Antigen binding proteins specific for transmembrane activators and CAML interactors (TACI)

Abstract

Provided herein are antigen binding proteins that specifically bind to and / or detect transmembrane activators and calcium modulators and cyclophilin ligand (CAML) interactors (TACI) / TNFRSF13B, where the antigen binding proteins comprise a CDR sequence having GFSITSDYA (SEQ ID NO: 1) in relation to CDRH1, ISSYSGST (SEQ ID NO: 2) in relation to CDRH2, ARVVSTSFDS (SEQ ID NO: 3) in relation to CDRH3, ESVDNYGISF (SEQ ID NO: 4) in relation to CDRL1, VAS (SEQ ID NO: 5) in relation to CDRL2, and QQSKEVPYT (SEQ ID NO: 6) in relation to CDRL3, or has an amino acid sequence at least 85% identical to the sequence, or has one or two amino acid sequences different from the sequence. Also provided herein are polynucleotides, vectors, and host cells of the antigen binding proteins. Further provided herein are pharmaceutical compositions and methods of treating a disease, such as TACI-positive multiple myeloma.

Description

Technical Field

[0001] Broadly speaking, the present disclosure relates to antigen-binding proteins that bind to transmembrane activator and CAML interactor (TACI). The present disclosure also relates to therapeutic uses, compositions, and methods for generating such antigen-binding proteins. Background of the Invention

[0003] Transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor (TACI) is a member of the tumor necrosis factor receptor (TNFR) superfamily and is also named TNFRSF13B. It was first identified as a binding partner of the CAML protein in Jurkat T cells. TACI functions as a co-inducer of nuclear factor of activated T cells (NF-AT) in activated T cells. Cross-linking of TACI by anti-TACI antibodies also leads to the activation of the transcription factors AP-1 and NF-κB. Subsequently, together with B cell maturation antigen (BCMA), TACI was identified as a receptor that can bind B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) (two important B cell cytokines), and has been shown to play an important role in B cell activation and differentiation.

[0004] Although BAFF and APRIL are known to play important stimulatory roles in B cells, the initial characterization of TACI-deficient mice showed that TACI plays an unexpected inhibitory role in B cell activation in vivo, as TACI− / − mice exhibit splenomegaly with increased mature B cells. Subsequent studies have demonstrated that TACI is important for BAFF- and APRIL-induced immunoglobulin (Ig) isotype switching to IgG1, IgA, and IgE in murine B cells. Additionally, TACI has been shown to be essential for the differentiation and survival of plasmablasts and plasma cells. Interestingly, TACI is expressed on multiple myeloma (MM) cells.

[0005] Recent studies have shown the design of chimeric antigen receptors (CARs) using the receptor-binding domain of APRIL as a tumor antigen-targeting domain (APRIL-based chimeric antigen receptor; ACAR), which recognize both BCMA and TACI on MM cells, and may potentially achieve improved clinical outcomes for MM treatment. These results suggest that TACI is a potential target for developing immunotherapies against MM.

[0006] Accordingly, there is a need to provide alternative antigen-binding proteins that are specific for TACI. SUMMARY OF THE INVENTION

[0008] In one aspect, provided are antigen-binding proteins that specifically bind to and / or detect transmembrane activator and calcium modulator and cyclophilin ligand interactor (CAML) interactor (TACI) / TNFRSF13B, wherein the antigen-binding protein comprises CDR sequences having GFSITSDYA (SEQ ID NO:1) for CDRH1, ISYSGST (SEQ ID NO:2) for CDRH2, ARVVSTSFDS (SEQ ID NO:3) for CDRH3, ESVDNYGISF (SEQ ID NO:4) for CDRL1, VAS (SEQ ID NO:5) for CDRL2, and QQSKEVPYT (SEQ ID NO:6) for CDRL3, or having an amino acid sequence that is at least 85% identical to the sequences, or having a sequence with 1 or 2 amino acids different from the sequences.

[0009] In some instances, the antigen-binding protein activates transcription factor AP-1 and / or NF-κB.

[0010] In some instances, the antigen-binding protein is capable of regulating TACI-induced B cell activation and / or differentiation.

[0011] In some instances, the antigen-binding protein is a multi-specific antigen-binding protein that binds to and / or detects TACI and / or engages / activates other immune cells, optionally the antigen-binding protein is a bispecific antigen-binding protein that binds to and / or detects TACI and CD3.

[0012] In some instances, the antigen-binding protein is a monoclonal antibody.

[0013] In some instances, the antigen-binding protein is a neutralizing antibody and / or a humanized antibody.

[0014] In some instances, the antigen-binding protein has a heavy chain variable region that comprises SEQ ID NO:7 or has an amino acid sequence that is at least 80% identical to the sequence or has 1 or 2 amino acids different from the sequence, or a fragment thereof.

[0015] In some instances, the antigen-binding protein has a light chain variable region that comprises SEQ ID NO:8 or has an amino acid sequence that is at least 80% identical to the sequence or has 1 or 2 amino acids different from the sequence, or a fragment thereof.

[0016] In some instances, the antigen-binding protein has one or more CDR regions encoded by the following polynucleotide sequences: a polynucleotide sequence selected from the group consisting of GGCTTCTCAATCACCAGTGATTATGCC (SEQ ID NO:12) for CDRH1, ATAAGTTACAGTGGTAGCACT (SEQ ID NO:13) for CDRH2, GCAAGAGTTGTATCTACGTCTTTTGACTCC (SEQ ID NO:14) for CDRH3, GAAAGTGTTGATAATTATGGCATTAGTTTT (SEQ ID NO:15) for CDRL1, GTTGCATCC (SEQ ID NO:16) for CDRL2, and CAGCAAAGTAAGGAGGTTCCGTACACG (SEQ ID NO:17) for CDRL3, or a polynucleotide that is at least 85% identical to the sequence.

[0017] In some instances, the antigen-binding protein has a heavy chain variable region encoded by a polynucleotide sequence comprising SEQ ID NO:9 or a sequence that is at least 70% identical to the sequence.

[0018] In some instances, the antigen-binding protein comprises a light chain variable region encoded by a polynucleotide sequence comprising SEQ ID NO:10 or a sequence that is at least 70% identical to the sequence.

[0019] In some instances, the antigen-binding protein is expressed on chimeric antigen receptor T cells (CAR T cells) and / or chimeric antigen receptor NK cells (CAR NK cells).

[0020] In another aspect, there is provided a polynucleotide encoding the antigen-binding protein described herein.

[0021] In some instances, the polynucleotide comprises SEQ ID NO:9 and / or 10.

[0022] In yet another aspect, there is provided a cloning or expression vector that expresses the antigen-binding protein of the present disclosure or the polynucleotide of the present disclosure.

[0023] In yet another aspect, there is provided a host cell comprising the vector described herein.

[0024] In yet another aspect, there is provided a pharmaceutical composition comprising the antigen-binding protein described herein, and a suitable pharmaceutical excipient, diluent, carrier or additive.

[0025] In another aspect, there is provided an antigen-binding protein or composition or pharmaceutical composition as described herein for use in therapy and / or immunotherapy and / or as a therapeutic agent.

[0026] In another aspect, there is provided an antigen-binding protein or pharmaceutical composition as described herein for use in treating a proliferative disease and / or a TACI-positive tumor / cancer and / or multiple myeloma (MM) in a subject in need thereof.

[0027] In another aspect, there is provided the use of an antigen-binding protein or composition or pharmaceutical composition as described herein in the manufacture of a medicament for treating a disease in a subject in need thereof, optionally wherein the disease is a proliferative disease, optionally wherein the disease is a TACI-positive tumor / cancer, and / or multiple myeloma (MM).

[0028] In another aspect, there is provided a method of treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of an antigen-binding protein or composition or pharmaceutical composition as described herein.

[0029] In another aspect, there is provided a method of neutralizing an autoimmune disease and / or a tumor and / or cancer cells in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of an antigen-binding protein or composition or pharmaceutical composition as described herein to the subject.

[0030] Definitions

[0031] As used herein, the term "recombinant polypeptide" refers to a polypeptide that has been prepared by using any recombinant DNA technology.

[0032] As used herein, the term "fusion polypeptide" refers to a polypeptide comprising at least two domains that have been encoded by separate genes and joined together such that the two domains are transcribed and translated as a single unit, thereby resulting in a single polypeptide.

[0033] As used herein, the term "polypeptide" refers to a single linear chain of any number of amino acid residues linked via peptide bonds.

[0034] The term "antibody" is used in the broadest sense and specifically encompasses monoclonal antibodies (including full-length monoclonal antibodies and smaller molecules derived therefrom) and polyclonal antibodies. The term "antibody" also includes monovalent and multivalent antibodies, such as bivalent antibodies, trivalent antibodies, and tetravalent antibodies. The term "antibody" also includes monospecific and multispecific antibodies, such as bispecific antibodies, trispecific antibodies, tetra-specific antibodies, etc. Multispecific antibodies are antibodies capable of binding to two or more different antigens or two different epitopes of the same antigen.

[0035] As used herein, the term "sequence identity" refers to the percentage of sequence identity determined by aligning antibody sequences using the Kabat numbering convention. After alignment, if the target antibody region (e.g., the entire mature variable region of the heavy or light chain) is compared to the same region of a reference antibody, the percentage of sequence identity between the target and reference antibody regions is the number of positions occupied by the same amino acid in both the target and reference antibody regions divided by the total number of aligned positions in the two regions (where gaps are not counted), multiplied by 100 to convert to a percentage.

[0036] "At least 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 97%, or 98%, or 99%, or 100% identical to the sequence" as used herein is intended to mean an amino acid sequence that is 70%, 75%, 80%, 85%, 90%, 95%, 97%, 98%, 99% or more identical to a reference sequence over its full length, such as 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100% identical. Software programs can be used to calculate the percentage of identity.

[0037] As used herein, the term "immunoglobulin fragment" refers to an antibody that can be, but is not limited to: Fab, modified Fab, Fab', modified Fab', F(ab')2, Fv, Fab-Fv, Fab-dsFv, single domain antibody (e.g., VH or VL or VHH), scFv, bivalent, trivalent or tetravalent antibody, Bis-scFv, diabody, triabody, tetrabody, and an epitope-binding fragment of any of the foregoing (see, e.g., Holliger and Hudson, 2005, Nature Biotech. 23(9):1126-1136; Adair and Lawson, 2005, Drug Design Reviews-Online 2(3), 209-217). Methods for creating and preparing these antibody fragments are well known in the art (see, e.g., Verma et al., 1998, Journal of Immunological Methods, 216, 165-181).

[0038] The term "neutralize" with respect to an antigen-binding protein refers to the ability to bind to a target cell (e.g., a cancer cell) and recruit phagocytic cells to effect direct cytotoxicity against the target cell or secrete an agent that can induce apoptosis.

[0039] As used herein, the term "subject" includes patients and non-patients. The term "patient" refers to an individual suffering from or likely to suffer from a medical condition such as a proliferative disease (e.g., TACI-positive cancer or multiple myeloma), while "non-patient" refers to an individual not suffering from or likely not to suffer from the medical condition. "Non-patient" includes healthy individuals, individuals without disease, and / or individuals without a medical condition. The term "subject" includes humans and animals. Animals include murine, etc. "Murine" refers to any mammal from the family Muridae, such as mice, rats, etc.

[0040] As used herein, the terms "treatment" and "therapy" and their synonyms refer to therapeutic treatment and prophylactic or preventive measures, where the goal is to arrest or slow down (mitigate) a medical condition, which includes but is not limited to diseases (e.g., proliferative diseases, such as TACI-positive cancer or multiple myeloma), symptoms, and disorders. A medical condition also includes the body's response to a disease or disorder, such as inflammation. Persons in need of such treatment include those who already have a medical condition, as well as those who are predisposed to develop the medical condition or are at risk of remaining in it.

[0041] As used herein, the term "therapeutic agent" refers to drugs, proteins, peptides, genes, chemical compounds, and other pharmaceutically active ingredients.

[0042] "Vector" means any such molecule or composition that has the ability to carry a nucleic acid sequence into a suitable host cell where synthesis of the encoded polypeptide can occur. Typically and preferably, a vector is a nucleic acid that has been engineered using recombinant DNA techniques known in the art to incorporate the desired nucleic acid sequence (e.g., the nucleic acid of the present invention). Expression vectors typically contain one or more of the following components (if not already provided by the nucleic acid molecule): a promoter, one or more enhancer sequences, an origin of replication, a transcription termination sequence, a complete intron sequence containing donor and acceptor splice sites, a leader sequence for secretion, a ribosome binding site, a polyadenylation sequence, a polylinker region for insertion of the nucleic acid encoding the polypeptide to be expressed, and a selectable marker element.

[0043] As used herein, the term "micro" is broadly construed to include dimensions from about 1 micrometer to about 1000 micrometers.

[0044] As used herein, the term "nano" is broadly construed to include dimensions less than about 1000 nm.

[0045] Unless otherwise stated, the terms "coupled" or "linked" as used in this specification are intended to encompass direct linkage or linkage through one or more intervening means.

[0046] When referring to two elements, the term "associated with" as used herein refers to a broad relationship between the two elements. The relationship includes, but is not limited to, physical, chemical, or biological relationships. For example, when element A is associated with element B, elements A and B may be directly or indirectly attached to each other, or element A may contain element B, and vice versa.

[0047] When referring to two elements, the term "proximal to" as used herein means that one element is in close proximity to another element, and may but is not limited to the elements being in contact with each other, or may further include the elements being separated by one or more additional elements disposed therebetween.

[0048] The term "and / or", e.g., "X and / or Y", is understood to mean either "X and Y" or "X or Y", and should be regarded as providing explicit support for both meanings or for either meaning.

[0049] Further, in the descriptions herein, whenever used, the word "substantially" is understood to include, but not limited to, "entirely" or "completely", etc. Additionally, whenever used, terms such as "comprising", "containing", etc. are intended as non - restrictive descriptive languages, because they broadly include the elements / components described after such terms in addition to other components not explicitly described. For example, when using "comprising", referring to "a" feature also intends to refer to "at least one" of that feature. In a suitable context, terms such as "consisting of" can be considered as subsets of terms such as "comprising", "containing", etc. Thus, among the embodiments disclosed herein, by using terms such as "comprising", "containing", etc., it will be appreciated that these embodiments provide teachings regarding corresponding embodiments using terms such as "consisting of", etc. Further, whenever used, terms such as "about", "substantially", etc. typically mean reasonable variations, such as a variation of + / - 5% of the disclosed value, or a variation of 4% of the disclosed value, or a variation of 3% of the disclosed value, or a variation of 2% of the disclosed value, or a variation of 1% of the disclosed value.

[0050] Further, in the descriptions herein, certain values may be disclosed in a certain range. Values showing the endpoints of the range are intended to illustrate the preferred range. Whenever a range is described, it is intended to mean that the range encompasses and teaches all possible sub - ranges and individual numerical values within that range. That is, the endpoints of the range should not be construed as immutable limitations. For example, the description of the range from 1% to 5% is intended to specifically disclose the sub - ranges 1% to 2%, 1% to 3%, 1% to 4%, 2% to 3%, etc., and individually disclose the values within that range, such as 1%, 2%, 3%, 4%, and 5%. It should be appreciated that the individual numerical values within the said range also include integers, fractions, and decimals. Further, whenever a range is described, it is also intended to mean that the range encompasses and teaches values starting from the displayed numerical endpoints up to at most 2 additional decimal places or significant figures (where appropriate). For example, the description of the range from 1% to 5% is intended to specifically disclose the ranges 1.00% to 5.00% and also 1.0% to 5.0%, and all intermediate values across the said range (e.g., 1.01%, 1.02%... 4.98%, 4.99%, 5.00%, and 1.1%, 1.2%... 4.8%, 4.9%, 5.0%, etc.). The intention of the above - mentioned specific disclosure applies to any depth / width of the range.

[0051] In addition, when describing some embodiments, the present disclosure may have disclosed methods and / or processes in a specific order of steps. However, unless otherwise required, it will be appreciated that the method or process should not be limited to the specific order of steps disclosed. Other orders of steps are possible. The specific order of steps disclosed herein should not be construed as unduly limiting. Unless otherwise required, the methods and / or processes disclosed herein should not be limited to the steps being performed in the order written. The order of steps may vary and still remain within the scope of the present disclosure.

[0052] Further, it will be appreciated that while the present disclosure provides embodiments having one or more of the features / characteristics discussed herein, one or more of these features / characteristics may be waived in other alternative embodiments, and the present disclosure provides support for such waivers and these associated alternative embodiments.

[0053] Description of Embodiments

[0054] Exemplary non-limiting embodiments of antibodies that specifically bind and / or detect transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) / TNFRSF13B are disclosed hereinafter.

[0055] The present disclosure provides antigen-binding proteins that specifically bind and / or detect transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) / TNFRSF13B.

[0056] In some instances, the antigen-binding protein activates transcription factors, such as but not limited to AP-1, NF-κB, etc.

[0057] In some instances, the antigen-binding protein is capable of regulating TACI-induced B cell activation and / or differentiation, optionally the antigen-binding protein induces B cell activation and / or differentiation.

[0058] In some instances, the antigen-binding protein binds and / or detects a portion / fragment of TACI / TNFRSF13B, the TACI / TNFRSF13B comprising the sequence provided in NCBI accession number NM_012452, or having an amino acid sequence that is at least 85% identical, or 90% identical, or 95% identical, or 97% identical, or 98% identical, or 99% identical, or 100% identical to the sequence:

[0059] MSGLGRSRRGGRSRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCRKEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELRRQRSGEVENNSDNSGRYQGLEHRGSEASPALPGLKLSADQVALVYSTLGLCLCAVLCCFLVAVACFLKKRGDPCSCQPRSRPRQSPAKSSQDHAMEAGSPVSTSPEPVETCSFCFPECRAPTQESAVTPGTPDPTCAGRWGCHTRTTVLQPCPHIPDSGLGIVCVPAQEGGPGA (SEQ ID NO:11).

[0060] In some instances, the antigen-binding protein has one or more CDR regions, and the CDR regions have an amino acid sequence that is at least 85%, or 90%, or 95%, or 97%, or 98%, or 99%, or 100% identical to a sequence selected from the group consisting of GFSITSDYA (SEQ ID NO:1), ISYSGST (SEQ ID NO:2), ARVVSTSFDS (SEQ ID NO:3), ESVDNYGISF (SEQ ID NO:4), VAS (SEQ ID NO:5), and QQSKEVPYT (SEQ ID NO:6), or has a sequence with 1 or 2 amino acids different from its sequence.

[0061] Heavy chain

[0062] CDRH1: GFSITSDYA (SEQ ID NO:1)

[0063] CDRH2: ISYSGST (SEQ ID NO:2)

[0064] CDRH3: ARVVSTSFDS (SEQ ID NO:3)

[0065] Light chain

[0066] CDRL1: ESVDNYGISF (SEQ ID NO:4)

[0067] CDRL2: VAS (SEQ ID NO:5)

[0068] CDRL3: QQSKEVPYT (SEQ ID NO:6)

[0069] In some instances, the antigen-binding protein comprises two or more CDR regions, or three or more CDR regions, or four or more CDR regions, or five or more CDR regions, or all CDR regions, which have the sequences SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

[0070] In one aspect, there is provided an antigen-binding protein that specifically binds and / or detects transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) / TNFRSF13B, wherein the antigen-binding protein comprises CDR sequences that have GFSITSDYA (SEQ ID NO:1) for CDRH1, ISYSGST (SEQ ID NO:2) for CDRH2, ARVVSTSFDS (SEQ ID NO:3) for CDRH3, ESVDNYGISF (SEQ ID NO:4) for CDRL1, VAS (SEQ ID NO:5) for CDRL2, and QQSKEVPYT (SEQ ID NO:6) for CDRL3, or have an amino acid sequence that is at least 85% identical to the sequence, or have a sequence with 1 or 2 amino acids different from its sequence.

[0071] In some instances, the antigen-binding protein binds to one or more antigens or epitopes.

[0072] In some instances, the antigen-binding protein binds to two or more antigens or epitopes, or three or more antigens or epitopes, or four or more antigens or epitopes, or five or more antigens or epitopes. In some instances, the antigen-binding protein can be a multispecific antigen-binding protein. In some instances, the antigen-binding protein can be a bispecific or trispecific antigen-binding protein.

[0073] In some instances, the antigen-binding protein is a bispecific antigen-binding protein that binds and / or detects TACI and / or engages / activates other immune cells, such as NK cells, T lymphocytes, other B lymphocytes, etc.

[0074] In some instances, the antigen-binding protein can be expressed on CAR-T cells or NK cells or T or NK cell-engaging bispecific / multispecific antibodies to treat proliferative diseases, such as tumors or cancers, more particularly TACI-positive cancers.

[0075] In some instances, the antigen-binding protein is a bispecific antigen-binding protein that binds to and / or detects TACI and CD3.

[0076] In some instances, the antigen-binding protein is a recombinant / fusion polypeptide that comprises an immunoglobulin Fc fragment (region / domain), a protein capable of extending the half-life of the recombinant / fusion polypeptide (e.g., albumin, human albumin, etc.), a linker capable of enhancing binding avidity (e.g., a rigid linker or a flexible linker), or a combination thereof. For example, wherein the immunoglobulin Fc fragment is an IgG Fc fragment, such as a human IgG Fc fragment.

[0077] In some instances, the antigen-binding protein is an antibody, optionally a monoclonal antibody.

[0078] In some instances, the antigen-binding protein is a humanized antibody.

[0079] In some instances, the antigen-binding protein is a neutralizing antibody.

[0080] In some instances, the antigen-binding proteins described herein can induce / mediate antibody-dependent cell cytotoxicity (ADCC).

[0081] In some instances, the antigen-binding proteins described herein can induce the death of TACI-positive multiple myeloma cells (e.g., MMCL MM1R) in the presence of leukocytes (e.g., PBMC).

[0082] In some instances, the antigen-binding protein has a heavy chain variable region that has an amino acid sequence that is at least 80% identical, or 85% identical, or 90% identical, or 95% identical, or 97% identical, or 98% identical, or 99% identical, or 100% identical to the sequence comprising SEQ ID NO:7 or has 1 or 2 amino acids different from its sequence, or a fragment thereof.

[0083] As disclosed herein, SEQ ID NO:7 is as follows: DVQLQESGPGLVKPSQSLSLTCTVS GFSITSDY A WHWIRQFPGNKLEWVGY ISYSGST RYNPSLNSRISITRDTSKNQFFLQLKSVTTEDTATYFC ARVVSTSFDS WGLGTTLTVSSAKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGS (SEQ ID NO:7), wherein the underlines indicate the CDR regions.

[0084] In some instances, the antigen-binding protein has a heavy-chain variable region that comprises SEQ ID NO:7 or has an amino acid sequence that is at least 80% identical to the sequence or has 1 or 2 amino acids different from its sequence, or a fragment thereof.

[0085] In some instances, the antigen-binding protein has a light-chain variable region that has an amino acid sequence that is at least 80% identical, or 85% identical, or 90% identical, or 95% identical, or 97% identical, or 98% identical, or 99% identical, or 100% identical to the sequence comprising SEQ ID NO:8 or has 1 or 2 amino acids different from its sequence, or a fragment thereof.

[0086] As disclosed herein, SEQ ID NO:8 is as follows: GIVLTQSPPSLAVSLGQRATISCRAS ESVDNYG ISF MNWFQQKPGQP PKLLIY VAS NQGSGVPARFSGSGSGTDFSLNIHPMEEDDTAMYFC Q QSKEVPYT FGGGTKLEIKR (SEQ ID NO:8), where the underlined regions indicate the CDR regions.

[0087] In some instances, the antigen-binding protein has a light-chain variable region that comprises SEQ ID NO:8 or an amino acid sequence that is at least 80% identical to the sequence or has 1 or 2 amino acids different from its sequence, or a fragment thereof.

[0088] In some instances, the antigen-binding protein has one or more CDR regions encoded by a polynucleotide sequence that is at least 85% identical, or 90% identical, or 95% identical, or 97% identical, or 98% identical, or 99% identical, or 100% identical to a sequence selected from the group consisting of: GGCTTCTCAATCACCAGTGATTATGCC (SEQ ID NO:12), ATAAGTTACAGTGGTAGCACT (SEQ ID NO:13), GCAAGAGTTGTATCTACGTCTTTTGACTCC (SEQ ID NO:14), GAAAGTGTTGATAATTATGGCATTAGTTTT (SEQ ID NO:15), GTTGCATCC (SEQ ID NO:16), and CAGCAAAGTAAGGAGGTTCCGTACACG (SEQ ID NO:17).

[0089] Heavy chain

[0090] GGCTTCTCAATCACCAGTGATTATGCC (CDRH1; SEQ ID NO:12) ATAAGTTACAGTGGTAGCACT (CDRH2; SEQ ID NO:13)

[0091] GCAAGAGTTGTATCTACGTCTTTTGACTCC (CDRH3; SEQ ID NO:14)

[0092] Light chain

[0093] GAAAGTGTTGATAATTATGGCATTAGTTTT (CDRL1; SEQ ID NO:15)

[0094] GTTGCATCC (CDRL2; SEQ ID NO:16)

[0095] CAGCAAAGTAAGGAGGTTCCGTACACG (CDRL3; SEQ ID NO:17)

[0096] In some instances, the antigen-binding protein has one or more CDR regions encoded by the following polynucleotide sequences: a polynucleotide sequence selected from the group consisting of GGCTTCTCAATCACCAGTGATTATGCC (SEQ ID NO:12) for CDRH1, ATAAGTTACAGTGGTAGCACT (SEQ ID NO:13) for CDRH2, GCAAGAGTTGTATCTACGTCTTTTGACTCC (SEQ ID NO:14) for CDRH3, GAAAGTGTTGATAATTATGGCATTAGTTTT (SEQ ID NO:15) for CDRL1, GTTGCATCC (SEQ ID NO:16) for CDRL2, and CAGCAAAGTAAGGAGGTTCCGTACACG (SEQ ID NO:17) for CDRL3, or a polynucleotide that is at least 85% identical to the sequence.

[0097] In some instances, the antigen-binding protein has a heavy chain variable region encoded by a polynucleotide sequence that is at least 70%, or 75%, or 80%, or 85%, or 90%, or 95%, or 97%, or 98%, or 99%, or 100% identical to the sequence comprising SEQ ID NO:9.

[0098] As disclosed herein, SEQ ID NO:9 is as follows: GATGTGCAGCTTCAGGAGTCGGGACCTGGCCTGGTGAAACCTTCTCAGTCTCTGTCCCTCACCTGCACTGTCTCT GGCTTCTCAATCACCAGTGATTATGCC TGGCACTGGATCCGGCAGTTTCCAGGAAACAAACTGGAGTGGGTGGGCTAC ATAAGTTACAGTGGTAGCACT CGCTACAACCCATCTCTCAACAGTCGAATCTCTATCACTCGAGACACATCCAAGAACCAGTTCTTCCTGCAGTTGAAATCTGTGACTACTGAGGACACAGCCACATATTTTTGT GCAAGAGTTGTATCTACGTCTTTTGACTCC TGGGGCCTAGGCACCACTCTCACAGTTTCCTCAGCCAAAACGACACCCCCATCTGTCTATCCACTGGCCCCTGGATCTGCTGCCCAAACTAACTCCATGGTGACCCTGGGATGCCTGGTCAAGGGCTATTTCCCTGAGCCAGTGACAGTGACCTGGAACTCTGGATCCCTGTCCAGCGGTGTGCACACCTTCT(SEQ ID NO:9), wherein the underlined regions are the CDR regions.

[0099] In some examples, the antigen-binding protein has a heavy chain variable region encoded by a polynucleotide sequence comprising SEQ ID NO:9 or a sequence that is at least 70% identical to said sequence.

[0100] In some examples, the antigen-binding protein comprises a light chain variable region encoded by a polynucleotide sequence that is at least 70% identical, or 75% identical, or 80% identical, or 85% identical, or 90% identical, or 95% identical, or 97% identical, or 98% identical, or 99% identical, or 100% identical to a sequence comprising SEQ ID NO:10.

[0101] As disclosed herein, SEQ ID NO:10 is as follows: GGCATTGTGCTGACCCAATCTCCACCTTCTTTGGCTGTGTCTCTAGGGCAGAGGGCCACCATCTCCTGCAGAGCCAGC GAAAGTGTTGATAATTATGGCATTAGTTTT ATGAACTGGTTCCAACAGAAACCAGGACAGCCACCCAAACTCCTCATCTAT GTTGCATCCAACCAAGGATCCGGGGTCCCTGCCAGGTTTAGTGGCAGTGGGTCTGGGACAGACTTCAGCCTCAACATCCATCCTATGGAGGAGGATGATACTGCAATGTATTTCTGT CAGCAAAGTAAGGAGGTTCCGTACACG TTCGGAGGGGGGACCAAGCTGGAAATCAAACGG(SEQ ID NO:10), where the underlined part represents the CDR region.

[0102] In some instances, the antigen-binding protein comprises a light chain variable region encoded by a polynucleotide sequence comprising SEQ ID NO:10 or a sequence that is at least 70% identical to said sequence.

[0103] In some instances, the antibody can be a bivalent Y-shaped molecule that comprises two identical heavy chains and two identical light chains. Disulfide bonds link the heavy and light chain pairs as well as the two heavy chains together. Each chain consists of a variable domain that varies in sequence and is responsible for antigen binding, which are called the VH and VL domains for the heavy and light chains, respectively. Each chain also consists of at least one constant domain. In the light chain, there is a single constant domain (CL), while in the heavy chain, there are at least three (CH1, CH2, and CH3), and sometimes four (CH4), depending on the isotype. Five types of mammalian Ig heavy chains are known: α, δ, ε, γ, and μ, where the type of heavy chain defines the class (isotype) of the antibody. In humans, there are five different antibody classes or isotypes, including IgA (which includes IgA1 and IgA2), IgD, IgE, IgG (which includes the subclasses IgG1, IgG2, IgG3, and IgG4), and IgM.

[0104] In some instances, the antibody comprises heavy and light chain variable regions that are fused together to form a single-chain variable domain antibody (scFv) or a single-chain variable domain with an Fc portion (i.e., scFv-Fc, such as a minibody). In some instances, the antibody fragment is a bivalent or divalent single-chain variable fragment that is engineered by linking two scFvs in tandem (i.e., tandem scFv) or in a manner such that they dimerize to form a diabody. In some instances, the antibody is a trivalent single-chain variable fragment that is engineered by linking three scFvs in tandem or in a trimer-forming manner (to form a triabody). In some instances, the antibody is a tetravalent single-chain variable fragment antibody. In some instances, the antibody is a "linear antibody", which is an antibody that comprises a pair of tandem Fd segments (VH-CH1-VH-CH1) that form a pair of antigen-binding regions.

[0105] In some instances, the immunoglobulin fragment can include, but is not limited to, the Fc region / domain, one or more CH regions / domains, Fab, Fab', F(ab')2, single-chain Fv (ScFv) and / or Fv fragment, hinge region / domain, and fragments or portions thereof.

[0106] In some instances, the recombinant / fusion polypeptide can also contain portions of an immunoglobulin molecule or antibody, such as including but not limited to all or portions of the constant heavy chain, variable heavy chain, constant light chain, variable light chain, hinge region, and / or Fc domain of an Ig, and variants thereof. For example, the recombinant / fusion polypeptides described herein can be combined with portions of human IgG.

[0107] The amino acid composition of the light chain and / or heavy chain variable region of an antibody can be modified by amino acid insertions, deletions, or substitutions. An amino acid "substitution" includes replacement of an amino acid residue at a specific position in a polypeptide sequence with a different amino acid. In some instances, the substitution involves an amino acid residue that is not naturally occurring (not naturally occurring in that organism or in any organism) at a particular position. Alternatively, one or more substitutions can be amino acid residues that are residues that frequently occur in the sequences of similar related polypeptides in the same organism, such as conserved amino acid residues that frequently occur in the sequences of other antibodies from the same species. Substitution with conserved residues from a naturally occurring sequence (e.g., a human sequence) from the same species can reduce the likelihood of increased antigenicity for a polypeptide having one or more substitutions. Additionally, conservation of charge (e.g., relatively higher frequency of the same positively charged, negatively charged, or uncharged species) compared to the sequence of a related polypeptide in the same organism is also considered in the selection of amino acid residues for substitution. These charge considerations can have an impact on maintaining the structure and / or stability of an antibody containing one or more amino acid substitutions. To modify the pI of an antibody, the amino acid substitution involves replacement of an amino acid residue having a positive or negative charge with an amino acid residue having a neutral charge, and vice versa. Exemplary substitutions include, but are not limited to: (1) substitution of a neutrally charged amino acid with a positively charged amino acid to increase pI; (2) substitution of a negatively charged amino acid with a neutral or positively charged amino acid to increase pI; (3) substitution of a neutrally charged amino acid with a negatively charged amino acid to decrease pI; and (4) substitution of a positively charged amino acid with a neutral or negatively charged amino acid to decrease pI.

[0108] Such substitutions, insertions or deletions often involve genetic manipulation or mutagenesis that modifies the original nucleic acid molecule encoding the polypeptide, which is to be modified by inserting, deleting or substituting at least one nucleotide to generate a codon encoding the desired amino acid residue. More particularly, the codon encoding the original amino acid residue is replaced with the codon encoding the amino acid residue to be introduced by said modification. Such nucleic acid modifications can be made by those skilled in the art using well-known techniques such as site-directed mutagenesis or PCR mutagenesis.

[0109] In some instances, amino acid substitutions, insertions or deletions are introduced into one or more of the heavy chain polypeptides of the antibody of interest. In some instances, amino acid substitutions, insertions or deletions are introduced into the variable region of the heavy chain of the antibody of interest. The variable region of the heavy chain is subdivided into hypervariable regions, called complementarity determining regions (CDRs). The three CDRs in the variable region of the heavy chain are named CDR1, CDR2 and CDR3, for each of the variable regions. The CDRs are separated by more conserved regions called framework regions (FRs). These FR regions are specific for positioning the contact amino acid residues of the CDRs, which are responsible for most of the binding capacity of the antibody, in an appropriate spatial conformation. Each VH consists of three CDRs and four FRs, which are arranged in the following order from the amino terminus to the carboxyl terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The exact boundaries of these CDRs are defined differently according to different systems. The system described by Kabat (Kabat et al., Sequences of Proteins of Immunological Interest (National Institutes of Health, Bethesda, Md. (1987) and (1991)), which is hereby incorporated by reference in its entirety) as used herein (when referring to residues of the variable region of the heavy chain) not only provides a clear residue numbering system applicable to any variable region of an antibody, but also provides precise residue boundaries defining the three CDRs. These CDRs are referred to as Kabat CDRs.

[0110] In some instances, the antigen-binding protein is an antibody having an isotype selected from the group consisting of IgG, IgA, IgM, IgE, IgD, IgY, and the like.

[0111] In some instances, the antigen-binding protein is an antibody selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgA1, IgA2, and the like.

[0112] In some instances, the antigen-binding protein is expressed on chimeric antigen receptor T cells (CAR T cells) and / or chimeric antigen receptor NK cells (CAR NK cells).

[0113] In some aspects, provided are methods of detecting TACI-positive cells (e.g., TACI-positive tumors or cancers), which include contacting the cells with the antigen-binding proteins disclosed herein. In some instances, the method of detecting TACI-positive cells can be a method of diagnosing a disease.

[0114] In another aspect, provided are polynucleotides encoding the antigen-binding proteins described herein.

[0115] In some instances, the polynucleotide comprises SEQ ID NO:9 and / or 10.

[0116] In yet another aspect, provided are vectors expressing the antigen-binding proteins or polynucleotides described herein. In some instances, provided are cloning or expression vectors expressing the antigen-binding proteins or polynucleotides disclosed herein.

[0117] In some instances, the vector is a bicistronic vector expressing the constant region of IgG (e.g., the constant region of trastuzumab IgG1).

[0118] In some instances, the vector further comprises an antibiotic resistance gene (e.g., zeocin resistance gene) to produce chimeric antigen-binding proteins.

[0119] In yet another aspect, provided are host cells comprising the vectors described herein.

[0120] In yet another aspect, provided are compositions comprising the antigen-binding proteins described herein.

[0121] In yet another aspect, provided are pharmaceutical compositions comprising the antigen-binding proteins described herein, and suitable pharmaceutical excipients / carriers / additives. In some instances, provided are pharmaceutical compositions comprising the antigen-binding proteins disclosed herein, and suitable pharmaceutical excipients, diluents, carriers or additives.

[0122] In yet another aspect, provided are the antigen-binding proteins or compositions or pharmaceutical compositions described herein for use in therapy and / or immunotherapy and / or as a therapeutic agent.

[0123] In some instances, the antigen-binding proteins or compositions or pharmaceutical compositions described herein are used for treating proliferative diseases and / or TACI-positive tumors / cancers and / or multiple myeloma (MM) in a subject in need thereof.

[0124] In another aspect, there is provided the use of the antigen-binding proteins or compositions or pharmaceutical compositions described herein in the preparation of a medicament for treating a disease in a subject in need thereof.

[0125] In another aspect, there is provided a method for treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of the antigen-binding proteins or compositions or pharmaceutical compositions of the present disclosure.

[0126] In some instances, the disease is a proliferative disease.

[0127] In some instances, the proliferative disease is a plasma cell-related disease, such as an autoimmune disease and / or a tumor and / or a cancer.

[0128] In some instances, the disease is a TACI-positive tumor / cancer and / or multiple myeloma (MM).

[0129] In another aspect, there is provided a method for neutralizing autoimmune diseases and / or tumor and / or cancer cells in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of the antigen-binding proteins or compositions or pharmaceutical compositions of the present disclosure.

[0130] In some instances, the disease is a proliferative disease.

[0131] In some instances, the proliferative disease is a plasma cell-related disease, such as an autoimmune disease and / or a tumor and / or a cancer.

[0132] In some instances, the disease is a TACI-positive tumor / cancer, and / or multiple myeloma (MM).

[0133] In some instances, the antigen-binding protein or composition is administered to the subject by administration methods known in the art, including but not limited to intramuscularly, subcutaneously, intravenously, intraarterially, intraarticularly, intraperitoneally, intranasally, parenterally, etc.

[0134] In some instances, the subject is a mammal, such as a monkey, rabbit, mouse, rat, pig or dog. In some instances, the subject is a human.

[0135] In some instances, the antigen-binding protein can be provided as a kit. Accordingly, kits are provided that contain the antigen-binding proteins disclosed herein. In some instances, the kit may further comprise instructions for using the antigen-binding proteins disclosed herein in its methods.

[0136] Also disclosed are the antigen-binding proteins / antibodies / methods / uses / compositions described herein. Brief Description of the Drawings

[0138] From the following discussion (where applicable, in conjunction with the appended Figure 1 drawings), the exemplary embodiments of the present disclosure will be better understood and will be readily apparent to those of ordinary skill in the art. It should be appreciated that other modifications can be made to the structural regions, constant regions, or variable regions of the antigen-binding proteins without departing from the scope of the invention. Exemplary embodiments are not necessarily mutually exclusive, as some embodiments can be combined with one or more embodiments to form new exemplary embodiments. The exemplary embodiments should not be construed as limiting the scope of the present disclosure.

[0139] Figure 1 Shown is the generation of anti-human TACI monoclonal antibodies by using DNA vaccination and hybridoma technology. (A) FACS analysis of TACI binding of three clones (T11C5, T20F2, and T21D11) of anti-TACI antibodies, where HEK 293T (HEK 293-TACI) cells expressing TACI (blue line) were used. Parental HEK 293T cells (red line) were used as a negative control. (B) FACS analysis of TACI binding of antibody clone T11C5, where MMCLs (MM1R and RPMI8226) expressing TACI were used. TACI-negative MMCLs (KMS28 and H929) were used as controls.

[0140] Figure 2 Shown are the Ig heavy and light chain sequences of anti-TACI monoclonal antibody T11C5 and specificity verification. (A) DNA sequences of the Ig heavy and light chains of mouse anti-human TACI antibody T11C5. (B) Protein sequences of the Ig heavy and light chains of T11C5. (C) FACS analysis of TACI binding of chimeric antibody T11C5 containing the variable region of mouse T11C5 antibody and the constant region of human IgG1 antibody, where HEK 293T cells expressing TACI were used. HEK 293T cells expressing BCMA were used as a negative control. (D) FACS analysis of the killing of MMCL MM1R human PBMCs expressing TACI mediated by a T cell-redirecting and TACI-targeting bispecific antibody (BsAb) having the Ig variable sequence of T11C5.

[0141] Experimental section

[0142] Generation of mouse anti - human TACI antibody

[0143] Balb / c mice (InVivos Pte Ltd, Singapore) were immunized via hydrodynamic tail vein (HTV) injection with DNA plasmids in lactated Ringer's solution. Mice were primed first with an injection of 10 μg of mFlt3L plasmid DNA. Three days after priming, the mice were immunized weekly via HTV injection with 50 μg of hTACI plus 2.5 μg of mGM-CSF and 2.5 μg of mIL-21 DNA plasmids for 4 weeks. After a 2-month rest, 3 days before sacrificing the mice, a final dose of HTV immunization was used to boost the mice.

[0144] Spleen cells were harvested from the immunized mice and fused with SP2 / 0 mouse myeloma cells (ATCC, USA) by using the ClonaCell TM -HY Hybridoma Kit (Stem Cell Technologies, Canada). Clones producing anti-hTACI antibodies were screened by flow cytometry using 293T cells expressing hTACI.

[0145] A total of three positive antibody clones, namely T11C5, T20F2, and T21D11, which specifically bind to HEK 293T (HEK 293T-TACI) cells expressing TACI ( Figure 1 A). Next, several multiple myeloma cell lines (MMCLs), such as MM1R, RPMI 8226, KMS28, and H929, were stained. The inventors found that the antibodies disclosed herein, such as T11C5, were able to specifically stain MM1R and RPMI 8226 expressing TACI, but not TACI-negative KMS28 and H929 ( Figure 1 B).

[0146] Sequencing of anti - human TACI antibody T11C5

[0147] After subcloning the positive clones of the hybridoma cells, the genes encoding the variable (V) regions of the immunoglobulin (Ig) heavy and light chains (HC and LC) were amplified by PCR and cloned using the TArget Clone-Plus Kit (TOYOBO), followed by sequencing. The cDNA and translated protein sequences of the VH and VL fragments of clone T11C5 are shown in Figure 2 A and 2B, respectively.

[0148] Specificity of anti - human TACI antibody T11C5

[0149] The inventors further cloned the VH and VL gene fragments into a triple-cistronic vector expressing the constant region of trastuzumab IgG1 and the zeocin resistance gene to generate a chimeric anti-hTACI monoclonal antibody. FACS analysis confirmed that the chimeric anti-TACI antibody could specifically bind to TACI( Figure 2 C). Additionally, the inventors generated a bispecific antibody (bsAb) TACI×CD3 and found that the bsAb could kill TACI-positive MMCL MM1R in the presence of PBMC( Figure 2 D).

Claims

1. An antigen-binding protein that specifically binds to and / or detects the transmembrane activator and calcium modulator and cyclophilin ligand (CAML) interactor (TACI) / TNFRSF13B, wherein the antigen-binding protein comprises CDR sequences having GFSITSDYA (SEQ ID NO:1) for CDRH1, ISYSGST (SEQ ID NO:2) for CDRH2, ARVVSTSFDS (SEQ ID NO:3) for CDRH3, ESVDNYGISF (SEQ ID NO:4) for CDRL1, VAS (SEQ ID NO:5) for CDRL2, and QQSKEVPYT (SEQ ID NO:6) for CDRL3, or having an amino acid sequence that is at least 85% identical to the sequence, or having a sequence with 1 or 2 amino acids different from its sequence.

2. The antigen-binding protein according to claim 1, wherein the antigen-binding protein activates transcription factor AP-1 and / or NF-κB.

3. The antigen-binding protein according to claim 1 or 2, wherein the antigen-binding protein is capable of regulating TACI-induced B cell activation and / or differentiation.

4. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein is a multi-specific antigen-binding protein that binds to and / or detects TACI and / or engages / activates other immune cells, optionally wherein the antigen-binding protein is a bispecific antigen-binding protein that binds to and / or detects TACI and CD3.

5. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein is a monoclonal antibody.

6. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein is a neutralizing antibody and / or a humanized antibody.

7. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein has a heavy chain variable region that comprises SEQ ID NO:7 or has an amino acid sequence that is at least 80% identical to the sequence or has 1 or 2 amino acids different from its sequence, or a fragment thereof.

8. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein has a light chain variable region that comprises SEQ ID NO:8 or an amino acid sequence that is at least 80% identical to the sequence or has 1 or 2 amino acids different from its sequence, or a fragment thereof.

9. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein has one or more CDR regions encoded by the following polynucleotide sequences: a polynucleotide sequence selected from the group consisting of GGCTTCTCAATCACCAGTGATTATGCC (SEQ ID NO:12) for CDRH1, ATAAGTTACAGTGGTAGCACT (SEQ ID NO:13) for CDRH2, GCAAGAGTTGTATCTACGTCTTTTGACTCC (SEQ ID NO:14) for CDRH3, GAAAGTGTTGATAATTATGGCATTAGTTTT (SEQ ID NO:15) for CDRL1, GTTGCATCC (SEQ ID NO:16) for CDRL2, and CAGCAAAGTAAGGAGGTTCCGTACACG (SEQ ID NO:17) for CDRL3, or a polynucleotide that is at least 85% identical to the sequence.

10. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein has a heavy chain variable region encoded by a polynucleotide sequence comprising SEQ ID NO:9 or a sequence that is at least 70% identical to the sequence.

11. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein comprises a light chain variable region encoded by a polynucleotide sequence comprising SEQ ID NO:10 or a sequence that is at least 70% identical to the sequence.

12. The antigen-binding protein according to any one of the preceding claims, wherein the antigen-binding protein is expressed on chimeric antigen receptor T cells (CAR T cells) and / or chimeric antigen receptor NK cells (CAR NK cells).

13. A polynucleotide encoding the antigen-binding protein according to any one of the preceding claims.

14. The polynucleotide according to claim 12, wherein the polynucleotide comprises SEQ ID NO:9 and / or 10.

15. A cloning or expression vector that expresses the antigen-binding protein according to any one of claims 1 to 12 or the polynucleotide according to any one of claims 13 or 14.

16. A host cell comprising the vector according to claim 15.

17. A pharmaceutical composition comprising the antigen-binding protein according to any one of claims 1 to 12, and a suitable pharmaceutical excipient, diluent, carrier or additive thereof.

18. The antigen-binding protein, composition or pharmaceutical composition according to any one of claims 1 to 12, for use in therapy and / or immunotherapy and / or as a therapeutic agent.

19. The antigen-binding protein according to any one of claims 1 to 12 or the pharmaceutical composition according to claim 17, for use in treating a proliferative disease and / or a TACI-positive tumor / cancer and / or multiple myeloma (MM) in a subject in need thereof.

20. Use of the antigen-binding protein or composition or pharmaceutical composition according to any one of claims 1 to 12 in the manufacture of a medicament for treating a disease in a subject in need thereof, optionally wherein the disease is a proliferative disease, optionally wherein the disease is a TACI-positive tumor / cancer, and / or multiple myeloma (MM).

21. A method of treating a disease in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of the antigen-binding protein or composition or pharmaceutical composition according to any one of claims 1 to 12 to the subject.

22. A method of neutralizing an autoimmune disease and / or tumor and / or cancer cells in a subject in need thereof, wherein the method comprises administering a therapeutically effective amount of the antigen-binding protein or composition or pharmaceutical composition according to any one of claims 1 to 12 to the subject.

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