VL comprising an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 57, 58 and 36, preferably said amino acid changes not occurring in the CDR region.

[0229] In some specific embodiments, amino acids that differ from the amino acid sequences shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37, and 39 are predominantly (or all) present in the FR region (backbone region). In some specific embodiments, amino acids that differ from the amino acid sequences shown in any of SEQ ID NOs: 57, 58, 36, 38, and 40 are predominantly (or all) present in the FR region (backbone region).

[0230] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0231] (1) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 47, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0232] (2) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 48, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0233] (3) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 49, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57;

[0234] (4) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 50, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0235] (5) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 51, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0236] (6) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 52, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0237] (7) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 53, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0238] (8) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 54, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0239] (9) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 55, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0240] (10) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 56, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0241] (11) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 35, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 36; or

[0242] (12) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 37, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 38; or

[0243] (13) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 39, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 40.

[0244] In this region, all amino acids that differ from the amino acid sequences shown with at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with respect to any of the amino acid sequences shown with SEQ ID NOs: 35, 36, 37, 38, 39, 40, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 and 58 are present in the FR region.

[0245] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0246] (1) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 47, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0247] (2) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 48, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0248] (3) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 49, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57;

[0249] (4) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 50, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0250] (5) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 51, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 57; or

[0251] (6) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 52, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0252] (7) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 53, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0253] (8) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 54, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0254] (9) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 55, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0255] (10) A VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 56, and a VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 58; or

[0256] (11) VH having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 35, and VL having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 36;

[0257] All amino acids differing from the amino acid sequences shown in any of SEQ ID NOs: 35, 36, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 and 58, having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity, are present in the FR region.

[0258] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises: VH as shown in any one of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37 and 39, and VL as shown in any one of SEQ ID NOs: 57, 58, 36, 38 and 40.

[0259] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises: VH as shown in any one of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56 and 35, and VL as shown in any one of SEQ ID NOs: 57, 58 and 36.

[0260] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0261] (1) VH shown in SEQ ID NO: 47 and VL shown in SEQ ID NO: 57; or

[0262] (2) VH shown in SEQ ID NO: 48 and VL shown in SEQ ID NO: 57; or

[0263] (3) VH shown in SEQ ID NO: 49 and VL shown in SEQ ID NO: 57; or

[0264] (4) VH shown in SEQ ID NO: 50 and VL shown in SEQ ID NO: 57; or

[0265] (5) VH shown in SEQ ID NO: 51 and VL shown in SEQ ID NO: 57; or

[0266] (6) VH shown in SEQ ID NO: 52 and VL shown in SEQ ID NO: 58; or

[0267] (7) VH shown in SEQ ID NO: 53 and VL shown in SEQ ID NO: 58; or

[0268] (8) VH shown in SEQ ID NO: 54 and VL shown in SEQ ID NO: 58; or

[0269] (9) VH shown in SEQ ID NO: 55 and VL shown in SEQ ID NO: 58; or

[0270] (10) VH shown in SEQ ID NO: 56 and VL shown in SEQ ID NO: 58; or

[0271] (11) VH shown in SEQ ID NO: 35 and VL shown in SEQ ID NO: 36; or

[0272] (12) VH shown in SEQ ID NO: 37 and VL shown in SEQ ID NO: 38; or

[0273] (13) VH shown in SEQ ID NO: 39 and VL shown in SEQ ID NO: 40.

[0274] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0275] (1) VH shown in SEQ ID NO: 47 and VL shown in SEQ ID NO: 57; or

[0276] (2) VH shown in SEQ ID NO: 48 and VL shown in SEQ ID NO: 57; or

[0277] (3) VH shown in SEQ ID NO: 49 and VL shown in SEQ ID NO: 57; or

[0278] (4) VH shown in SEQ ID NO: 50 and VL shown in SEQ ID NO: 57; or

[0279] (5) VH shown in SEQ ID NO: 51 and VL shown in SEQ ID NO: 57; or

[0280] (6) VH shown in SEQ ID NO: 52 and VL shown in SEQ ID NO: 58; or

[0281] (7) VH shown in SEQ ID NO: 53 and VL shown in SEQ ID NO: 58; or

[0282] (8) VH shown in SEQ ID NO: 54 and VL shown in SEQ ID NO: 58; or

[0283] (9) VH shown in SEQ ID NO: 55 and VL shown in SEQ ID NO: 58; or

[0284] (10) VH shown in SEQ ID NO: 56 and VL shown in SEQ ID NO: 58; or

[0285] (11) VH shown in SEQ ID NO: 35 and VL shown in SEQ ID NO: 36.

[0286] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0287] (1) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 47, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0288] (2) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 48, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0289] (3) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 49, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0290] (4) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 50, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0291] (5) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 51, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0292] (6) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 52, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0293] (7) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 53, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0294] (8) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 54, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0295] (9) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 55, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0296] (10) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 56, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0297] (11) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 35, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 36; or

[0298] (12) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 37, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 38; or

[0299] (13) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 39, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 40.

[0300] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0301] (1) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 47, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0302] (2) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 48, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0303] (3) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 49, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0304] (4) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 50, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0305] (5) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 51, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 57; or

[0306] (6) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 52, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0307] (7) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 53, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0308] (8) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 54, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0309] (9) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 55, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0310] (10) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 56, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 58; or

[0311] (11) A VH having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 35, and a VL having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, 1) amino acid changes compared to the amino acid sequence shown in SEQ ID NO: 36.

[0312] In particular, all amino acids in the amino acid sequence that differ from the amino acid sequence shown by any one of SEQ ID NOs: 35, 36, 37, 38, 39, 40, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57 and 58 are present in the FR region.

[0313] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application further includes a heavy chain constant region and a light chain constant region.

[0314] In a further preferred embodiment, the heavy chain constant region is selected from the constant regions of human IgG1, IgG2, IgG3, and IgG4, or variants thereof, and the light chain constant region is selected from the constant regions of human κ and λ chains, or functional variants thereof. Exemplary variants include IgG1, IgG2, or IgG4 heavy chain constant region variants with site-specific modifications and amino acid substitutions, such as the LALA mutation (L234A / L235A), AAA mutation, DLE mutation (Shields et al., 2002; Lazar et al., 2006), YTE mutation (M252Y / S254T / T256E), and LS mutation (M428L / N434S) known in the art (Ghetie et al., 1997; Zalevsky et al., 2010), YTE+KF mutation (M252Y / S254T / T256E / H433K / N434F), YTE+FF mutation (M252Y / S254T / T256E / H433F / N434F), M252Y / V308P / N434Y mutation, H285D / T307Q / A378V mutation; and heavy chain constant region variants modified by glycosylation or deglycosylation, such as defucosylation.

[0315] In some embodiments, the heavy chain constant region (CH) is an IgG1 or IgG4 heavy chain constant region, preferably a human IgG1 heavy chain constant region, or a defucosylated IgG1 variant. In some embodiments, the heavy chain constant region includes the amino acid sequence shown in SEQ ID NO:87, or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with it, or an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to it.

[0316] In some embodiments, the light chain constant region is the human κ chain constant region. In some embodiments, the light chain constant region comprises the amino acid sequence shown in SEQ ID NO: 86, or an amino acid sequence having at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity with it, or an amino acid sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to it.

[0317] In some embodiments, the anti-BAFFR antibody comprises a heavy chain and a light chain, wherein,

[0318] The heavy chain comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 96%, 97%, 98, 99, 100, 101, 102, 103, 88, 90, and 92 sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 94, 95, 96, 97%, 98%, 99%, or more; and the light chain comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or more sequence identity with the amino acid sequence shown in any one of SEQ ID NOs: 104, 105, 89, 91, and 93.

[0319] In a preferred embodiment, the anti-BAFFR antibody comprises a heavy chain and a light chain, wherein,

[0320] The heavy chain comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98, 99, 100, 101, 102, 103, and 88 sequence identity with the amino acid sequence shown in any of SEQ ID NOs: 94, 95, 96, 97, 98, 99, 99, 99% or more; and the light chain comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in any of SEQ ID NOs: 104, 105, and 89.

[0321] In some embodiments, all amino acids that differ from the amino acid sequences shown with any of SEQ ID NOs: 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, and 105 are present in the FR region or constant region.

[0322] In some embodiments, the anti-BAFFR antibody comprises a heavy chain and a light chain, wherein,

[0323] The heavy chain comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in any of SEQ ID NOs: 129, 130, 131, 132, 133, 134, 135, 136, 137 and 138; and the light chain comprises a sequence having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104.

[0324] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0325] (1) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 94, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0326] (2) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 95, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0327] (3) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 96, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0328] (4) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 97, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0329] (5) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 98, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0330] (6) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 99, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0331] (7) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 100, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0332] (8) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 101, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0333] (9) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 102, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0334] (10) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 103, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0335] (11) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 88, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 89; or

[0336] (12) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 90, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 91; or

[0337] (13) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 92, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 93.

[0338] In some preferred embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application comprises:

[0339] (1) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 94, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0340] (2) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 95, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0341] (3) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 96, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0342] (4) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 97, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0343] (5) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 98, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 104; or

[0344] (6) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 99, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0345] (7) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 100, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0346] (8) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 101, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0347] (9) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 102, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0348] (10) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 103, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 105; or

[0349] (11) A heavy chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 88, and a light chain having at least 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99% or more sequence identity with the amino acid sequence shown in SEQ ID NO: 89.

[0350] In some embodiments, the anti-BAFFR antibody comprises a heavy chain and a light chain, wherein,

[0351] The heavy chain comprises an amino acid sequence shown in any one of SEQ ID NOs: 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 88, 90, and 92; and the light chain comprises an amino acid sequence shown in any one of SEQ ID NOs: 104, 105, 89, 91, and 93.

[0352] In a preferred embodiment, the anti-BAFFR antibody comprises a heavy chain and a light chain, wherein,

[0353] The heavy chain comprises an amino acid sequence shown in any one of SEQ ID NOs: 94, 95, 96, 97, 98, 99, 100, 101, 102, 103 and 88; and the light chain comprises an amino acid sequence shown in any one of SEQ ID NOs: 104, 105 and 89.

[0354] In some embodiments, the anti-BAFFR antibody comprises:

[0355] (1) The heavy chain shown in SEQ ID NO: 94; and the light chain shown in SEQ ID NO: 104; or

[0356] (2) The heavy chain shown in SEQ ID NO: 95; and the light chain shown in SEQ ID NO: 104; or

[0357] (3) The heavy chain shown in SEQ ID NO: 96; and the light chain shown in SEQ ID NO: 104; or

[0358] (4) The heavy chain shown in SEQ ID NO: 97; and the light chain shown in SEQ ID NO: 104; or

[0359] (5) The heavy chain shown in SEQ ID NO: 98; and the light chain shown in SEQ ID NO: 104; or

[0360] (6) The heavy chain shown in SEQ ID NO: 99; and the light chain shown in SEQ ID NO: 105; or

[0361] (7) The heavy chain shown in SEQ ID NO: 100; and the light chain shown in SEQ ID NO: 105; or

[0362] (8) The heavy chain shown in SEQ ID NO: 101; and the light chain shown in SEQ ID NO: 105; or

[0363] (9) The heavy chain shown in SEQ ID NO: 102; and the light chain shown in SEQ ID NO: 105; or

[0364] (10) The heavy chain shown in SEQ ID NO: 103; and the light chain shown in SEQ ID NO: 105; or

[0365] (11) The heavy chain shown in SEQ ID NO: 88; and the light chain shown in SEQ ID NO: 89; or

[0366] (12) The heavy chain shown in SEQ ID NO: 90; and the light chain shown in SEQ ID NO: 91; or

[0367] (13) The heavy chain shown in SEQ ID NO: 92; and the light chain shown in SEQ ID NO: 93.

[0368] In a preferred embodiment, the anti-BAFFR antibody comprises:

[0369] (1) The heavy chain shown in SEQ ID NO: 94; and the light chain shown in SEQ ID NO: 104; or

[0370] (2) The heavy chain shown in SEQ ID NO: 95; and the light chain shown in SEQ ID NO: 104; or

[0371] (3) The heavy chain shown in SEQ ID NO: 96; and the light chain shown in SEQ ID NO: 104; or

[0372] (4) The heavy chain shown in SEQ ID NO: 97; and the light chain shown in SEQ ID NO: 104; or

[0373] (5) The heavy chain shown in SEQ ID NO: 98; and the light chain shown in SEQ ID NO: 104; or

[0374] (6) The heavy chain shown in SEQ ID NO: 99; and the light chain shown in SEQ ID NO: 105; or

[0375] (7) The heavy chain shown in SEQ ID NO: 100; and the light chain shown in SEQ ID NO: 105; or

[0376] (8) The heavy chain shown in SEQ ID NO: 101; and the light chain shown in SEQ ID NO: 105; or

[0377] (9) The heavy chain shown in SEQ ID NO: 102; and the light chain shown in SEQ ID NO: 105; or

[0378] (10) The heavy chain shown in SEQ ID NO: 103; and the light chain shown in SEQ ID NO: 105; or

[0379] (11) The heavy chain shown in SEQ ID NO: 88; and the light chain shown in SEQ ID NO: 89.

[0380] In a preferred embodiment, the anti-BAFFR antibody comprises:

[0381] (1) The heavy chain shown in SEQ ID NO: 129; and the light chain shown in SEQ ID NO: 104; or

[0382] (2) The heavy chain shown in SEQ ID NO: 130; and the light chain shown in SEQ ID NO: 104; or

[0383] (3) The heavy chain shown in SEQ ID NO: 131; and the light chain shown in SEQ ID NO: 104; or

[0384] (4) The heavy chain shown in SEQ ID NO: 132; and the light chain shown in SEQ ID NO: 104; or

[0385] (5) The heavy chain shown in SEQ ID NO: 133; and the light chain shown in SEQ ID NO: 104; or

[0386] (6) The heavy chain shown in SEQ ID NO: 134; and the light chain shown in SEQ ID NO: 104; or

[0387] (7) The heavy chain shown in SEQ ID NO: 135; and the light chain shown in SEQ ID NO: 104; or

[0388] (8) The heavy chain shown in SEQ ID NO: 136; and the light chain shown in SEQ ID NO: 104; or

[0389] (9) The heavy chain shown in SEQ ID NO: 137; and the light chain shown in SEQ ID NO: 104; or

[0390] (10) The heavy chain shown in SEQ ID NO: 138; and the light chain shown in SEQ ID NO: 104.

[0391] In some embodiments, the anti-BAFFR antibody comprises a heavy chain and a light chain, wherein,

[0392] The heavy chain includes a sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 88, 90, and 92); and the light chain includes a sequence having one or more (preferably no more than 10, more preferably no more than 5, 4, 3, 2, or 1) amino acid changes (preferably amino acid substitutions, more preferably conservative substitutions) compared to the amino acid sequence shown in any of SEQ ID NOs: 104, 105, 89, 91, and 93. In some embodiments, all amino acids differing from the amino acid sequences shown as any of SEQ ID NOs: 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, and 105 are present in the FR region or constant region.

[0393] In one embodiment of this application, the amino acid alteration described herein includes the substitution, addition, or deletion of amino acids. Preferably, the amino acid alteration described herein is an amino acid substitution, and more preferably a conservative substitution.

[0394] In some implementations, the substitution may occur in the CDR region of the antibody. Typically, the resulting variant has modifications (e.g., improvements) relative to the parent antibody in certain biological properties (e.g., increased affinity) and / or will have some biological properties that are substantially retained by the parent antibody.

[0395] In some preferred embodiments, the amino acid changes described herein occur in regions outside the CDR (e.g., FR). More preferably, the amino acid changes described herein occur in regions outside the heavy chain variable region and / or outside the light chain variable region.

[0396] In some embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibody provided herein to create Fc region variants to alter one or more functional properties of the antibody, such as serum half-life, complement binding, complement-dependent cytotoxicity, Fc receptor binding, and / or antibody-dependent cytotoxicity.

[0397] In some embodiments, the antibodies provided herein are modified to increase or decrease the degree of antibody glycosylation. The addition or deletion of glycosylation sites on the antibody can be conveniently achieved by altering the amino acid sequence to create or remove one or more glycosylation sites.

[0398] For example, one or more amino acid substitutions can be performed to eliminate one or more variable region glycosylation sites, thereby eliminating glycosylation at that site. Such glycosylation can increase the antibody's affinity for the antigen. See, for example, U.S. Patents 5,714,350 and 6,350,861. Antibodies with altered types of glycosylation can be prepared, such as hypofucosylated antibodies with reduced amounts of fucosylated residues or antibodies with increased isomeric GlcNac structures. Such altered glycosylation patterns have been shown to increase the antibody's ADCC ability. This type of glycosylation modification can be achieved, for example, by expressing the antibody in host cells with an altered glycosylation system. Alternatively, fucosidases can be used to cleave the fucosylated residues of the antibody; for example, fucosidase α-L-fucosidase removes fucosylated residues from the antibody (Tarentino et al. (1975) Biochem. 14:5516-23).

[0399] In some embodiments, one or more amino acid modifications may be introduced into the Fc region of the antibody provided herein to create Fc region variants, thereby enhancing the efficacy of the antibody for treating, for example, cancer or proliferative diseases. Modifications to the Fc region include amino acid changes (substitution, deletion, and insertion), glycosylation or deglycosylation, and the addition of multiple Fc regions. Modifications to the Fc region can also alter the half-life of the antibody in a therapeutic antibody, thereby enabling less frequent dosing and thus increased convenience and reduced material usage. See Presta (2005) J. Allergy Clin. Immunol. 116:731, 734-735.

[0400] In one embodiment, the number of cysteine ​​residues in the antibody can be altered to modify antibody properties. For example, the hinge region of CH1 can be modified to change (e.g., increase or decrease) the number of cysteine ​​residues in the hinge region. This method is further described in U.S. Patent No. 5,677,425. The number of cysteine ​​residues in the hinge region of CH1 can be changed to, for example, promote the assembly of light and heavy chains or increase or decrease the stability of the antibody.

[0401] Optionally, the antibodies of this application include post-translational modifications to the antibody chain. Exemplary post-translational modifications include disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other operation, such as conjugation with labeled components.

[0402] In one embodiment of the present invention, the antibody or fragment of the present invention is glycosylated with engineered yeast N-linked glycans or CHON-linked glycans.

[0403] In some embodiments, the antibodies provided herein may be further modified to contain other non-protein moieties known in the art and readily available. Suitable moieties for antibody derivatization include, but are not limited to, water-soluble polymers. Non-limiting examples of water-soluble polymers include, but are not limited to, polyethylene glycol (PEG), ethylene glycol / propylene glycol copolymers, carboxymethyl cellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, poly-1,3-diane, poly-1,3,6-triane, ethylene / maleic anhydride copolymers, polyamino acids (homogeneous or random copolymers), and dextran or poly(n-vinylpyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide / ethylene oxide copolymers, polyoxyethylated polyols (e.g., glycerol), polyvinyl alcohol, and mixtures thereof.

[0404] Another modification of the antibody or fragment thereof described herein that is covered by this application is pegylation. Antibodies can be pegylated to, for example, increase the biological (e.g., serum) half-life of the antibody. As used herein, the term "polyethylene glycol" is intended to cover any form of PEG that has been used to derivatize other proteins, such as mono(C1-C10)alkoxy- or aryloxy polyethylene glycol or polyethylene glycol-maleimide. In some embodiments, the antibody to be pegylated is a glycosylated antibody. Methods for pegylating proteins are known in the art and can be applied to the antibodies of this invention, see, for example, EP0154316 and EP0401384.

[0405] In this paper, the various variants of the anti-BAFFR antibodies or their antigen-binding fragments described above retain the ability to specifically bind to the BAFFR antigen.

[0406] In some embodiments, the anti-BAFFR antibody described in this application may be a murine antibody, a chimeric antibody, a humanized antibody, or a fully human antibody.

[0407] In some embodiments, the antibody molecules of this application are chimeric antibodies.

[0408] In some embodiments, at least a portion of the frame sequence of the antibody molecule of this application is a human common frame sequence.

[0409] In some embodiments, the antibodies of this application are humanized. Different methods for humanizing antibodies are known to those skilled in the art, as reviewed by Almagro & Fransson, the contents of which are incorporated herein by reference in their entirety (Almagro JC and Fransson J (2008) Frontiers in Bioscience 13:1619-1633).

[0410] In a preferred embodiment, the antibody of this application is a human antibody or a humanized antibody. Various techniques known in the art can be used to prepare human antibodies or humanized antibodies.

[0411] In some embodiments, the anti-BAFFR antibody described in this application may be a monoclonal antibody, a polyclonal antibody, a monospecific antibody, or a multispecific antibody (such as a bispecific antibody), preferably a monoclonal antibody.

[0412] In some embodiments, the antigen-binding fragment of the anti-BAFFR antibody described in this application is selected from Fab fragments, Fab' fragments, F(ab')2 fragments, Fd fragments, Fv fragments, dAb fragments, isolated CDR regions, scFv, and nanobodies.

[0413] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application is of type IgG1, IgG2, IgG3 or IgG4.

[0414] In most cases, the C-terminal lysine (K) of the antibody heavy chain is lost to varying degrees. This is usually caused by carboxypeptidase produced during cell culture, resulting in each heavy chain of the generated antibody having 0 or 1 lysine at the C-terminus, thus making the antibody exhibit C-terminal heterogeneity. However, this does not affect the activity of the antibody itself. The antibodies described in this disclosure cover various antibodies with C-terminal heterogeneity.

[0415] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment described in this application may exhibit one or more combinations of the following properties:

[0416] (1) The EC50 value of the anti-BAFFR antibody or its antigen-binding fragment binding to human BAFFR is less than 1 μg / mL, less than 0.5 μg / mL, less than 0.2 μg / mL, less than 0.1 μg / mL, less than 0.07 μg / mL, less than 0.05 μg / mL, and less than 0.03 μg / mL;

[0417] (2) The EC50 value of the anti-BAFFR antibody or its antigen-binding fragment binding to cells containing human BAFFR is less than 1 μg / mL, less than 0.5 μg / mL, less than 0.2 μg / mL, less than 0.1 μg / mL, less than 0.07 μg / mL, less than 0.05 μg / mL, less than 0.02 μg / mL, and less than 0.015 μg / mL;

[0418] (3) The anti-BAFFR antibody or its antigen-binding fragment has an IC50 value of less than 1 μg / mL, less than 0.5 μg / mL, less than 0.2 μg / mL, less than 0.1 μg / mL, less than 0.05 μg / mL, less than 0.03 μg / mL, less than 0.02 μg / mL, less than 0.01 μg / mL, and the blocking rate can reach at least 50%, for example at least 60%, 70%, 80%, 90% or higher.

[0419] (4) The affinity constant of the anti-BAFFR antibody or its antigen-binding fragment to human BAFFR is less than 10 nM, less than 8 nM, less than 5 nM, less than 3 nM, or less than 1 nM.

[0420] The amino acid and nucleotide sequences of the antibodies or antigen-binding fragments described in this application are shown in Tables 2-1 and 2-2.

[0421]

[0422] Nucleotide molecules, carriers, and host cells

[0423] This application relates to a nucleic acid molecule encoding the aforementioned anti-BAFFR antibody or its antigen-binding fragment, a vector (e.g., an expression vector) containing the aforementioned nucleic acid molecule, and a host cell incorporating the aforementioned nucleic acid molecule or its vector.

[0424] In some embodiments, the expression vector may be any expression vector capable of expressing the antibody or its antigen-binding moiety described herein, including but not limited to naked plasmids, phage particles, yeast plasmids, adenoviruses, adeno-associated viruses, herpesviruses (such as herpes simplex virus), retroviruses (such as lentiviruses), poxviruses, papillomaviruses, papillomaviruses (such as SV40), rod-shaped viruses, or baculoviruses. For ease of production and purification, the expression vector may also contain secretory signal peptides, expression tags, etc.

[0425] It is known to those skilled in the art that, due to codon degeneracy, each antibody or polypeptide amino acid sequence can be encoded by multiple nucleic acid sequences. The nucleic acid sequence encoding the antibody or fragment thereof of this application can be synthesized using methods known in the art (e.g., de novo solid-phase DNA synthesis, PCR amplification). Given that specific amino acid sequences have been described in this application, those skilled in the art can easily modify the respective coding sequences of each antibody or antigen-binding fragment of this application by one or more codons to prepare many different nucleic acids without altering the amino acid sequences.

[0426] In some embodiments, the nucleic acid molecule encoding an anti-BAFFR antibody or its antigen-binding fragment comprises a nucleic acid sequence encoding a heavy chain variable region (VH) and / or a light chain variable region (VL) of an anti-BAFFR antibody or its antigen-binding fragment, or a nucleic acid sequence having at least 80% sequence identity with it.

[0427] In some embodiments, the nucleic acid sequence encoding the heavy chain variable region (VH) comprises a nucleic acid sequence shown as any one of SEQ ID NO: 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 41, 43 and 45, or a nucleic acid sequence having at least 80% sequence identity with it.

[0428] In some embodiments, the nucleic acid sequence encoding the light chain variable region (VL) comprises a nucleic acid sequence shown in any of SEQ ID NO: 69, 70, 42, 44 and 46, or a nucleic acid sequence having at least 80% sequence identity with it.

[0429] In some embodiments, the nucleic acid molecule encoding an anti-BAFFR antibody or an antigen-binding fragment thereof comprises a nucleic acid sequence encoding a heavy chain and / or a light chain of an anti-BAFFR antibody or an antigen-binding fragment thereof.

[0430] In some embodiments, the nucleic acid sequence encoding the heavy chain comprises a nucleic acid sequence shown as any one of SEQ ID NO: 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 108, 110 and 112, or a nucleic acid sequence having at least 80% sequence identity with it.

[0431] In some embodiments, the nucleic acid sequence encoding the light chain comprises a nucleic acid sequence shown in any of SEQ ID NO: 124, 125, 109, 111 and 113, or a nucleic acid sequence having at least 80% sequence identity with it.

[0432] Those skilled in the art can use conventional methods known in the art to construct nucleic acids encoding the antibodies or their antigen-binding fragments, or bispecific antibodies of this application, into suitable vectors for introduction into host cells for expression of the target protein. Vector components may include, but are not limited to, signal sequences, origin of replication, one or more marker genes, enhancer elements, promoters, and transcription termination sequences. In the vector, the nucleic acid encoding the target protein is operatively linked to the promoter.

[0433] In some embodiments, the host cell is a prokaryotic cell. In other embodiments, the host cell is a eukaryotic cell. In some embodiments, the host cell is selected from yeast cells, mammalian cells, or any other cells suitable for preparing antigen-binding constructs. In some examples, the mammalian cell is, for example, Chinese hamster (CHO) ovarian cells, CHO-S cells, 293 cells, or monkey kidney cells.

[0434] The above-described expression vector can be introduced into suitable host cells using any conventional means known in the art, such as protoplast fusion, calcium phosphate precipitation, electroporation, viral transfection, gene gun, liposome transfection, or other conventional techniques, but not limited thereto.

[0435] Under conditions suitable for the expression of the target protein, the host cells described above are cultured under conventional conditions, and then the antibodies described herein are recovered from the host cells or the culture medium of the host cells by conventional protein separation and purification methods (such as high performance liquid chromatography, ion exchange chromatography, gel electrophoresis, affinity chromatography (such as Protein A column affinity chromatography), size exclusion chromatography, etc.).

[0436] Antibody conjugates

[0437] This application relates to antibody conjugates comprising the aforementioned anti-BAFFR antibody or its antigen-binding fragment.

[0438] In some embodiments, this application provides antibody-drug conjugates (ADCs) and antibody-oligonucleotide conjugates (AOCs) comprising the aforementioned anti-BAFFR antibody or its antigen-binding fragment conjugated to a therapeutic agent. Therapeutic agents that can be conjugated to the aforementioned anti-BAFFR antibody or its antigen-binding fragment may include, but are not limited to, cytotoxic drugs, radioisotopes, immunomodulators, oligonucleotides, or antibodies. In some embodiments, the oligonucleotides include: antisense oligonucleotides (ASOs), small interfering RNA (siRNA), aptamers, microRNAs (miRNAs), small activating RNAs (saRNAs), and CpG oligonucleotides (CpG oligonuceotides), etc.

[0439] In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment is directly conjugated to the therapeutic agent. In some embodiments, the anti-BAFFR antibody or its antigen-binding fragment is conjugated to the therapeutic agent via a linker. In the ADC, the linker for antibody-therapeutic agent conjugation can be a cleavable linker, such as a peptide linker, disulfide bond, or hydrazone linker, or a non-cleavable linker.

[0440] Chimeric antigen receptor (CAR)

[0441] This application also provides a chimeric antigen receptor comprising the anti-BAFFR antibody of this application or its antigen-binding fragment.

[0442] The chimeric antigen receptor described above may include: (a) an extracellular antigen-binding domain containing an anti-BAFFR antibody or its antigen-binding fragment; (b) a transmembrane domain; and (c) an intracellular signal transduction domain.

[0443] CARs can be further enhanced with elements that increase T cell proliferation, persistence, and antitumor activity, such as cytokines and co-stimulatory ligands. This application also provides engineered immune effector cells containing the CAR provided herein.

[0444] Pharmaceutical Composition

[0445] This application relates to pharmaceutical compositions comprising: the above-described anti-BAFFR antibody or its antigen-binding fragment, the above-described antibody-drug conjugate, a chimeric antigen receptor, and optionally pharmaceutically acceptable excipients.

[0446] In some embodiments, the pharmaceutical composition further comprises additional therapeutic agents.

[0447] The excipients described herein can be any pharmaceutically acceptable excipient, such as, but not limited to, solvents, carriers, sustained-release agents, excipients, propellants, solubilizers, cosolvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH adjusters, surfactants, diluents, etc. For other pharmaceutically acceptable pharmaceutical excipients, please refer to, for example, *Handbook of Pharmaceutical Excipients* (4th Edition), by RC Luo et al., translated by Zheng Junmin, Chemical Industry Press, 2005.

[0448] In some embodiments, the pharmaceutical composition may be in the form of a sterile aqueous solution, microemulsion, liposome, or powder. In some embodiments, the pharmaceutical composition may be in the form of a unit dose to facilitate administration to the patient at the desired dosage. In some embodiments, the dosage range of the pharmaceutical composition may be from about 0.0001 to 100 mg / kg body weight, for example, 0.1-50 mg / kg body weight.

[0449] The dosage range of the pharmaceutical compositions described herein can be determined by clinicians based on experience, taking into account factors such as the method of administration (including administration time, administration interval, and route of administration), the patient's age, weight, gender or pathological condition, diet, excretion rate, and sensitivity to the drug.

[0450] Combination products or pillboxes

[0451] This application also provides a combination product comprising the antibody or its antigen-binding fragment described in this invention, or its antibody-drug conjugate, and one or more other therapeutic agents (e.g., anti-angiogenic agents, chemotherapeutic agents, other antibodies, cytotoxic agents, vaccines, anti-infective agents, small molecule drugs, or immunomodulators, etc.).

[0452] This application relates to a kit comprising the aforementioned anti-BAFFR antibody or its antigen-binding fragment, the aforementioned antibody-drug conjugate, chimeric antigen receptor, or pharmaceutical composition.

[0453] In some embodiments, the pillbox may further include instructions for use. In some embodiments, the pillbox may further include reagents for diagnosing the patient. In some embodiments, the pillbox may further include a device for administering medication to the patient, such as a syringe.

[0454] In some embodiments, the kit may further include pharmaceutical excipients, such as sterile water or saline, for assisting in administering the aforementioned anti-BAFFR antibody or its antigen-binding fragment, the aforementioned antibody conjugate, chimeric antigen receptor, or pharmaceutical composition to the patient.

[0455] Uses and treatments

[0456] This application relates to the use of the above-mentioned anti-BAFFR antibody or its antigen-binding fragment, the above-mentioned antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, or cassette in the preparation of BAFFR inhibitors.

[0457] This application relates to the use of the aforementioned anti-BAFFR antibody or its antigen-binding fragment, the aforementioned antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, or cassette in the preparation of a medicament for the treatment or prevention of cancer or autoimmune diseases. Alternatively, this application relates to a method of treating cancer or autoimmune diseases, comprising administering the aforementioned anti-BAFFR antibody or its antigen-binding fragment, the aforementioned antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, or cassette to a subject in need. Alternatively, this application relates to the aforementioned anti-BAFFR antibody or its antigen-binding fragment, the aforementioned antibody-drug conjugate, chimeric antigen receptor, pharmaceutical composition, or cassette for the treatment or prevention of cancer or autoimmune diseases.

[0458] In some embodiments, the cancerous diseases include B-cell abnormal proliferation diseases, including but not limited to Hodgkin lymphoma and non-Hodgkin lymphoma, such as diffuse large B-cell lymphoma (DLBCL), marginal zone B-cell lymphoma (MZL), mucosa-associated lymphoid tissue lymphoma (MALT), small lymphocytic lymphoma (SLL), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), Burkitt lymphoma, lymphoplasmacytic lymphoma, nodular marginal zone B-cell lymphoma (NMZL), splenic marginal zone lymphoma (SMZL), intravascular lymphoma, lymphomatoid granuloma, primary central nervous system lymphoma, ALK+ large B-cell lymphoma, plasmablastic lymphoma, etc.

[0459] In some embodiments, the autoimmune diseases include autoimmune diseases mediated by abnormal B cell proliferation or abnormal antibody secretion, including but not limited to systemic lupus erythematosus (SLE), cutaneous lupus, discoid lupus, lupus nephritis, multiple sclerosis, dermatomyositis (DM), polymyositis (PM), psoriasis, rheumatoid arthritis, myasthenia gravis, Sjögren's syndrome, systemic sclerosis, inflammatory bowel disease, and type 1 diabetes mellitus.

[0460] The anti-BAFFR antibody or its antigen-binding fragment, the antibody-drug conjugate, the chimeric antigen receptor, the pharmaceutical composition, or the kit described in this application may be used to block the binding of BAFF to BAFFR, clear excessively proliferating B lymphocytes, inhibit the proliferation of B lymphocytes, and inhibit the growth of B-cell tumors.

[0461] The anti-BAFFR antibody or its antigen-binding fragment described above, the antibody-drug conjugate, the chimeric antigen receptor, the pharmaceutical composition, or the kit described above can also be used to diagnose the presence of the relevant antigen (BAFFR) in a sample.

[0462] The anti-BAFFR antibody or its antigen-binding fragment, the antibody-drug conjugate, chimeric antigen receptor or pharmaceutical composition described above in this application can be prepared into any dosage form known in the art, such as injection, suspension, solution, powder, emulsion, spray, tablet, pill, capsule, granule, ointment, suppository, gel, etc.

[0463] The anti-BAFFR antibody or its antigen-binding fragment, the antibody-drug conjugate, the chimeric antigen receptor, or the pharmaceutical composition described herein are suitable for intravenous, intramuscular, intra-articular, intra-articular, subcapsular, subarachnoid, intraorbital, intracardiac, subcutaneous, extracorporeal, intraperitoneal, intraspinal, intranasal, or epidermal administration (e.g., by injection or infusion). The anti-BAFFR antibody or its antigen-binding fragment, the antibody-drug conjugate, the chimeric antigen receptor, or the pharmaceutical composition described herein may be formulated into sterile aqueous solutions, microemulsions, liposomes, or powders.

[0464] Unless otherwise stated, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art.

[0465] definition

[0466] The term "antibody" in this document refers to a protein or polypeptide that can specifically recognize and bind to an antigen, encompassing natural and artificial antibodies of various structures, including but not limited to monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies, single-domain antibodies, full-length antibodies, and antibody fragments that exhibit the desired biological activity, and can be classified into five isotypes based on heavy chain class, namely IgG, IgM, IgD, IgA, and IgE.

[0467] The term "antigen-binding fragment" in antibody refers to a portion or segment of a full-length antibody or antibody with fewer amino acid residues than the full-length antibody, but capable of binding antigens or competing with full-length antibodies (i.e., full-length antibodies from which the antigen-binding fragment originates) for antigen binding. Antigen-binding fragments can be prepared using recombinant DNA technology or by enzymatic or chemical cleavage of complete antibodies. Antigen-binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fd, Fv, single-chain Fv, diabody antibodies, single-domain antibodies (sdAb), and nanobodies. For example, Fab fragments can be obtained by digesting full-length antibodies with papain. Furthermore, digestion of complete antibodies with pepsin below the disulfide bonds in the hinge region produces F(ab')2, a dimer of Fab' and a divalent antibody fragment. F(ab')2 can be reduced under neutral conditions by breaking the disulfide bonds in the hinge region, thereby converting the F(ab')2 dimer into Fab' monomers. Fab' monomers are essentially Fab fragments with hinge regions. The Fv fragment consists of VL (light chain variable region) and VH (heavy chain variable region) domains on one arm of the antibody. The two domains, VL and VH, can be encoded by independent genes, but they can also be generated as a single protein chain using a recombinant approach, connecting the two domains with a synthetic linker peptide. In this single protein chain, the VL and VH regions pair to form a single-chain Fv (scFv).

[0468] The term "scFv" in this article includes the VH and VL domains of an antibody that are present in a single polypeptide chain.

[0469] The term “CDR” (complementarity-determining region), also known as “hypervariant region (HVR)”, as used in this article, refers to each region of an antibody variable domain that is highly variable in sequence and / or forms a structurally defined loop. Natural antibodies typically contain three CDRs (i.e., HCDR1 to HCDR3) located in the heavy chain variable region and three CDRs (LCDR1 to LCDR3) located in the light chain variable region. Various numbering systems known in the art can be used to sequentially number the CDRs of heavy and light chains starting from the N-end. For example, Chothia, based on the three-dimensional structure of the antibody and the topology of the CDR loop; Kabat (Kabat et al., Sequences of Proteins of Immunological Interest, 4th edition, USDepartment of Health and Human Services, National Institutes of Health (1987)), AbM (University of Bath), Contact (University College London), the International ImMunoGeneTics (IMGT) database (the international ImMunoGeneTics information system, http: / / imgt.cines.fr), and the North CDR definition based on affinity propagation clustering using a large number of crystal structures (North et al., “A New Clustering of Antibody CDR Loop Conformations”, Journal of Molecular Biology, 406, 228-256 (2011)).

[0470] CDRs determined using different numbering systems

[0471]

[0472] When referring to antibodies, the terms "variable region," "V region," or "variable domain" are used interchangeably. They refer to the structural domains of the antibody heavy or light chain that participate in the specific binding of the antibody to the antigen. They typically include an amino acid sequence arranged from the N-terminus to the C-terminus in the order FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4.

[0473] The term "chimeric antibody" refers to an antibody containing sequences derived from two different antibodies (often from different species), for example, (a) altering, replacing, or exchanging a constant region or a portion thereof so that the antigen-binding site is linked to a constant region of different or altered class, effector function, and / or species origin, or to a completely different molecule (e.g., enzyme, toxin, hormone, growth factor, drug) that confers new properties to the chimeric antibody; or (b) altering, replacing, or exchanging a variable region or a portion thereof with a variable region of different or altered antigen specificity.

[0474] The term “humanized antibody” as used in this article refers to an antibody that retains the antigen-specific reactivity of a non-human antibody (such as an alpaca monoclonal antibody) while exhibiting low immunogenicity when administered to humans as a therapeutic agent; it typically includes CDRs derived from non-human animals, FR regions derived from humans, and constant regions derived from humans.

[0475] The term "epitope," also known as "antigenic determinant," as used in this article, refers to an antigenic moiety that can be recognized and specifically bound by antibodies. An antigen may have multiple epitopes, which are typically composed of surface groups of a molecule, such as amino acids or sugar side chains.

[0476] Antibody-dependent cell-mediated cytotoxicity (ADCC) is an immune mechanism mediated by natural killer (NK) cells, macrophages, and neutrophils expressing IgG Fc receptors. In this process, these cells specifically kill target cells by recognizing the Fc fragments of IgG antibodies bound to the surface of the target cells. NK cells, in particular, are activated primarily through the FcγRⅢA (CD16a) receptor, releasing toxic substances such as perforin and granzymes, triggering target cell lysis or apoptosis.

[0477] The terms “flexible linker peptide”, “linker peptide”, or “linker” used in this article refer to a short amino acid sequence composed of amino acids used for linking peptide segments, and may include glycine (G), alanine (A), threonine (T) residues, etc.

[0478] The term "operably linked" as used herein refers to the linking of amino acid sequences, peptides, or proteins with different functional properties, such as linking a VH domain to a VL domain, or linking scFv to Fc, or linking scFv to a Fab or IgG domain, using the adapters described herein. In the case of nucleic acids, the term "operably linked" refers to the functional linking of a nucleic acid to a second nucleic acid, encompassing the functional linking of two or more nucleic acid molecules. For example, those skilled in the art can use conventional methods known in the art to construct nucleic acids encoding the antibodies or their antigen-binding fragments, or bispecific antibodies of this application, in suitable vectors for introduction into host cells for expression of the target protein. Vector components may include, but are not limited to, signal sequences, origins of replication, one or more marker genes, enhancer elements, promoters, and transcription termination sequences. In said vector, the nucleic acid encoding the target protein is operably linked to the promoter.

[0479] As used herein, the terms “binding” or “specific binding” mean that the binding is selective to the target antigen and can be distinguished from unwanted or nonspecific interactions. For example, an antibody that specifically binds to a target antigen means that the antibody has higher affinity, stronger binding activity, easier binding, and / or longer binding duration when binding to the target antigen compared to binding to other non-target molecules.

[0480] "Affinity" or "binding affinity" is an intrinsic binding capacity used to reflect the interaction between members of a binding pair. For example, the affinity of molecule X for its partner Y can usually be expressed by the equilibrium dissociation constant (K0). D The equilibrium dissociation constant is the dissociation rate constant (K). dis or K off ) and association rate constant (K a or K on The ratio of affinity to kinetic binding affinity. Affinity can be measured using common methods known in the art. One specific method for measuring affinity is the ForteBio kinetic binding assay.

[0481] The terms "identity" or "sequence identity" refer to the sequence similarity between two aggregate molecules, such as between two nucleic acid molecules (e.g., between two DNA molecules) or between two amino acid sequences. The "percentage of identity" for a nucleic acid / amino acid sequence refers to the percentage of nucleic acid / amino acid residues in the candidate sequence that are identical to the reference sequence, relative to the total number of residues in the candidate sequence, after aligning the candidate sequence with a reference sequence and, if necessary, introducing vacancies to achieve the maximum percentage of sequence identity, and without considering any conserved substitutions as part of sequence identity. The percentage of sequence identity for a nucleic acid / amino acid sequence can be determined by aligning two or more sequences using tools known in the art, such as BLASTn, BLASTp, ClustalW2 (see Higgins DG et al., MethodsEnzymol 1996, 266:383-402; Larkin MA et al., Bioinformatics 2007, 23:2947-2948), ALIGN, or Megalign (DNASTAR) software. For example, the term “at least about 80% sequence identity” is intended to explicitly cover all sequence variants that have 80% or higher identity with a reference sequence, specifically including but not limited to: at least about 80%, at least about 81%, at least about 82%, at least about 83%, at least about 84%, at least about 85%, at least about 86%, at least about 87%, at least about 88%, at least about 89%, at least about 90%, at least about 91%, at least about 92%, at least about 93%, at least about 94%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, and at least about 99% sequence identity.

[0482] For polypeptide sequences, "conservative substitution" refers to the replacement, deletion, or addition of amino acids in the polypeptide sequence with other amino acids of the same class (e.g., amino acids with similar chemical properties or functions), without substantially altering the desired functional activity of the polypeptide sequence. For example, conservative substitution often results in the replacement of a particular amino acid with a chemically similar amino acid. Providing a list of conservative substitutions of functionally similar amino acids is well known in the art. Conservative substitutions of amino acids include, but are not limited to, substitutions between amino acids in the following groups: (i) small nonpolar amino acids: alanine (Ala), methionine (Met), isoleucine (Ile), leucine (Leu), and valine (Val); (ii) small polar amino acids: glycine (Gly), serine (Ser), threonine (Thr), and cysteine ​​(Cys); (iii) amide amino acids: glutamine (Gln) and asparagine (Asn); (iv) aromatic amino acids: phenylalanine (Phe), tyrosine (Tyr), and tryptophan (Trp); (v) basic amino acids: lysine (Lys), arginine (Arg), and histidine (His); and (vi) acidic amino acids: glutamic acid (Glu) and aspartic acid (Asp). Electroneutral substitutions and substitutions of residues with smaller residues can also be considered “conservative substitutions,” even if the residues belong to different groups (e.g., phenylalanine replaced by the smaller isoleucine). The term “conservative substitution” also includes the use of amino acid analogs, variants, or non-protein-forming amino acids or non-standard amino acids.

[0483] The term "combination product" refers to a fixed or non-fixed combination or a kit for combination administration in the form of a dose unit, wherein two or more therapeutic agents can be administered independently at the same time or separately at time intervals, especially where these time intervals allow the combination partners to exhibit synergy, e.g., a co-existing effect. The term "fixed combination" refers to the simultaneous administration of the antibody and combination partner (e.g., other therapeutic agents) of the present invention to a patient as a single entity or dose. The term "non-fixed combination" means that the antibody and combination partner (e.g., other therapeutic agents) of the present invention are administered to a patient as separate entities simultaneously, in parallel, or sequentially, without a specific time limit, wherein such administration provides a therapeutically effective level of both therapeutic agents in the patient. The latter also applies to cocktail therapies, such as the administration of three or more therapeutic agents. In a preferred embodiment, the drug combination is a non-fixed combination.

[0484] The terms “subject,” “patient,” and “individual” are used interchangeably herein and include mammals or non-mammalian vertebrates (such as chickens, emus, and fish), including but not limited to domesticated animals (e.g., cattle, sheep, cats, dogs, pigs, and horses), primates (e.g., humans, non-human primates such as monkeys), rabbits, and rodents (e.g., mice, rats, guinea pigs, and hamsters), preferably humans.

[0485] The term "treating" (or "treatment") as used herein refers to reducing or alleviating a disease or symptom, slowing the onset or progression of a disease or symptom, reducing the risk of developing a disease or symptom, delaying the development of symptoms associated with a disease or symptom, reducing or terminating symptoms associated with a disease or symptom, achieving complete or partial reversal of a disease or symptom, curing a disease or symptom, or a combination of the above. Desired therapeutic effects as described herein include, but are not limited to, preventing the onset or recurrence of disease, alleviating symptoms, reducing any direct or indirect pathological consequences of the disease, preventing metastasis, slowing the rate of disease progression, improving or mitigating the disease state, and alleviating or improving prognosis.

[0486] When used herein, “prevention” includes the suppression of the occurrence or development of a disease or condition or symptoms of a particular disease or condition. In some implementations, subjects with a family history of cancer are candidates for preventative protocols. Generally, in the context of cancer, the term “prevention” refers to the administration of a drug prior to the onset of signs or symptoms of cancer, particularly in subjects at risk of cancer.

[0487] As used herein, the term “optional” indicates whether the object it modifies is present or not; for example, “a pharmaceutical composition contains optional pharmaceutically acceptable excipients” means that the pharmaceutical composition may or may not contain pharmaceutically acceptable excipients.

[0488] The term "therapeutic effective amount" or "effective dose" refers to a dose or concentration at which the desired dose and duration of treatment are effectively achieved to prevent or improve symptoms associated with a disease or condition and / or reduce the severity of the disease or condition. The therapeutically effective amount of the formulations, antibodies, or antigen-binding fragments thereof, bispecific antibodies, or compositions of this application can vary depending on various factors such as disease state, individual age, sex, weight, and the ability of the antibody or antigen-binding portion to elicit the desired response in an individual. A therapeutically effective amount can also be considered as the therapeutic benefit of the formulation, antibody, or antigen-binding fragment thereof, bispecific antibody, or composition significantly outweighing any toxic or harmful effects it causes. The term "effective amount" refers to the amount of an active ingredient or agent sufficient to provide a clinical benefit to a subject (including, but not limited to, improvement, relief, or reduction of a disease, condition, or related symptoms, delaying or stopping disease progression). "Prophylactic effective amount" refers to the amount at which the desired preventative outcome is effectively achieved at the desired dose and duration of treatment. The terms “pharmaceutical acceptable” or “medicinally acceptable” in this article mean that the carrier, solvent, diluent, excipient and / or salt is generally chemically and / or physically compatible with the other ingredients in the formulation and physiologically compatible with the subject.

[0489] In this paper, the terms "X" and "Xaa" are equivalent and refer to unspecified amino acids. Their scope is defined in the relevant descriptions. To distinguish multiple "X"s within the same amino acid sequence, each consecutive "X" is numbered (i.e., written as X...). n And define the scope of each of them.

[0490] Unless otherwise stated, the terms “comprise”, “comprises”, and “comprising” or their equivalents (contain, contain, containing, include, include, including) used herein are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0491] Unless otherwise stated, all figures used herein to represent amounts of components, measurements, or reaction conditions should be understood to be modified in all cases by the term “about,” which means within an acceptable margin of error for the corresponding value. When used with percentages, the term “about” can mean, for example, ±1%, preferably ±0.5%, more preferably ±0.1%.

[0492] Unless the context clearly indicates otherwise, singular terms in this document encompass the plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" in this document is intended to include "and".

[0493] For purposes of description and disclosure, all patents, patent applications and other publications are expressly incorporated herein by reference. These publications are provided only because their publication predates the filing date of this application. All statements regarding the dates of these documents or representations of their contents are based on information available to the applicant and do not constitute any admission of the accuracy of the dates or contents of these documents.

[0494] Example

[0495] The present invention will be further described below through specific embodiments, but the present invention is not limited to these embodiments, and these embodiments are only for more detailed description and should not be construed as limiting the present application in any way.

[0496] Unless otherwise stated, all reagents, reagent consumables, and instruments used in this application are commercially available products. The main reagents and consumables are shown in Table A.

[0497] Table A: Main Reagents and Consumables

[0498]

[0499] Example 1: Animal Immunization

[0500] Six- to eight-week-old female Balb / c mice were selected and grouped into groups of six. Recombinant human BAFFR protein (Baipusaisi, catalog number BAR-H5257) was used as the immunogen. The recombinant protein was mixed with quickantibody-Mouse5W (Boaolong, catalog number KX0210041) at a 1:1 ratio and administered subcutaneously, intramuscularly, and intraperitoneally, with each immunization consisting of 20 μg. The immunization cycle was 14 days. A total of four immunizations were performed, and serum samples were collected from mice on days 14, 28, and 42 for antibody titer testing. Mice with satisfactory antibody titers received a booster immunization 10 days after the last immunization. No adjuvant was added to the booster immunization, and the recombinant protein was administered at 40 μg per mouse.

[0501] Example 2: Detection of antibody levels in animals after immunization

[0502] 2.1 ELISA method for detecting antibody titer

[0503] Recombinant human BAFFR protein (Bipsys, catalog number BAR-H52H3) was diluted to the working concentration (2 μg / ml) with coating buffer, and 100 µL was added to each well of the ELISA plate. The plate was sealed with a sealing membrane and incubated overnight at 4°C. On the second day, after washing three times with PBST, 300 μL of 2% BSA blocking buffer was added, and the plate was sealed with a sealing membrane and incubated at 37°C for 1.5 h. After washing, test serum and negative serum were serially diluted (initial dilution 300-fold, serial dilution 3-fold to 656-100-fold), and 100 μL was added to each well. The plate was sealed with a sealing membrane and incubated at 37°C for 1 h. After washing, HRP-labeled goat anti-mouse IgG H&L antibody (ABCAM, catalog number: ab6789) was added, 100 μL to each well, and the plate was sealed with a sealing membrane and incubated at 37°C for 1 h. After washing, 100 μL of Pierce 1-Step Ultra TMB-ELISA substrate solution was added to each well. The plate was sealed with the membrane and incubated at room temperature for 3 min. 100 μL of stop solution was added to each well to terminate the reaction. The OD was read at 450 nm using a microplate reader. Unimmunized mouse serum served as the blank control, an equal volume of PBS served as the negative control, and an equal volume of PBS wells not coated with human BAFFR served as the blank control. The results are shown in Table 3 below. Although there were differences among individuals, all six mice successfully produced specific antibodies against BAFFR. Using the average OD value of unimmunized mouse serum (0.076) as the baseline, an OD value greater than twice that (i.e., >0.15) was considered positive. The antibody titer was defined as the highest serum dilution that produced a positive reaction; the intraperitoneal immunization group had the highest titer (up to 1:72900).

[0504] Table 3

[0505] 2.2 FACS method for detecting antibody titer

[0506] To further verify the antibody's ability to recognize native conformation proteins, the human BAFFR gene was introduced into 293T cells, resulting in cells overexpressing the human BAFFR protein, named 293T-BAFFR (constructed by Kangyuan Bocheng Biotechnology (Beijing) Co., Ltd.). 293T-BAFFR cells (2 × 10⁶ cells) were then used to... 6Cells were added to 96-well polypropylene microplates (Thermo, 267350) at 1500 rpm for 5 min at 4 °C, and the supernatant was removed. 50 μL of mouse serum at different dilutions (from an initial 300-fold dilution to 656-100-fold serial dilutions) were added to each well, mixed by pipetting, and incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. Goat F(ab')2 anti-mouse IgG-Fc(PE) (Abcam, catalog number ab98742) was diluted 400-fold with 2% FBS / 1×PBS solution, added to the cells, mixed by pipetting, and incubated at 4 °C in the dark for 40 min. Cells were washed twice and then resuspended in 200 μl of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxT Acoustic Focusing Cytometer, Invitrogen), and the data were analyzed. Unimmunized mouse serum served as a blank control, an equal volume of PBS served as a negative control, and wells containing only cells without fluorescent antibody served as a blank control. The results are shown in Table 4 below. A fluorescence intensity greater than twice the median fluorescence intensity of unimmunized mouse serum (12.5) was considered positive. Antibody titer was defined as the highest serum dilution that produced a positive reaction; the intraperitoneal immunization group had the highest titer (up to 1:218700).

[0507] Table 4

[0508]

[0509] Example 3: Cell Fusion and Screening

[0510] 3.1 Cell Fusion

[0511] Spleens and lymph nodes of mice meeting the titer requirements were harvested and ground to release lymphocytes. The lymphocytes were collected after filtration through a 40 μm sterile cell sieve, washed with RPMI-1640 medium, and counted. Simultaneously, SP2 / 0 mouse myeloma cells in the logarithmic growth phase were collected using RPMI-1640 medium. Lymphocytes and SP2 / 0 cells were mixed at a 2:1 ratio, and the suspension was centrifuged at 1500 rpm (309 g) for 5 min. The supernatant was discarded, and the cells were washed twice with electrofusion buffer (BTX, 47-0001). Finally, the cells were resuspended in 9 mL of electrofusion buffer and subjected to electrofusion. Each well was prepared with 1.5 × 10⁻⁶ cells / well. 4 The cells were plated into 40 plates and incubated at 37°C in a 5% CO2 incubator for 10 days.

[0512] 3.2 Hybridoma Screening

[0513] On day 10 post-fusion, cell culture supernatant was collected for preliminary ELISA screening. ELISA-positive clones were then screened for FACS binding using 293T-BAFFR. Finally, species-specific assays and assays were performed on FACS-positive clones to detect their activity in blocking the binding of human BAFF to 293T-BAFFR.

[0514] (1) ELISA detection of the binding activity between hybridoma antibody and recombinant human BAFFR protein

[0515] Recombinant human BAFFR protein (Bipsys, catalog number BAR-H52H3) was diluted to the working concentration (1 μg / mL) with coating buffer, and 50 µL was added to each well of the ELISA plate. The plate was sealed with a sealing membrane and incubated overnight at 4°C. On the second day, after washing three times with PBST, 300 µL of 2% BSA blocking buffer was added, the plate was sealed with a sealing membrane, and incubated at 37°C for 1.5 h. After washing, 50 µL of cell culture supernatant was added to each well, the plate was sealed with a sealing membrane, and incubated at 37°C for 1 h. After washing, 50 µL of HRP-labeled goat anti-mouse IgG Fc antibody (Sigma, catalog number A0168) was added to each well, the plate was sealed with a sealing membrane, and incubated at room temperature for 3 min. Finally, 50 µL of stop solution was added to each well to terminate the reaction. Place the sample into a microplate reader and read the OD450nm value. Use polyclonal antibody serum as a positive control and PBS as a negative control. An OD450nm value greater than 0.5 is considered positive.

[0516] (2) FACS detection of the binding activity of hybridoma antibody to 293T-BAFFR

[0517] 293T-BAFFR cells (2×10⁻⁶) 6Cells were added to a 96-well polypropylene microplate (Thermo, 267350) at 1500 rpm for 5 min at 4 °C, and the supernatant was removed. 50 μL of cell culture supernatant from ELISA-positive clones was added to each well, and the cells were incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. Goat F(ab')2 anti-mouse IgG-Fc(PE) (Abcam, catalog number ab98742) was diluted 400-fold with 2% FBS / 1×PBS solution, added to the cells, and mixed thoroughly by pipetting. The cells were incubated at 4 °C in the dark for 40 min. The cells were washed twice, then resuspended in 200 μL of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured using an Attune NxT Acoustic Focalizing Cytometer (Invitrogen), and the data were analyzed. Immunized polyclonal antibody serum was used as a positive control, while serum from unimmunized negative mice and PBS were used as negative controls. An MFI value greater than 1000 was considered positive.

[0518] (3) ELISA detection of the binding activity between hybridoma antibody and recombinant monkey BAFFR protein

[0519] Recombinant monkey BAFFR protein (Bipsys, catalog number BAR-C52H4) was diluted to the working concentration (1 μg / mL) with coating buffer, and 50 µL was added to each well of the ELISA plate. The plate was sealed with a sealing membrane and incubated overnight at 4°C. On the second day, after washing three times with PBST, 300 µL of 2% BSA blocking buffer was added, the plate was sealed with a sealing membrane, and incubated at 37°C for 1.5 h. After washing, 50 µL of cell culture supernatant was added to each well, the plate was sealed with a sealing membrane, and incubated at 37°C for 1 h. After washing, 50 µL of HRP-labeled goat anti-mouse IgG Fc antibody (Sigma, catalog number A0168) was added to each well, the plate was sealed with a sealing membrane, and incubated at room temperature for 3 min. Finally, 50 µL of stop solution was added to each well to terminate the reaction. The sample was placed in an ELISA reader and its OD450nm value was read. Immunized polyclonal antibody serum served as a positive control, while serum from unimmunized negative mice and PBS served as negative controls. An OD450nm value greater than 0.8 was considered to indicate binding activity with monkey BAFFR.

[0520] (4) FACS detection of the activity of hybridoma antibody in blocking the binding of human BAFF to 293T-BAFFR.

[0521] 293T-BAFFR cells (2×10⁻⁶) 6Cells were added to a 96-well polypropylene microplate (Thermo, 267350) at 1500 rpm for 5 min at 4 °C, and the supernatant was removed. 50 μL of cell culture supernatant from ELISA-positive clones was added to each well, and the cells were incubated at room temperature for 30 min. Then, 150 μL of 0.1 μg / mL biotin-labeled recombinant human BAFF protein (Bepsys, catalog number BAF-H82Q2) was added to each well, and the cells were incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. PE-Streptavidin (Abcam, catalog number ab279318) was diluted 400-fold with 2% FBS / 1×PBS solution, added to the cells, and mixed thoroughly by pipetting. The cells were incubated at 4 °C in the dark for 40 min. Cells were washed twice and then resuspended in 200 μL of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxT Acoustic Focalizing Cytometer, Invitrogen), and the data were analyzed. A blocking rate greater than 85% was considered to indicate activity in blocking the binding of human BAFF to 293T-BAFFR.

[0522] Through the screening methods described above, a total of three clones were obtained that can simultaneously bind to human BAFFR protein and monkey BAFFR protein and have the activity of blocking the binding of human BAFF to 293T-BAFFR: m27C5Y6P, m34B12, and m55E11.

[0523] Example 4 Sequencing of the variable region gene of hybridoma antibody

[0524] RNA lysis buffer (74136, QIAGEN) was added to hybridoma cells (1×10^ 6 RNA was extracted from DH5α competent cells using an RNA extraction kit (74136, QIAGEN). After extraction, RNA concentration was measured using Nanodrop, and the RNA was reverse transcribed into cDNA using 5'-RACE. After reverse transcription, PCR amplification of the antibody's light and heavy chain variable regions was performed using specific primers. After the reaction, the PCR stock solution was recovered using agarose gel electrophoresis (CW2302M, Kangwei Century), and the recovered product concentration was measured using Nanodrop. After the assay, the fragment was ligated to a vector using a seamless cloning enzyme (C116-02, Novozymes) and transformed into DH5α competent cells. The cells were then plated onto LB plates containing ampicillin and sent to a sequencing company for single-clone sequencing the following day. The data were analyzed using SnapGene software.

[0525] Example 5 Expression and purification of chimeric antibodies

[0526] The antibody variable region gene obtained from sequencing was cloned into the pcDNA3.4 vector using a seamless cloning enzyme. The heavy chain constant region is the human IgG1 constant region (shown as SEQ ID NO: 107), and the light chain constant region is the human κ chain constant region (shown as SEQ ID NO: 106). A mammalian cell expression plasmid was constructed, and HEK293F cells were transfected using liposomes. After 72 hours, the supernatant was collected, and the expressed antibody was purified using Protein A. The purified antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 were analyzed by SDS-PAGE and SEC-HPLC, showing a purity greater than 95%. (See attached figures). Figure 1 .

[0527] Example 6: In vitro activity detection of chimeric antibodies

[0528] 6.1 FACS detection of the binding activity of chimeric antibody to 293T-BAFFR

[0529] 293T-BAFFR cells (2×10⁻⁶) 6 Cells were added to a 96-well polypropylene microplate (Thermo, 267350) at 1500 rpm for 5 min at 4 °C, and the supernatant was removed. 50 μL of chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 at different concentrations (starting from 20 μg / mL, serially diluted 3.16-fold in 12 steps) were added to the wells, mixed thoroughly by pipetting, and incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. Goat F(ab')2 anti-human IgG-Fc(PE) (Abcam, catalog number ab98596) was diluted 400-fold with 2% FBS / 1×PBS solution, added to the cells, mixed thoroughly by pipetting, and incubated at 4 °C in the dark for 40 min. Cells were washed twice and then resuspended in 200 μL of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxT AcousticFocusing Cytometer, Invitrogen), and the data were analyzed. EC50 values ​​were calculated using four-parameter nonlinear fitting in GraphPad Prism7 software. An IgG1 isotype control antibody (HumanIgG1 Isotype) was used as a negative control. Results are shown in Table 5 below. Figure 2All three chimeric antibodies exhibited typical dose-dependent binding curves, producing extremely strong specific fluorescence signals (MFI.Max > 132000) at saturation concentrations, with minimal differences in their values. Among them, the EC55E11-hIgG1... 50 The lowest value indicates a significant combined advantage.

[0530] Table 5

[0531]

[0532] 6.2 FACS detection of the activity of chimeric antibody in blocking the binding of human BAFF to 293T-BAFFR

[0533] 293T-BAFFR cells (2×10⁻⁶) 6 Cells / mL, 50 μL / well) were added to a 96-well polypropylene microplate (Thermo, 267350) and centrifuged at 1500 rpm for 5 min at 4 °C, removing the supernatant. 50 μL of different concentrations of chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 (starting from 20 μg / mL, serially diluted 3.16-fold, 12 gradients) were added to each well. After mixing by pipetting, the mixture was incubated at room temperature for 30 min. Then, 150 μL of 0.1 μg / mL biotin-labeled recombinant human BAFF protein (Bepsys, catalog number BAF-H82Q2) was added to each well and incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. PE-Streptavidin (Abcam, catalog number ab279318) was diluted 400-fold with 2% FBS / 1×PBS solution, then added to the cells and mixed by pipetting. The cells were incubated at 4°C in the dark for 40 min. The cells were washed twice and then resuspended in 200 μL of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxTAcoustic Focusing Cytometer, Invitrogen), and the data were analyzed. The IC50 values ​​were calculated using a four-parameter nonlinear fitting method in GraphPad Prism7 software. An IgG1 isotype control antibody (Human IgG1 Isotype) was used as a negative control. The results are shown in Table 6 below. Figure 3 All three chimeric antibodies achieved a maximum blocking rate of >99%, which is crucial for treating autoimmune diseases caused by excessive BAFF signaling, such as systemic lupus erythematosus and rheumatoid arthritis.

[0534] Table 6

[0535]

[0536] 6.3 FACS detection of the activity of chimeric antibody binding to Raji cells

[0537] Raji cells are human Burkitt's lymphoma cells (purchased from Wuhan Pronosai Life Science Technology Co., Ltd.), and their growth and survival are associated with BAFF / BAFFR signaling. Raji cells (2 × 10⁻⁶) were used to... 6 Cells were added to a 96-well polypropylene microplate (Thermo, 267350) at 1500 rpm for 5 min at 4 °C, and the supernatant was removed. 50 μL of chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 at different concentrations (starting from 20 μg / mL, serially diluted 3.16-fold in 12 steps) were added to the wells, mixed thoroughly by pipetting, and incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. Goat F(ab')2 anti-human IgG-Fc(PE) (Abcam, catalog number ab98596) was diluted 400-fold with 2% FBS / 1×PBS solution, added to the cells, mixed thoroughly by pipetting, and incubated at 4 °C in the dark for 40 min. Cells were washed twice and then resuspended in 200 μL of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxT Acoustic Focusing Cytometer, Invitrogen), and the data were analyzed. EC50 values ​​were calculated using four-parameter nonlinear fitting in GraphPad Prism7 software. An IgG1 isotype control antibody (Human IgG1 Isotype) was used as a negative control. Results are shown in Table 7 below. Figure 4 All three chimeric antibodies exhibited potent binding to Raji cells endogenously expressing BAFFR, directly demonstrating their potential to target cells associated with relevant diseases. This provides direct evidence for subsequent efficacy testing in B-cell malignancies (such as certain lymphomas) or autoimmune diseases (targeting abnormally activated B cells). Among them, the m55E11-hIgG1 EC50... 50 The lowest value indicates a significant combined advantage.

[0538] Table 7

[0539]

[0540] 6.4 FACS detection of the activity of chimeric antibody in blocking the binding of human BAFF to Raji cells

[0541] Raji cells (2×10) 6 Cells / mL, 50 μL / well) were added to a 96-well polypropylene microplate (Thermo, 267350) and centrifuged at 1500 rpm for 5 min at 4 °C, removing the supernatant. 50 μL of different concentrations of chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 (starting at 20 μg / mL, serially diluted 3.16-fold in 12 steps) were added to each well. After mixing by pipetting, the mixture was incubated at room temperature for 30 min. Then, 150 μL of 0.1 μg / mL biotin-labeled recombinant human BAFF protein (Bepsys, catalog number BAF-H82Q2) was added to each well and incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. PE-Streptavidin (Abcam, catalog number ab279318) was diluted 400-fold with 2% FBS / 1×PBS solution, then added to the cells and mixed by pipetting. The cells were incubated at 4°C in the dark for 40 min. The cells were washed twice and then resuspended in 200 μl of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxTAcoustic Focusing Cytometer, Invitrogen), and the data were analyzed. The IC50 values ​​were calculated using a four-parameter nonlinear fitting method in GraphPad Prism7 software. An IgG1 isotype control antibody (Human IgG1 Isotype) was used as a negative control. The results are shown in Table 8 below. Figure 5 All three antibodies dose-dependently inhibited the binding of BAFF to Raji cells, with m55E11-hIgG1 exhibiting the lowest IC50. 50 With the highest blocking rate, it shows a clear blocking advantage.

[0542] Table 8

[0543]

[0544] 6.5 FACS Detection of the Activity of Chimeric Antibody in Blocking the Binding of Human BAFF to SU-DHL-4 Cells

[0545] SU-DHL-4 is a human diffuse large B-cell lymphoma cell line (purchased from Wuhan Pronosai Life Science Technology Co., Ltd.). SU-DHL-4 cells (2 × 10⁻⁶) were... 6Cells / mL, 50 μL / well) were added to a 96-well polypropylene microplate (Thermo, 267350) and centrifuged at 1500 rpm for 5 min at 4 °C, removing the supernatant. 50 μL of different concentrations of chimeric antibodies m27C5Y6P-hIgG1, m34B12-hIgG1, and m55E11-hIgG1 (starting at 20 μg / mL, serially diluted 3.16-fold in 12 steps) were added to each well. After mixing by pipetting, the mixture was incubated at room temperature for 30 min. Then, 150 μL of 0.1 μg / mL biotin-labeled recombinant human BAFF protein (Bepsys, catalog number BAF-H82Q2) was added to each well and incubated at 4 °C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. PE-Streptavidin (Abcam, catalog number ab279318) was diluted 400-fold with 2% FBS / 1×PBS solution, then added to the cells and mixed by pipetting. The cells were incubated at 4°C in the dark for 40 min. The cells were washed twice and then resuspended in 200 μl of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxTAcoustic Focusing Cytometer, Invitrogen), and the data were analyzed. The IC50 values ​​were calculated using a four-parameter nonlinear fitting method in GraphPad Prism7 software. An IgG1 isotype control antibody (Human IgG1 Isotype) was used as a negative control. The results are shown in Table 9 below. Figure 6 In SU-DHL-4 cells, m55E11-hIgG1 had the lowest IC50. 50 Compared to the results on Raji cells (~75%), all antibodies on SU-DHL-4 cells achieved a maximum blocking rate of 85%-95%, with m55E11-hIgG1 achieving a maximum blocking rate of nearly 95%.

[0546] Table 9

[0547]

[0548] Example 7 Antibody Humanization

[0549] First, through sequence similarity comparison, the human germline template sequence with the highest similarity to antibody m55E11 was matched in known databases. The CDR region sequence of the mouse antibody was transplanted into the selected human germline sequence. Then, the antibody with the most similar structure was searched in the PDB database for structural modeling analysis. Key sites in the FR region that interact with the CDR region were identified and reversed by mutation. At the same time, the post-translational modification (PTM) sites and sites affecting stability and druggability of the antibody were analyzed. Based on this, 10 versions of the sequence were designed. The sequence information is shown in Tables 10 and 11 below. The antibody variable region gene was synthesized and cloned into a vector expressing the constant region of the IgG1 antibody. The vector was transfected with 293F for antibody expression. After purification with Protein A, humanized antibody variants hu55E11V1-hIgG1~hu55E11V10-hIgG1 were obtained. The specific method is the same as in Example 5. The results are shown in... Figure 7 The purity of the antibodies was greater than 95%.

[0550] Table 10

[0551]

[0552] Table 11

[0553]

[0554] 7.1 ELISA detection of the binding activity of humanized antibody to recombinant human BAFFR protein

[0555] Recombinant human BAFFR protein (Bipsys, catalog number BAR-H52H3) was diluted to the working concentration (1 μg / mL) with coating buffer, and 50 µL was added to each well of the ELISA plate. The plate was sealed with a sealing membrane and incubated overnight at 4°C. On the second day, after washing three times with PBST, 300 µL of 2% BSA blocking buffer was added, the plate was sealed with a sealing membrane, and incubated at 37°C for 1.5 h. After washing, different concentrations of humanized antibody (starting from 20 μg / mL, serially diluted 3.16 times, 12 times) were added, 50 µL to each well, the plate was sealed with a sealing membrane, and incubated at 37°C for 1 h. After washing, HRP-labeled goat anti-human IgG Fc antibody (Sigma, catalog number A0170) was added, 50 µL to each well, the plate was sealed with a sealing membrane, and incubated at 37°C for 1 h. After washing, add 50 μL of Pierce 1-Step Ultra TMB-ELISA substrate solution to each well, seal the plate with the membrane, and incubate at room temperature for 3 min. Add 50 μL of stop solution to each well to terminate the reaction. Read the OD at 450 nm using a microplate reader. The control antibody was a MOR6654 analog (clinical drug name VAY-736, sequence disclosed in CN102119174B), and the IgG1 isotype control antibody (Human IgG1 Isotype) was used as a negative control. The EC50 values ​​were calculated using four-parameter nonlinear fitting in GraphPad Prism7 software. The results are shown in Table 12 below. Figure 8 Humanized antibodies and maternal chimeric antibodies all showed similar or stronger binding activity to the control antibodies.

[0556] Table 12

[0557]

[0558] 7.2 ELISA detection of the binding activity between humanized antibody and monkey BAFFR recombinant protein

[0559] Recombinant monkey BAFFR protein (Bipsys, catalog number BAR-C52H4) was diluted to the working concentration (1 μg / mL) with coating buffer, and 50 µL was added to each well of the ELISA plate. The plate was sealed with a sealing membrane and incubated overnight at 4°C. On the second day, after washing three times with PBST, 300 µL of 2% BSA blocking buffer was added, and the plate was sealed with a sealing membrane and incubated at 37°C for 1.5 h. After washing, different concentrations of humanized antibody (starting from 20 μg / mL, serially diluted 3.16 times, 12 times) were added, 50 µL to each well, and the plate was sealed with a sealing membrane and incubated at 37°C for 1 h. After washing, HRP-labeled goat anti-human IgG Fc antibody (Sigma, catalog number A0170) was added, 50 µL to each well, and the plate was sealed with a sealing membrane and incubated at 37°C for 1 h. After washing, add 50 μL of Pierce 1-Step Ultra TMB-ELISA substrate solution to each well, seal the plate with the membrane, and incubate at room temperature for 3 min. Add 50 μL of stop solution to each well to terminate the reaction. Read the OD at 450 nm using a microplate reader. The control antibody was a MOR6654 analog, and the IgG1 isotype control antibody (Human IgG1 Isotype) served as a negative control. The EC50 values ​​were calculated using a four-parameter nonlinear fitting method in GraphPad Prism 7 software. The results are shown in Table 13 below. Figure 9 All humanized antibodies and chimeric antibodies showed stronger binding activity than control antibodies.

[0560] Table 13

[0561]

[0562] 7.3 FACS detection of the binding activity of humanized antibodies to Raji cells

[0563] Raji cells (1E5 cells / well) were added to 96-well polypropylene microplates (Thermo, 267350) and centrifuged at 1500 rpm for 5 min at 4°C, removing the supernatant. 50 μL of humanized antibodies of different concentrations (starting from 20 μg / mL, serially diluted 3.16-fold in 12 steps) were added to each well, mixed thoroughly by pipetting, and incubated at 4°C in the dark for 1 h. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. Goat F(ab')2 anti-human IgG-Fc(PE) (Abcam, catalog number ab98596) was diluted 400-fold with 2% FBS / 1×PBS solution, added to the cells, mixed thoroughly by pipetting, and incubated at 4°C in the dark for 40 min. Cells were washed twice and then resuspended in 200 μL of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxT Acoustic Focusing Cytometer, Invitrogen), and the data were analyzed. EC50 values ​​were calculated using four-parameter nonlinear fitting in GraphPad Prism7 software. An equal volume of PBS was used as a negative control. The results are shown in Table 14 below. Figure 10 .

[0564] Table 14

[0565]

[0566] 7.4 FACS detection of the activity of humanized antibody in blocking the binding of human BAFF to Raji cells

[0567] Raji cells (1E5 cells / well) were added to 96-well polypropylene microplates (Thermo, 267350) and centrifuged at 1500 rpm for 5 min at 4°C, removing the supernatant. 50 μL of humanized antibody at different concentrations (starting from 20 μg / mL, serially diluted 3.16-fold in 12 steps) was added to each well, mixed thoroughly by pipetting, and incubated at room temperature for 30 min. Then, 150 μL of biotin-labeled recombinant human BAFF protein (Bepsys, catalog number BAF-H82Q2) at a concentration of 0.1 μg / mL was added to each well and incubated at 4°C in the dark for 1 hour. After the reaction, the cells were washed with 400 μL of 2% FBS / 1×PBS solution. PE-Streptavidin (Abcam, catalog number ab279318) was diluted 400-fold with 2% FBS / 1×PBS solution, added to the cells, mixed thoroughly by pipetting, and incubated at 4°C in the dark for 40 min. Cells were washed twice and then resuspended in 200 μL of 2% FBS / 1×PBS solution. The median fluorescence intensity of the cells was measured by flow cytometry (Attune NxT Acoustic Focusing Cytometer, Invitrogen), and the data were analyzed. The IC50 values ​​were calculated using a four-parameter nonlinear fitting method in GraphPad Prism7 software. Wells containing only recombinant human BAFF and cells served as negative controls. The results are shown in Table 15 below. Figure 11 .

[0568] Table 15

[0569]

[0570] Example 8 Antibody Affinity Assay

[0571] The affinity constants between the humanized antibody and recombinant human BAFFR protein (Bestsys, catalog number BAR-H52H3) were determined using a Molecular interaction analyzer (Fortebio, OCTETRED96E). The control antibody was a MOR6654 analog. The results are shown in Table 16. The humanized antibody according to this application showed higher affinity than the control antibody.

[0572] Table 16

[0573]

[0574] Example 9 Antibody ADCC Activity Detection

[0575] FcγRⅢA (CD16a) can mediate ADCC activity of NK cells against tumor cells. In this study, Jurkat-NFAT-Luc2-CD16a-V158 was used as an alternative effector cell to co-incubate with target cells, thereby activating the NFAT-luc2 luciferase reporter system. The ADCC activity of the antibody can be detected by measuring the luciferase content.

[0576] The effector cells Jurkat-NFAT-Luc2-CD16a-V158 were constructed by Kangyuan Biotech (Beijing) Co., Ltd., and Raji cells were purchased from Peking Union Medical College Cell Bank.

[0577] Jurkat-NFAT-Luc2-CD16a-V158 cells (culture conditions: RPMI-1640 + 10% FBS + 300 μg / mL Hygromycin B + 0.75 μg / mL Puromycin) and target cells Raji cells (culture conditions: RPMI-1640 containing 10% FBS) were seeded at a 1:1 ratio. 45 µL of cell suspension was added to each well of a 96-well plate, seeding 20,000 cells per well. Different concentrations of humanized antibodies hu55E11V2-hIgG1, hu55E11V4-hIgG1, hu55E11V5-hIgG1, and control antibody (working concentration up to 300 ng / mL, serially diluted 5-fold in RPMI-1640 medium containing 10% FBS, 10 concentrations) were added to each well, and the plates were incubated at 37°C and 5% CO2 for 6 hours. The microplate reader (BMG LABTEC, CLARIOstar® Plus) and the Bright-Lite Luciferase Assay System kit (Novazia, DD1204) were used for analysis. Experimental data were calculated using the log(agonist) vs. response-variable slope (four parameters) parameter fitting method in GraphPad Prism7 software. 50 The values ​​and Top values ​​were used to assess the ADCC effect intensity of the antibody. The control antibody was a MOR6654 analog, and the IgG1 isotype control antibody served as a negative control. Results are shown in Table 17. Figure 12 The results showed that the humanized antibody of this application exhibited ADCC activity similar to or better than the control antibody.

[0578] Table 17

[0579]

[0580] Example 10 Raji Cell Killing Experiment

[0581] To further validate the antibody-mediated cytotoxic effect in a peripheral blood mononuclear cell (PBMC) system, a co-culture system of fluorescein-labeled tumor cell lines and PBMCs was used for evaluation. This system was used to assess the in vitro cytotoxic response of NK cells in PBMCs under the action of specific antibodies.

[0582] Specifically, Raji-Luc2 cells (constructed by Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.) were used as target cells, with 10,000 cells per well seeded into 96-well plates. PBMCs (purchased from Aoneng Biotechnology) were added, and 300,000 cells per well were seeded into the same 96-well plates. Different concentrations of antibodies hu55E11V2-hIgG1, hu55E11V4-hIgG1, and control antibody (final concentration 0.8 μg / mL, serially diluted 5-fold in RPMI-1640 medium containing 10% FBS, for a total of 7 concentration gradients, with 3 replicates for each concentration) were added, and the plates were incubated at 37 ℃ and 5% CO2 for 72 hours. Luciferase analysis was performed using the Bright-Lite Luciferase Assay System reagents as described in Example 9. Experimental data were calculated using a four-parameter nonlinear fitting method in GraphPad Prism7 software to determine EC50. 50 The values ​​and Top values ​​were used to assess the ADCC effect intensity of the antibody. The control antibody was a MOR6654 analog, and the IgG1 isotype control antibody served as a negative control. Results are shown in Table 18. Figure 13 The percentage of target cell lysis (Killing, %) is calculated using the following formula:

[0583] Killing(%)=[1-(Luciferase Test – Luciferase PBMC ) / Luciferase NC )]*100%.

[0584] in,

[0585] Luciferase NC : Luciferase signal value in the control group without test substance (target cells + PBMC cells);

[0586] Luciferase Test : Luciferase signal values ​​in the experimental group (target cells + PBMC cells + antibody test substance);

[0587] Luciferase PBMC : Luciferase signal value in PBMC control group (PBMC cells only).

[0588] The results showed that the humanized antibodies hu55E11V2-hIgG1 and hu55E11V4-hIgG1 exhibited ADCC activities similar to or better than the control antibodies. At a concentration of 0.8 μg / mL, hu55E11V4-hIgG1 (P < 0.0001) and hu55E11V2-hIgG1 (P = 0.0017) showed significant differences in cell-killing activity compared to the control antibodies.

[0589] Table 18

[0590]

[0591] *Top killing (%) refers to the maximum percentage of cells killed.

[0592] Example 11: Subcutaneous xenograft tumor model of human lymphoma Raji cells

[0593] Following the method described in Example 5, defucosylated CHO cells (purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.) were transfected to express and purify hu55E11V4-hIgG1 and control antibody (MOR6654 analog, clinical drug alternative name VAY-736), which were named hu55E11V4KOF and control antibody KOF, respectively.

[0594] Eighteen female SCID mice (purchased from Vital Rivers) were subcutaneously injected with Raji cells at a rate of 5E6 cells per mouse to construct a human lymphoma Raji cell subcutaneous heterotopic transplantation model. The tumor volume was increased to 100 mm². 3 Mice were divided into groups (n = 6) and administered antibody hu55E11V4KOF and control antibody KOF via tail vein injection at a dose of 10 mg / kg every 3 days for 21 days. G1 was the PBS solvent group, G2 was the hu55E11V4KOF drug group, and G3 was the control antibody KOF drug group (MOR6654 analog). Tumor volume and body weight were measured simultaneously from the start of administration (D0) to evaluate the inhibitory effect of the drugs on tumors. Results were analyzed using GraphPad Prism7 (mean ± SEM, n = 6). Results are shown in Table 19 and... Figure 14A -B. The tumor growth inhibition rate is calculated using the following formula:

[0595] Tumor growth inhibition rate = (Tumor volume in control group - Tumor volume in treatment group) / Tumor volume in control group * 100%

[0596] The results showed that no mice died during the experiment, and no significant weight loss, arched backs, or ruffled fur were observed, indicating that the mice tolerated the drug well. In the drug group, the tumor growth inhibition rate reached approximately 40% one week after administration, significantly inhibiting tumor growth. Furthermore, the tumor inhibition rate of the antibody of this invention was higher than that of the control antibody.

[0597] Table 19. Human lymphoma Raji cell subcutaneous xenograft tumor model—tumor suppression rate (%)

[0598] Example 12 Long-term modification of antibodies and detection of binding and killing activity

[0599] The hu55E11V4-hIgG1 antibody underwent the following long-acting modifications to prolong its therapeutic period. Specific mutation sites are shown in Table 20. Detailed sequence information is shown in Table 2-2. The mutations are numbered sequentially (containing mutations 1-5 as shown in Table 20): hu55E11V4YTEKOF, hu55E11V4LSKOF, hu55E11V4YPYKOF, hu55E11V4DQVKOF, hu55E11V4YTEFFKOF; hu55E11V2YTEKOF, hu55E11V2LSKOF, hu55E11V2YPYKOF, hu55E11V2DQVKOF, and hu55E11V2YTEFFKOF.

[0600] Following the method described in Example 5, defucosylated CHO cells (purchased from Baiying Biotechnology) were transfected to express and purify the modified antibody of this application and the control antibody (MOR6654 analog, clinical drug alternative name VAY-736). The activity of the modified antibody was then tested according to a similar protocol to that in Examples 6.1 and 6.2. The cell-killing ability of the modified antibody was then tested using Nalm-6-Luc (human B-lymphoblastic leukemia cells, purchased from Nanmo Biotechnology) as target cells, following a similar method to that in Example 10.

[0601] See results Figure 15-17 And Tables 21-23. Figure 15 The results in Table 21 show that the modified antibodies prepared in this embodiment can effectively bind to human BAFFR protein, and the binding activity is maintained compared with the antibody before modification. Figure 16 The results in Table 22 show that the blocking activity of the modified antibody in this application was maintained compared to the original antibody. Figure 17The results in Table 23 show that at 48 hours, all tested antibodies exhibited significantly better ADCC effects than the control antibody KOF. In particular, the EC50 value of hu55E11V4YPYKOF was nearly four times lower than that of the control antibody KOF, suggesting that this antibody has higher potency in in vitro ADCC experiments, meaning a lower dose is required to achieve the same killing effect. In drug development, this translates to potentially lower dosages, better safety, and lower costs.

[0602] Furthermore, after long-term testing, the modified antibody of this application achieved the expected long-term characteristics and maintained its activity.

[0603] Table 20. Mutation sites involved in the modified antibodies

[0604]

[0605] Table 21 Binding activity of the modified antibodies

[0606]

[0607] Table 22 Blocking activity of the modified antibodies

[0608]

[0609] Table 23 Cell-killing activity of the modified antibodies

[0610]

[0611] The embodiments described above are merely examples for clearly illustrating the present disclosure and are not intended to limit the implementation of the present disclosure. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all possible implementations. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of this disclosure should be included within the scope of protection of the claims of this disclosure.

Claims

1. An anti-BAFFR antibody or its antigen-binding fragment, comprising: HCDR1 shown in SEQ ID NO: 1, SEQ ID NO: 7 or SEQ ID NO: 12, HCDR2 shown in SEQ ID NO: 128 or SEQ ID NO: 8, HCDR3 shown in SEQ ID NO: 3, SEQ ID NO: 9 or SEQ ID NO: 13; and / or LCDR1 shown in SEQ ID NO: 4, SEQ ID NO: 10 or SEQ ID NO: 14, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6, SEQ ID NO: 11 or SEQ ID NO:

15.

2. The anti-BAFFR antibody or its antigen-binding fragment as described in claim 1, comprising: (1) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 128, HCDR3 shown in SEQ ID NO: 3; LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6; or (2) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 2, HCDR3 shown in SEQ ID NO: 3; LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6; or (3) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 126, HCDR3 shown in SEQ ID NO: 3; LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6; or (4) HCDR1 shown in SEQ ID NO: 1, HCDR2 shown in SEQ ID NO: 127, HCDR3 shown in SEQ ID NO: 3; LCDR1 shown in SEQ ID NO: 4, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 6; or (5) HCDR1 shown in SEQ ID NO: 7, HCDR2 shown in SEQ ID NO: 8, HCDR3 shown in SEQ ID NO: 9; LCDR1 shown in SEQ ID NO: 10, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO: 11; or (6) HCDR1 shown in SEQ ID NO: 12, HCDR2 shown in SEQ ID NO: 8, HCDR3 shown in SEQ ID NO: 13; LCDR1 shown in SEQ ID NO: 14, LCDR2 shown in SEQ ID NO: 5, and LCDR3 shown in SEQ ID NO:

15.

3. The anti-BAFFR antibody or its antigen-binding fragment as described in claim 1 or 2, comprising a heavy chain variable region and / or a light chain variable region, wherein, The heavy chain variable region (VH) includes: (1) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 73, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (2) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 73, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (3) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 127, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 73, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (4) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 76, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (5) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 76, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (6) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 77, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (7) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 77, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (8) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 72, HCDR2 shown in SEQ ID NO: 127, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 77, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (9) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 78, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (10) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 71, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 75, HCDR2 shown in SEQ ID NO: 126, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 78, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 74; (11) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 16, HCDR1 shown in SEQ ID NO: 1, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 17, HCDR2 shown in SEQ ID NO: 2, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 18, HCDR3 shown in SEQ ID NO: 3, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19; (12) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 24, HCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 7, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 25, HCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 26, HCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 9, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19; or (13) HFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 31, HCDR1 shown in SEQ ID NO: 12, HFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 25, HCDR2 shown in SEQ ID NO: 8, HFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 32, HCDR3 shown in SEQ ID NO: 13, and HFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 19; The light chain variable region (VL) includes: (1) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 79, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 4, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 80, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 81, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 6, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82; (2) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 83, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 4, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 84, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 85, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 6, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 82; (3) LFR1, LCDR1, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 20; LFR2, LCDR2, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 21; LFR3, LCDR3, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 22; and LFR4, which has at least 80% identity with the amino acid sequence shown in SEQ ID NO: 23; (4) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 27, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 10, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 28, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 29, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 11, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 30; or (5) LFR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 33, LCDR1 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 14, LFR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 21, LCDR2 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 5, LFR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 34, LCDR3 having at least 80% identity with the amino acid sequence shown in SEQ ID NO: 15, and LFR4 having at least 80% identity with the amino acid sequence shown in SEQ ID NO:

30.

4. The anti-BAFFR antibody or its antigen-binding fragment as described in any one of claims 1-3, comprising a heavy chain variable region and / or a light chain variable region, wherein, The heavy chain variable region (VH): (i) An amino acid sequence having at least 80% identity with or consisting of the amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37 and 39; or (ii) Contains or consists of the amino acid sequence shown by any one of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37 and 39; or (iii) An amino acid sequence comprising or consisting of an amino acid sequence having one or more amino acid changes compared to the amino acid sequence shown in any of SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37 and 39, preferably the amino acid changes not occurring in the CDR region; The light chain variable region (VL): (i) Contains or consists of an amino acid sequence having at least 80% identity with the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38 and 40; or (ii) Contains or consists of the amino acid sequence shown by any one of SEQ ID NOs: 57, 58, 36, 38 and 40; or (iii) An amino acid sequence comprising or consisting of an amino acid sequence having one or more amino acid changes compared to the amino acid sequence shown in any of SEQ ID NOs: 57, 58, 36, 38 and 40, preferably the amino acid changes not occurring in the CDR region; Preferably, the amino acid differences in the amino acid sequence having at least 80% identity with any of the amino acid sequences shown in SEQ ID NOs: 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 35, 37 and 39 are mainly located in the FR region; and / or The amino acids that differ from the amino acid sequences shown with at least 80% identity with any of the amino acid sequences shown in SEQ ID NOs: 57, 58, 36, 38 and 40 are mainly located in the FR region.

5. The anti-BAFFR antibody or its antigen-binding fragment as described in any one of claims 1-4, comprising: (1) VH shown in SEQ ID NO: 47 and VL shown in SEQ ID NO: 57; or (2) VH shown in SEQ ID NO: 48 and VL shown in SEQ ID NO: 57; or (3) VH shown in SEQ ID NO: 49 and VL shown in SEQ ID NO: 57; or (4) VH shown in SEQ ID NO: 50 and VL shown in SEQ ID NO: 57; or (5) VH shown in SEQ ID NO: 51 and VL shown in SEQ ID NO: 57; or (6) VH shown in SEQ ID NO: 52 and VL shown in SEQ ID NO: 58; or (7) VH shown in SEQ ID NO: 53 and VL shown in SEQ ID NO: 58; or (8) VH shown in SEQ ID NO: 54 and VL shown in SEQ ID NO: 58; or (9) VH shown in SEQ ID NO: 55 and VL shown in SEQ ID NO: 58; or (10) VH shown in SEQ ID NO: 56 and VL shown in SEQ ID NO: 58; or (11) VH shown in SEQ ID NO: 35 and VL shown in SEQ ID NO: 36; or (12) VH shown in SEQ ID NO: 37 and VL shown in SEQ ID NO: 38; or (13) VH shown in SEQ ID NO: 39 and VL shown in SEQ ID NO:

40.

6. The anti-BAFFR antibody or antigen-binding fragment thereof of any one of claims 1-5, wherein, The anti-BAFFR antibody or its antigen-binding fragment further includes a heavy chain constant region and a light chain constant region, wherein the heavy chain constant region includes the amino acid sequence shown in SEQ ID NO: 87, or an amino acid sequence having at least 80% identity with it, or an amino acid sequence having one or more amino acid changes compared to it; And / or, the light chain constant region includes the amino acid sequence shown in SEQ ID NO: 86, or an amino acid sequence having at least 80% identity with it, or an amino acid sequence having one or more amino acid changes compared to it.

7. The anti-BAFFR antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein, The anti-BAFFR antibody comprises a heavy chain and a light chain, wherein, The heavy chain comprises a sequence having at least 80% sequence identity with the amino acid sequence shown in any of SEQ ID NOs: 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 88, 90, 92, and 129-138; and, The light chain includes a sequence having at least 80% sequence identity with the amino acid sequence shown in any of SEQ ID NOs: 104, 105, 89, 91 and 93; In particular, all amino acids that differ from the amino acid sequences shown in any of SEQ ID NOs: 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105 and 129-138 are present in the FR region or constant region.

8. The anti-BAFFR antibody or antigen-binding fragment thereof of any one of claims 1-7, wherein, The antigen-binding fragment of the anti-BAFFR antibody is selected from monoclonal antibodies, polyclonal antibodies, monospecific antibodies, multispecific antibodies, antibody-drug conjugates, Fab fragments, Fab' fragments, F(ab')2 fragments, Fd fragments, Fv fragments, dAb fragments, isolated CDR regions, scFv, nanobodies, and chimeric antigen receptors.

9. A pharmaceutical combination product comprising the anti-BAFFR antibody or its antigen-binding fragment as described in any one of claims 1-8.

10. Use of the anti-BAFFR antibody or its antigen-binding fragment as described in any one of claims 1-8 in the preparation of a BAFFR inhibitor or in the preparation of a medicament for the treatment or prevention of cancer or autoimmune diseases.

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