Trispecific binding proteins, methods, and uses thereof

TWI932491BActive Publication Date: 2026-07-21SANOFI SA(FR)
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Patent Information

Application Number
TW109111809
Authority / Receiving Office
TW · TW
Patent Type
Patents
Current Assignee / Owner
Priority Date
2019-10-02
Filing Date
2020-04-08
Publication Date
2026-07-21
Estimated Expiration
2040-04-07

AI Technical Summary

Technical Problem

Current monoclonal antibody-based therapies face limitations in effectively targeting and activating T cells to combat complex diseases such as cancer and chronic viral infections, as tumor-specific T cells are often restricted and viral infections induce immunosuppression and latency, hindering their therapeutic potential.

Method used

Development of trispecific binding proteins with three antigen binding sites that specifically target CD28, CD3, and tumor-associated antigens like HER2 or CD38, recruiting and activating T cells to kill nearby cancer cells or expand virus-specific memory T cells, utilizing a staggered orientation of dual variable domains for enhanced efficacy.

Benefits of technology

The trispecific binding proteins effectively recruit and activate T cells to kill cancer cells and expand virus-specific memory T cells, providing therapeutic potential for cancer treatment and chronic infections by enhancing T cell activation and proliferation.

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Abstract

This document provides trispecific and / or trivalent binding proteins comprising four polypeptide chains forming three antigen-binding sites that specifically bind to one or more target proteins, wherein a first pair of polypeptides forming the binding protein has dual variable domains with staggered orientations, and wherein a second pair of polypeptides has a single variable domain forming a single antigen-binding site. In some embodiments, the binding protein comprises a binding site for binding a CD28 polypeptide, a binding site for binding a CD3 polypeptide, and a binding site for binding a third polypeptide (e.g., a tumor target protein). This document also relates to methods for preparing trispecific and / or trivalent binding proteins and uses of such binding proteins.
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Description

Technical field

Prior Technology

Content of invention

Implementation

Claims

1. A binding protein comprising four polypeptide chains forming three antigen-binding sites, wherein the first polypeptide chain comprises a structure represented by the following formula: VL2-L1-VL1-L2-CL[I] and the second polypeptide chain comprises a structure represented by the following formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and the third polypeptide chain comprises a structure represented by the following formula: VH3-CH1-hinge-CH2-CH3[III] and the fourth polypeptide chain comprises a structure represented by the following formula: VL3-CL[IV] wherein: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3 is an immunoglobulin CH3 heavy chain constant domain; a hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3, and L4 are amino acid linkers; wherein the polypeptide of Formula I and the polypeptide of Formula II form an interleaved light chain-heavy chain pair; and wherein VH1 and VL1 form a first antigen binding site; VH2 and VL2 form a second antigen-binding site for the CD3 polypeptide. The VH2 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence containing the amino acid sequence IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence containing the amino acid sequence RGVYYALSPFDY (SEQ ID NO: 57). The VL2 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHX1NX2X3TY (SEQ ID NO: 180) where X1 is E or Q, X2 is A or L, and X3 is Q, R, or F; a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 64); and a CDR-H3 sequence containing GQGTQYPFT (SEQ ID NO: 57). The CDR-L3 sequence of the amino acid sequence of 65); and VH3 and VL3 form the third antigen binding site.

2. The binding protein as claimed in claim 1, wherein the first binding site binds the CD28 polypeptide.

3. The binding protein as claimed in claim 2, wherein the VH1 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYTFTSYY (SEQ ID NO: 49), a CDR-H2 sequence containing the amino acid sequence IYPGNVNT (SEQ ID NO: 50), and a CDR-H3 sequence containing the amino acid sequence TRSHYGLDWNFDV (SEQ ID NO: 51); and the VL1 domain comprises: a CDR-L1 sequence containing the amino acid sequence QNIYVW (SEQ ID NO: 52), a CDR-L2 sequence containing the amino acid sequence KAS (SEQ ID NO: 53), and a CDR-L3 sequence containing the amino acid sequence QQGQTYPY (SEQ ID NO: 54).

4. The binding protein as claimed in claim 3, wherein the VH1 domain comprises the amino acid sequence QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGNVNTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDVWGKGTTVTVSS (SEQ ID NO: 91), and / or the VL1 domain comprises the amino acid sequence DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQGQTYPYTFGQGTKLEIK (SEQ ID NO: 92).

5. The binding protein as claimed in any one of claims 1 to 4, wherein the CDR-L1 sequence of the VL2 domain comprises an amino acid sequence selected from the following: QSLVHQNAQTY (SEQ ID NO: 59), QSLVHENLQTY (SEQ ID NO: 60), QSLVHENLFTY (SEQ ID NO: 61) and QSLVHENLRTY (SEQ ID NO: 62).

6. The binding protein as claimed in claim 5, wherein the VH2 domain comprises QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93) or QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYASSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93). The amino acid sequence of 302), and / or the VL2 domain comprising an amino acid sequence selected from the following: DIVMTQTPLSLSVTPGQPASISCKSSQSLVHQNAQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95). 96), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 97) and DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLRTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 98).

7. The binding protein as claimed in any one of claims 1 to 6, wherein the third antigen binding site binds to the tumor target protein.

8. The binding protein as claimed in any one of claims 1 to 6, wherein the third antigen binding site binds to the human CD38 polypeptide.

9. The binding protein as described in claim 8, wherein: (a) The VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYTFTSYA (SEQ ID NO: 13), a CDR-H2 sequence containing the amino acid sequence IYPGQGGT (SEQ ID NO: 14), and a CDR-H3 sequence containing the amino acid sequence ARTGGLRRAYFTY (SEQ ID NO: 15); and the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSVSSYGQGF (SEQ ID NO: 16), a CDR-L2 sequence containing the amino acid sequence GAS (SEQ ID NO: 17), and a CDR-L3 sequence containing the amino acid sequence QQNKEDPWT (SEQ ID NO: 18); (b) The VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYTLTEFS (SEQ ID NO: 19), a CDR-H2 sequence containing the amino acid sequence FDPEDGET (SEQ ID NO: 18), and a CDR-H3 sequence containing the amino acid sequence GYTLTEFS (SEQ ID NO: 19). (c) The VL3 domain comprises: a CDR-H2 sequence containing the amino acid sequence QSVISRF (SEQ ID NO: 22), a CDR-H3 sequence containing the amino acid sequence TTGRFFDWF (SEQ ID NO: 21); and the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSVISRF (SEQ ID NO: 22), a CDR-L2 sequence containing the amino acid sequence GAS (SEQ ID NO: 23), and a CDR-L3 sequence containing the amino acid sequence QQDSNLPIT (SEQ ID NO: 24); and the VL3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYAFTTYL (SEQ ID NO: 25), a CDR-H2 sequence containing the amino acid sequence INPGSGST (SEQ ID NO: 26), and a CDR-H3 sequence containing the amino acid sequence ARYAYGY (SEQ ID NO: 27); and the VL3 domain comprises: a CDR-H3 sequence containing the amino acid sequence QNVGTA (SEQ ID NO: 28). (d) The VH3 domain comprises: a CDR-L1 sequence containing the amino acid sequence of SEQ ID NO: 28), a CDR-L2 sequence containing the amino acid sequence of SAS (SEQ ID NO: 29), and a CDR-L3 sequence containing the amino acid sequence of QQYSTYPFT (SEQ ID NO: 30);The VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHSNGNTY (SEQ ID NO: 34), a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 35), and a CDR-L3 sequence containing the amino acid sequence SQSTHVPLT (SEQ ID NO: 36); (e) the VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFSSYG (SEQ ID NO: 37), a CDR-H2 sequence containing the amino acid sequence IWYDGSNK (SEQ ID NO: 38), and a CDR-H3 sequence containing the amino acid sequence ARDPGLRYFDGGMDV (SEQ ID NO: 39); and the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QGISSY (SEQ ID NO: 40), a CDR-L2 sequence containing the amino acid sequence AAS (SEQ ID NO: 39), and a CDR-L3 sequence containing the amino acid sequence AAS (SEQ ID NO: 39). 41) The CDR-L2 sequence of the amino acid sequence and the CDR-L3 sequence of the amino acid sequence containing QQLNSFPYT (SEQ ID NO: 42); or (f) the VH3 domain comprises: the CDR-H1 sequence of the amino acid sequence containing GFTFSSYG (SEQ ID NO: 43), the CDR-H2 sequence of the amino acid sequence containing IWYDGSNK (SEQ ID NO: 44), and the CDR-H3 sequence of the amino acid sequence containing ARMFRGAFDY (SEQ ID NO: 45); and the VL3 domain comprises: the CDR-L1 sequence of the amino acid sequence containing QGIRND (SEQ ID NO: 46), the CDR-L2 sequence of the amino acid sequence containing AAS (SEQ ID NO: 47), and the CDR-L3 sequence of the amino acid sequence containing LQDYIYYPT (SEQ ID NO: 48).

10. The binding protein as claimed in claim 9, wherein: (a) The VH3 domain contains the amino acid sequence QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYAMHWVKEAPGQRLEWIGYIYPGQGGTNYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFCARTGGLRRAYFTYWGQGTLVTVSS (SEQ ID NO: 79), and / or the VL3 domain contains the amino acid sequence DIVLTQSPATLSLSPGERATISCRASQSVSSYGQGFMHWYQQKPGQPPRLLIYGASSRATGIPARFSGSGSGTDFTLTISPLEPEDFAVYYCQQNKEDPWTFGGGTKLEIK (SEQ ID NO: 80); (b) The VH3 domain contains the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKVSGYTLTEFSIHWVRQAPGQGLEWMGGFDPEDGETIYAQKFQGRVIMTEDTSTDTAYMEMNSLRSEDTAIYYCTTGRFFDWFWGQGTLVTVSS (SEQ ID NO: 81), and / or the VL3 domain contains the amino acid sequence EIILTQSPAILSLSPGERATLSCRASQSVISRFLSWYQVKPGLAPRLLIYGASTRATGIPVRFSGSGSGTDFSLTISSLQPEDCAVYYCQQDSNLPITFGQGTRLEIK (SEQ ID NO: 82); (c) The VH3 domain contains the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYLVEWIRQRPGQGLEWMGVINPGSGSTNYAQKFQGRVTMTVDRSSTTAYMELSRLRSDDTAVYYCARYAYGYWGQGTLVTVSS (SEQ ID NO: 83), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQNVGTAVAWYQQKPGKSPKQLIYSASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYSTYPFTFGQGTKLEIK (SEQ ID NO: 84);(d) The VH3 domain contains the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYAVHWVRQAPGQGLEWMGVISPYYGDTTYAQKFQGRVTMTVDKSSSTAYMELSRLRSDDTAVYYCARRFEGFYYSMDYWGQGTLVTVSS (SEQ ID NO: 85), and / or the VL3 domain contains the amino acid sequence DVVMTQSPLSLPVTLGQPASISCRPSQSLVHSNGNTYLNWYQQRPGQSPKLLIYKVSKRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGGGTKVEIK (SEQ ID NO: 86); (e) The VH3 domain contains the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMYWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCARDPGLRYFDGGMDVWGQGTTVTVSS (SEQ ID NO: 87), and / or the VL3 domain contains the amino acid sequence DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIFAASTLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSFPYTFGQGTKLEIK (SEQ ID NO: 88); or (f) The VH3 domain contains the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYCARMFRGAFDYWGQGTLVTVSS (SEQ ID NO: 89), and / or the VL3 domain contains the amino acid sequence AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYCLQDYIYYPTFGQGTKVEIK (SEQ ID NO: 90).

11. The binding protein as described in claim 8, wherein: (a) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159; (b) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160; The first polypeptide chain contains an amino acid sequence of SEQ ID NO: 161 that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; the third polypeptide chain contains an amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; and the fourth polypeptide chain contains an amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; (c) the first polypeptide chain contains an amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain contains an amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the third polypeptide chain contains an amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; and the fourth polypeptide chain contains an amino acid sequence of SEQ ID NO: 161 that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; and the fourth polypeptide chain contains an amino acid sequence of SEQ ID NO: 161 that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; (d) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;The fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; (e) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175; (f) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

175. The first polypeptide chain contains at least 95% identical amino acid sequences of SEQ ID NO: 176; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; (g) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 181; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 182; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 176; the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 177; the fifth polypeptide chain contains the amino acid sequence of SEQ ID NO: 178; the sixth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the seventh polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the eighth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the ninth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the tenth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the eleven ... The fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 183; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 184; or (h) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185;The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

188.

12. The binding protein as claimed in any one of claims 1 to 7, wherein the third antigen binding site binds to the human HER2 polypeptide.

13. The binding protein as described in claim 12, wherein: (a) The VH3 domain comprises: a CDR-H1 sequence containing an amino acid sequence of GFNIKDTY (SEQ ID NO: 1) or GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence containing an amino acid sequence of IYPTNGYT (SEQ ID NO: 3), IYPTQGYT (SEQ ID NO: 4) or IYPTNAYT (SEQ ID NO: 5), and a CDR-H3 sequence containing an amino acid sequence of SRWGGDGFYAMDY (SEQ ID NO: 6), SRWGGEGFYAMDY (SEQ ID NO: 7), or SRWGGSGFYAMDY (SEQ ID NO: 8); and the VL3 domain comprises: a CDR-L1 sequence containing an amino acid sequence of QDVNTA (SEQ ID NO: 9) or QDVQTA (SEQ ID NO: 10), a CDR-H2 sequence containing an amino acid sequence of SAS (SEQ ID NO: 10), and a CDR-H3 sequence containing an amino acid sequence of GFNIKDTY (SEQ ID NO: 10). (a) The VH3 domain comprises: (b) the CDR-L2 sequence of an amino acid sequence containing GFNIKDTY (SEQ ID NO: 1), the CDR-L3 sequence of an amino acid sequence containing QQHYTTP (SEQ ID NO: 12); and (c) the VH3 domain comprises: (a) the CDR-L1 sequence of an amino acid sequence containing GFNIKDTY (SEQ ID NO: 1), the CDR-L2 sequence of an amino acid sequence containing IYPTNGYT (SEQ ID NO: 3), and the CDR-L3 sequence of an amino acid sequence containing SRWGGDGFYAMDY (SEQ ID NO: 6); and the VL3 domain comprises: (a) the CDR-L1 sequence of an amino acid sequence containing QDVNTA (SEQ ID NO: 9), the CDR-L2 sequence of an amino acid sequence containing SAS (SEQ ID NO: 11), and the CDR-L3 sequence of an amino acid sequence containing QQHYTTP (SEQ ID NO: 12); The CDR-H1 sequence of the amino acid sequence NO: 2), the CDR-H2 sequence of the amino acid sequence containing IYPTQGYT (SEQ ID NO: 4), and the CDR-H3 sequence of the amino acid sequence containing SRWGGEGFYAMDY (SEQ ID NO: 7); and the VL3 domain comprises: the CDR-L1 sequence of the amino acid sequence containing QDVNTA (SEQ ID NO: 9), the CDR-L2 sequence of the amino acid sequence containing SAS (SEQ ID NO: 11), and the CDR-L3 sequence of the amino acid sequence containing QQHYTTP (SEQ ID NO: 12);(d) The VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence containing the amino acid sequence IYPTNAYT (SEQ ID NO: 5), and a CDR-H3 sequence containing the amino acid sequence SRWGGSGFYAMDY (SEQ ID NO: 8); and the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QDVNTA (SEQ ID NO: 9), a CDR-L2 sequence containing the amino acid sequence SAS (SEQ ID NO: 11), and a CDR-L3 sequence containing the amino acid sequence QQHYTTP (SEQ ID NO: 12); (e) The VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFNIRDTY (SEQ ID NO: 2), a CDR-H2 sequence containing the amino acid sequence IYPTQGYT (SEQ ID NO: 2), a CDR-H3 sequence containing the amino acid sequence SRWGGSGFYAMDY (SEQ ID NO: 8), and a CDR-H3 sequence containing the amino acid sequence SRWGGSGFYAMDY (SEQ ID NO: 8). 4) The CDR-H2 sequence of the amino acid sequence and the CDR-H3 sequence of the amino acid sequence containing SRWGGSGFYAMDY (SEQ ID NO: 8); and the VL3 domain comprises: the CDR-L1 sequence of the amino acid sequence containing QDVNTA (SEQ ID NO: 9), the CDR-L2 sequence of the amino acid sequence containing SAS (SEQ ID NO: 11), and the CDR-L3 sequence of the amino acid sequence containing QQHYTTP (SEQ ID NO: 12); (f) The VH3 domain comprises: the CDR-H1 sequence of the amino acid sequence containing GFNIRDTY (SEQ ID NO: 2), the CDR-H2 sequence of the amino acid sequence containing IYPTNAYT (SEQ ID NO: 5), and the CDR-H3 sequence of the amino acid sequence containing SRWGGEGFYAMDY (SEQ ID NO: 7); and the VL3 domain comprises: the CDR-H2 sequence of the amino acid sequence containing QDVNTA (SEQ ID NO: 9), the CDR-H3 sequence of the amino acid sequence containing SAS (SEQ ID NO: 11), and the CDR-H3 sequence of the amino acid sequence containing QQHYTTP (SEQ ID NO: 12); 9) The CDR-L1 sequence of the amino acid sequence, the CDR-L2 sequence of the amino acid sequence containing SAS (SEQ ID NO: 11), and the CDR-L3 sequence of the amino acid sequence containing QQHYTTP (SEQ ID NO: 12); or (g) the VH3 domain comprises: the CDR-H1 sequence of the amino acid sequence containing GFNIKDTY (SEQ ID NO: 1), the CDR-H2 sequence of the amino acid sequence containing IYPTNGYT (SEQ ID NO: 3), and the CDR-H3 sequence of the amino acid sequence containing SRWGGDGFYAMDY (SEQ ID NO: 6);Furthermore, the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QDVQTA (SEQ ID NO: 10), a CDR-L2 sequence containing the amino acid sequence SAS (SEQ ID NO: 11), and a CDR-L3 sequence containing the amino acid sequence QQHYTTP (SEQ ID NO: 12).

14. The binding protein as described in claim 13, wherein: (a) The VH3 domain contains the amino acid sequence of EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 73), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 74), EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 75), or EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 76), and / or the VL3 domain contains the amino acid sequence of DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77) or DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 78);(b) The VH3 domain contains the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77); (c) The VH3 domain contains the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 73), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77); (d) The VH3 domain contains the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 75), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77);(e) The VH3 domain contains the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTQGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGSGFYAMDYWGQGTLVTVSS (SEQ ID NO: 74), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77); (f) The VH3 domain contains the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFNIRDTYIHWVRQAPGKGLEWVARIYPTNAYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGEGFYAMDYWGQGTLVTVSS (SEQ ID NO: 76), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 77); or (g) The VH3 domain contains the amino acid sequence EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSS (SEQ ID NO: 72), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQDVQTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIK (SEQ ID NO: 78).

15. The binding protein as described in claim 12, wherein: (a) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 100 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 100; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 101 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 101; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 102 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 102; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 103 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 103; (b) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 104 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 104; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 105 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 104; The first polypeptide chain contains at least 95% identical amino acid sequences to SEQ ID NO: 105; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 106 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 106; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 107 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 107; (c) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 112 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 112; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 113 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 113; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 114 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 114; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO:

105. (d) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 115 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 115; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 117 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 117; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 118 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 118;The fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 119 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 119; (e) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 120 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 120; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 121 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 121; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 122 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 122; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 123 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 123; (f) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 124 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

123. The first polypeptide chain contains at least 95% identical amino acid sequences to SEQ ID NO: 124; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 125; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 126 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 126; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 127 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 127; (g) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 128 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 128; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 129 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 124; the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 125 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 129; the fifth polypeptide chain contains the amino acid sequence of SEQ ID NO: 124; the sixth polypeptide chain contains the amino acid sequence of SEQ ID NO: 125; the seventh polypeptide chain contains the amino acid sequence of SEQ ID NO: 125; the eighth polypeptide chain contains the amino acid sequence of SEQ ID NO: 125; the ninth polypeptide chain contains the amino acid sequence of SEQ ID NO: 125; the tenth polypeptide chain contains the amino acid sequence of SEQ ID NO: 125; the eleventh polypeptide chain contains the amino acid sequence of SEQ ID NO: 125; the eleventh polypeptide chain contains the amino acid sequence of SEQ ID NO: 125; The fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 130 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 130; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 131 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 131; (h) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 132 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 132;The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 133 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 133; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 134 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 134; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 135 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 135; (i) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 136 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 136; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 137 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 138 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 137; The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 138, which is at least 95% identical to the amino acid sequence of SEQ ID NO: 139; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 141, which is at least 95% identical to the amino acid sequence of SEQ ID NO: 141; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 142, which is at least 95% identical to the amino acid sequence of SEQ ID NO: 142; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 143, which is at least 95% identical to the amino acid sequence of SEQ ID NO: 143; (k) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 140, which is at least 95% identical to the amino acid sequence of SEQ ID NO: 140; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 141, which is at least 95% identical to the amino acid sequence of SEQ ID NO: 143; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 142, which is at least 95% identical to the amino acid sequence of SEQ ID NO: 143; The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 144 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 144; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 145 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 145; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 146 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 146; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 147 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 147.(l) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 148 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 148; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 149 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 149; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 150 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 150; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 151 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 151; (m) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 152 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 152; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 153 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 152; The first polypeptide chain contains an amino acid sequence of SEQ ID NO: 286 or an amino acid sequence of SEQ ID NO: 287 or an amino acid sequence of SEQ ID NO: 287; the second polypeptide chain contains an amino acid sequence of SEQ ID NO: 288 or an amino acid sequence of SEQ ID NO: 288; and the third polypeptide chain contains an amino acid sequence of SEQ ID NO: 288 or an amino acid sequence of SEQ ID NO: 288; and the fourth polypeptide chain contains an amino acid sequence of SEQ ID NO:

287. (o) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 289 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 289; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 291 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 291; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 292 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 292;The fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 293 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 293; (p) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 294 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 294; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 295 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 295; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 296 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 296; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 297 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 297; or (q) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 298 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

297. The first polypeptide chain contains at least 95% identical amino acid sequences to SEQ ID NO: 298; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 299 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 299; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 300 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 300; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 301 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

301.

16. The binding protein as claimed in any one of claims 1 to 15, wherein at least one of L1, L2, L3 or L4 is independently zero amino acid in length.

17. The binding protein of any one of claims 1 to 15, wherein (a) L1, L2, L3 and L4 are each independently zero amino acid in length or comprise a sequence selected from the group consisting of: GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68), GQPKAAP (SEQ ID NO: 67) and GGSGSSGSGG (SEQ ID NO: 71); or (b) L1, L2, L3 and L4 each independently comprise a sequence selected from the group consisting of: GGGGSGGGGS (SEQ ID NO: 69), GGGGSGGGGSGGGGS (SEQ ID NO: 70), S, RT, TKGPS (SEQ ID NO: 68), GQPKAAP (SEQ ID NO: 67) and GGSGSSGSGG (SEQ ID NO: 71).

18. The binding protein as claimed in any one of claims 1 to 15, wherein L1 comprises the sequence GQPKAAP (SEQ ID NO: 67), L2 comprises the sequence TKGPS (SEQ ID NO: 68), L3 comprises the sequence S, and L4 comprises the sequence RT.

19. The binding protein as claimed in any one of claims 1 to 15, wherein at least one of L1, L2, L3 or L4 comprises the sequence DKTHT (SEQ ID NO: 66).

20. The binding protein as claimed in claim 19, wherein L1, L2, L3 and L4 comprise the sequence DKTHT (SEQ ID NO: 66).

21. The binding protein as claimed in any one of claims 1 to 20, wherein the hinge-CH2-CH3 domain of the second and third polypeptide chains is a human IgG4 hinge-CH2-CH3 domain, and wherein each of the hinge-CH2-CH3 domains comprises an amino acid substitution at positions 234 and 235 corresponding to human IgG4 according to the EU index, wherein the amino acid substitution is F234A and L235A.

22. The binding protein as claimed in any one of claims 1 to 20, wherein the hinge-CH2-CH3 domain of the second and third polypeptide chains is a human IgG4 hinge-CH2-CH3 domain, and wherein each of the hinge-CH2-CH3 domains comprises an amino acid substitution at positions 233-236 corresponding to human IgG4 according to the EU index, wherein the amino acid substitution is E233P, F234V, L235A and a deletion at position 236.

23. The binding protein as claimed in any one of claims 1 to 22, wherein the hinge-CH2-CH3 domain of the second and third polypeptide chains is a human IgG4 hinge-CH2-CH3 domain, and wherein each of the hinge-CH2-CH3 domains comprises an amino acid substitution at positions 228 and 409 corresponding to human IgG4 according to the EU index, wherein the amino acid substitution is S228P and R409K.

24. The binding protein as claimed in any one of claims 1 to 20, wherein the hinge-CH2-CH3 domain of the second and third polypeptide chains is a human IgG1 hinge-CH2-CH3 domain, and wherein each of the hinge-CH2-CH3 domains comprises an amino acid substitution at positions 234, 235, and 329 corresponding to human IgG1 according to the EU index, wherein the amino acid substitution is L234A, L235A, and P329A.

25. The binding protein as claimed in any one of claims 1 to 20, wherein the hinge-CH2-CH3 domain of the second and third polypeptide chains is a human IgG1 hinge-CH2-CH3 domain, and wherein each of the hinge-CH2-CH3 domains comprises an amino acid substitution at positions 298, 299, and 300 corresponding to human IgG1 according to the EU index, wherein the amino acid substitution is S298N, T299A, and Y300S.

26. The binding protein of any one of claims 1 to 25, wherein the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions 349, 366, 368, and 407 corresponding to human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V; and wherein the hinge-CH2-CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions 354 and 366 corresponding to human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are S354C and T366W.

27. The binding protein of any one of claims 1 to 25, wherein the hinge-CH2-CH3 domain of the second polypeptide chain comprises amino acid substitutions at positions 354 and 366 corresponding to human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are S354C and T366W; and wherein the hinge-CH2-CH3 domain of the third polypeptide chain comprises amino acid substitutions at positions 349, 366, 368, and 407 corresponding to human IgG1 or IgG4 according to the EU index, wherein the amino acid substitutions are Y349C, T366S, L368A, and Y407V.

28. An isolated nucleic acid molecule comprising a nucleotide sequence encoding a binding protein as described in any one of claims 1 to 27.

29. A representation vector comprising a nucleic acid molecule as described in claim 28.

30. An isolated host cell comprising a nucleic acid molecule as described in claim 28 or an expression vector as described in claim 29.

31. The isolated host cell as described in claim 30, wherein the host cell is a mammalian cell or an insect cell.

32. A pharmaceutical composition comprising a binding protein as described in any one of claims 1 to 27 and a pharmaceutically acceptable carrier.

33. A method for preventing and / or treating cancer in a patient, the method comprising administering to the patient a therapeutically effective amount of at least one binding protein as described in any one of claims 7 to 27 or a pharmaceutical composition as described in claim 32.

34. The method of claim 33, wherein the at least one binding protein is co-administered with the chemotherapeutic agent.

35. The method as described in claim 33 or claim 34, wherein the patient is a human.

36. The method of any one of claims 33 to 35, wherein the third antigen binding site binds to a human CD38 polypeptide, and wherein cancer cells from the patient express CD38.

37. The method as described in claim 36, wherein the cancer is multiple myeloma.

38. The method as described in claim 36, wherein the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or B-cell lymphoma.

39. The method as described in any one of claims 36 to 38, wherein, Prior to administration of the binding protein, the patient had been treated with daratumumab without a clearance period.

40. The method of any one of claims 33 to 35, wherein the third antigen binding site binds to a human HER2 polypeptide, and wherein cancer cells from the patient express HER2.

41. The method as described in claim 40, wherein the cancer is breast cancer, colorectal cancer, gastric cancer, or non-small cell lung cancer (NSCLC).

42. The binding protein as described in any one of claims 7 to 27 or the pharmaceutical composition as described in claim 32, for the prevention and / or treatment of cancer in a patient.

43. The binding protein or composition for the purpose as described in claim 42, wherein the at least one binding protein is administered in conjunction with a chemotherapeutic agent.

44. The binding protein or composition for the purpose as described in claim 42 or claim 43, wherein the patient is a human.

45. The binding protein or composition for the purpose as claimed in any one of claims 42 to 44, wherein the third antigen binding site binds to a human CD38 polypeptide, and wherein cancer cells from the patient express CD38.

46. ​​The binding protein or composition for the purpose as described in claim 45, wherein the cancer is multiple myeloma.

47. The binding protein or composition for the purpose as described in claim 45, wherein the cancer is acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), or B-cell lymphoma.

48. The binding protein or composition for the said use as claimed in any one of claims 45 to 47, wherein, Prior to administration of the binding protein, the patient had been treated with daratumumab without a clearance period.

49. The binding protein or composition for the purpose as claimed in any one of claims 42 to 44, wherein the third antigen binding site binds to a human HER2 polypeptide, and wherein cancer cells from the patient express HER2.

50. The binding protein or composition for the purpose as described in claim 49, wherein the cancer is breast cancer, colorectal cancer, gastric cancer, or non-small cell lung cancer (NSCLC).

51. A method for expanding T cells, the method comprising contacting the T cells with a binding protein comprising four polypeptide chains forming three antigen-binding sites, wherein a first polypeptide chain comprises a structure represented by the following formula: VL2-L1-VL1-L2-CL[I] and a second polypeptide chain comprises a structure represented by the following formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and a third polypeptide chain comprises a structure represented by the following formula: VH3-CH1-hinge-CH2-CH3[III] and a fourth polypeptide chain comprises a structure represented by the following formula: VL3-CL[IV] where: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3 is an immunoglobulin CH3 heavy chain constant domain; a hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3, and L4 are amino acid linkers; wherein the polypeptide of Formula I and the polypeptide of Formula II form an interleaved light chain-heavy chain pair; and wherein VH1 and VL1 form a first antigen-binding site for binding the CD28 polypeptide; VH2 and VL2 form a second antigen-binding site for the CD3 polypeptide. The VH2 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence containing the amino acid sequence IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence containing the amino acid sequence RGVYYALSPFDY (SEQ ID NO: 57). The VL2 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHX1NX2X3TY (SEQ ID NO: 180) where X1 is E or Q, X2 is A or L, and X3 is Q, R, or F; a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 64); and a CDR-H3 sequence containing GQGTQYPFT (SEQ ID NO: 57). The CDR-L3 sequence of the amino acid sequence of 65); and VH3 and VL3 form the third antigen binding site for binding the CD38 polypeptide.

52. The method of claim 51, wherein the T cell expresses a chimeric antigen receptor (CAR) or contains a polynucleotide encoding a CAR on its cell surface.

53. The method as described in claim 51 or claim 52, wherein the T cell is a memory T cell or an effector T cell.

54. A method for amplifying virus-specific memory T cells, the method comprising contacting the virus-specific memory T cells with a binding protein comprising four polypeptide chains forming three antigen-binding sites, wherein a first polypeptide chain comprises a structure represented by the following formula: VL2-L1-VL1-L2-CL[I] and a second polypeptide chain comprises a structure represented by the following formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and a third polypeptide chain comprises a structure represented by the following formula: VH3-CH1-hinge-CH2-CH3[III] and a fourth polypeptide chain comprises a structure represented by the following formula: VL3-CL[IV] where: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3 is an immunoglobulin CH3 heavy chain constant domain; a hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3, and L4 are amino acid linkers; wherein the polypeptide of Formula I and the polypeptide of Formula II form an interleaved light chain-heavy chain pair; and wherein VH1 and VL1 form a first antigen-binding site for binding the CD28 polypeptide; VH2 and VL2 form a second antigen-binding site for the CD3 polypeptide. The VH2 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence containing the amino acid sequence IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence containing the amino acid sequence RGVYYALSPFDY (SEQ ID NO: 57). The VL2 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHX1NX2X3TY (SEQ ID NO: 180) where X1 is E or Q, X2 is A or L, and X3 is Q, R, or F; a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 64); and a CDR-H3 sequence containing GQGTQYPFT (SEQ ID NO: 57). The CDR-L3 sequence of the amino acid sequence of 65); and VH3 and VL3 form the third antigen binding site for binding the CD38 polypeptide.

55. The method of claim 54, wherein the virus-specific memory T cells are contacted with the binding protein in vitro or in vitro.

56. The method of claim 54 or claim 55, wherein contact between the virus-specific memory T cell and the binding protein causes activation and / or proliferation of the virus-specific memory T cell.

57. A method for treating chronic viral infection, the method comprising administering to a patient in need an effective amount of a binding protein comprising four polypeptide chains forming three antigen-binding sites, wherein a first polypeptide chain comprises a structure represented by the following formula: VL2-L1-VL1-L2-CL[I] and a second polypeptide chain comprises a structure represented by the following formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and a third polypeptide chain comprises a structure represented by the following formula: VH3-CH1-hinge-CH2-CH3[III] and a fourth polypeptide chain comprises a structure represented by the following formula: VL3-CL[IV] where: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3 is an immunoglobulin CH3 heavy chain constant domain; a hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3, and L4 are amino acid linkers; wherein the polypeptide of Formula I and the polypeptide of Formula II form an interleaved light chain-heavy chain pair; and wherein VH1 and VL1 form a first antigen-binding site for binding the CD28 polypeptide; VH2 and VL2 form a second antigen-binding site for the CD3 polypeptide. The VH2 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence containing the amino acid sequence IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence containing the amino acid sequence RGVYYALSPFDY (SEQ ID NO: 57). The VL2 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHX1NX2X3TY (SEQ ID NO: 180) where X1 is E or Q, X2 is A or L, and X3 is Q, R, or F; a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 64); and a CDR-H3 sequence containing GQGTQYPFT (SEQ ID NO: 57). The CDR-L3 sequence of the amino acid sequence of 65); and VH3 and VL3 form the third antigen binding site for binding the CD38 polypeptide.

58. The method as described in claim 57, wherein the patient is a human.

59. The method of claim 57 or claim 58, wherein the binding protein is delivered to the patient in a pharmaceutical formulation comprising the binding protein and a pharmaceutically acceptable carrier.

60. The method of any one of claims 57 to 59, wherein administration of the binding protein results in activation and / or proliferation of virus-specific memory T cells in the patient.

61. The method of any one of claims 53 to 56 and 60, wherein the memory T cell is a CD8+ or CD4+ memory T cell.

62. The method of any one of claims 53 to 56, 60 and 61, wherein the memory T cell is a central memory T cell (TCM) or an effector memory T cell (TEM).

63. The method of any one of claims 54 to 62, wherein the virus is human immunodeficiency virus (HIV), influenza virus, cytomegalovirus (CMV), hepatitis B virus (HBV), human papillomavirus (HPV), Estée Lauder virus (EBV), human foamy virus (HFV), herpes simplex virus 1 (HSV-1) or herpes simplex virus 2 (HSV-2).

64. The method of any one of claims 51 to 63, wherein the CD28 polypeptide is a human CD28 polypeptide, wherein the CD3 polypeptide is a human CD3 polypeptide, and wherein the CD38 polypeptide is a human CD38 polypeptide.

65. A binding protein for use in expanding T cells, wherein the binding protein is to contact the T cells, wherein the binding protein comprises four polypeptide chains forming three antigen-binding sites, wherein the first polypeptide chain comprises a structure represented by the following formula: VL2-L1-VL1-L2-CL[I] and the second polypeptide chain comprises a structure represented by the following formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and the third polypeptide chain comprises a structure represented by the following formula: VH3-CH1-hinge-CH2-CH3[III] and the fourth polypeptide chain comprises a structure represented by the following formula: VL3-CL[IV] where: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3 is an immunoglobulin CH3 heavy chain constant domain; a hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3, and L4 are amino acid linkers; wherein the polypeptide of Formula I and the polypeptide of Formula II form an interleaved light chain-heavy chain pair; and wherein VH1 and VL1 form a first antigen-binding site for binding the CD28 polypeptide; VH2 and VL2 form a second antigen-binding site for the CD3 polypeptide. The VH2 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence containing the amino acid sequence IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence containing the amino acid sequence RGVYYALSPFDY (SEQ ID NO: 57). The VL2 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHX1NX2X3TY (SEQ ID NO: 180) where X1 is E or Q, X2 is A or L, and X3 is Q, R, or F; a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 64); and a CDR-H3 sequence containing GQGTQYPFT (SEQ ID NO: 57). The CDR-L3 sequence of the amino acid sequence of 65); and VH3 and VL3 form the third antigen binding site for binding the CD38 polypeptide.

66. The binding protein for the stated purpose as claimed in claim 65, wherein the T cell expresses a chimeric antigen receptor (CAR) or contains a polynucleotide encoding a CAR on its cell surface.

67. A binding protein for the stated purpose as described in claim 65 or claim 66, wherein the T cell is a memory T cell or an effector T cell.

68. A binding protein for use in amplifying virus-specific memory T cells, wherein the binding protein is contacted with the virus-specific memory T cells, wherein the binding protein comprises four polypeptide chains forming three antigen-binding sites, wherein the first polypeptide chain comprises a structure represented by the following formula: VL2-L1-VL1-L2-CL[I] and the second polypeptide chain comprises a structure represented by the following formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and the third polypeptide chain comprises a structure represented by the following formula: VH3-CH1-hinge-CH2-CH3[III] and the fourth polypeptide chain comprises a structure represented by the following formula: VL3-CL[IV] where: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3 is an immunoglobulin CH3 heavy chain constant domain; a hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3, and L4 are amino acid linkers; wherein the polypeptide of Formula I and the polypeptide of Formula II form an interleaved light chain-heavy chain pair; and wherein VH1 and VL1 form a first antigen-binding site for binding the CD28 polypeptide; VH2 and VL2 form a second antigen-binding site for the CD3 polypeptide. The VH2 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence containing the amino acid sequence IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence containing the amino acid sequence RGVYYALSPFDY (SEQ ID NO: 57). The VL2 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHX1NX2X3TY (SEQ ID NO: 180) where X1 is E or Q, X2 is A or L, and X3 is Q, R, or F; a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 64); and a CDR-H3 sequence containing GQGTQYPFT (SEQ ID NO: 57). The CDR-L3 sequence of the amino acid sequence of 65); and VH3 and VL3 form the third antigen binding site for binding the CD38 polypeptide.

69. The binding protein for the stated purpose as described in claim 68, wherein the virus-specific memory T cells are to be contacted with the binding protein in vitro or ex vivo.

70. The binding protein for the stated purpose as described in claim 68 or 69, wherein contact between the virus-specific memory T cell and the trispecific binding protein induces activation and / or proliferation of the virus-specific memory T cell.

71. A binding protein for use in the treatment of chronic viral infection, wherein the binding protein is to be administered to a patient in need, wherein the binding protein comprises four polypeptide chains forming three antigen-binding sites, wherein the first polypeptide chain comprises a structure represented by the following formula: VL2-L1-VL1-L2-CL[I] and the second polypeptide chain comprises a structure represented by the following formula: VH1-L3-VH2-L4-CH1-hinge-CH2-CH3[II] and the third polypeptide chain comprises a structure represented by the following formula: VH3-CH1-hinge-CH2-CH3[III] and the fourth polypeptide chain comprises a structure represented by the following formula: VL3-CL[IV] wherein: VL1 is a first immunoglobulin light chain variable domain; VL2 is a second immunoglobulin light chain variable domain; VL3 is a third immunoglobulin light chain variable domain; VH1 is a first immunoglobulin heavy chain variable domain; VH2 is a second immunoglobulin heavy chain variable domain; VH3 is a third immunoglobulin heavy chain variable domain; CL is an immunoglobulin light chain constant domain; CH1 is an immunoglobulin CH1 heavy chain constant domain; CH2 is an immunoglobulin CH2 heavy chain constant domain; CH3 is an immunoglobulin CH3 heavy chain constant domain; a hinge is an immunoglobulin hinge region connecting the CH1 and CH2 domains; and L1, L2, L3, and L4 are amino acid linkers; wherein the polypeptide of Formula I and the polypeptide of Formula II form an interleaved light chain-heavy chain pair; and wherein VH1 and VL1 form a first antigen-binding site for binding the CD28 polypeptide; VH2 and VL2 form a second antigen-binding site for the CD3 polypeptide. The VH2 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFTKAW (SEQ ID NO: 55), a CDR-H2 sequence containing the amino acid sequence IKDKSNSYAT (SEQ ID NO: 56), and a CDR-H3 sequence containing the amino acid sequence RGVYYALSPFDY (SEQ ID NO: 57). The VL2 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHX1NX2X3TY (SEQ ID NO: 180) where X1 is E or Q, X2 is A or L, and X3 is Q, R, or F; a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 64); and a CDR-H3 sequence containing GQGTQYPFT (SEQ ID NO: 57). The CDR-L3 sequence of the amino acid sequence of 65); and VH3 and VL3 form the third antigen binding site for binding the CD38 polypeptide.

72. The binding protein for the stated purpose as described in claim 71, wherein the patient is a human.

73. A binding protein for the stated purpose as described in claim 71 or claim 72, wherein the binding protein is to be administered to the patient in a pharmaceutical formulation comprising the binding protein and a pharmaceutically acceptable carrier.

74. The binding protein for the purpose as claimed in any one of claims 71 to 73, wherein administration of the binding protein results in activation and / or proliferation of virus-specific memory T cells in the patient.

75. The binding protein for the purpose as claimed in any one of claims 67 to 70 and 74, wherein the memory T cell is a CD8+ or CD4+ memory T cell.

76. The binding protein for the said use as claimed in any one of claims 67 to 70, 74 and 75, wherein the memory T cell is a central memory T cell (TCM) or an effector memory T cell (TEM).

77. The binding protein for the said use as claimed in any one of claims 68 to 76, wherein the virus is human immunodeficiency virus (HIV), influenza virus, cytomegalovirus (CMV), hepatitis B virus (HBV), human papillomavirus (HPV), Estée Lauder virus (EBV), human foamy virus (HFV), herpes simplex virus 1 (HSV-1) or herpes simplex virus 2 (HSV-2).

78. The binding protein for the said use as claimed in any one of claims 65 to 77, wherein the CD28 polypeptide is a human CD28 polypeptide, wherein the CD3 polypeptide is a human CD3 polypeptide, and wherein the CD38 polypeptide is a human CD38 polypeptide.

79. The method or binding protein for the said use as claimed in any one of claims 51 to 78, wherein the VH1 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYTFTSYY (SEQ ID NO: 49), a CDR-H2 sequence containing the amino acid sequence IYPGNVNT (SEQ ID NO: 50), and a CDR-H3 sequence containing the amino acid sequence TRSHYGLDWNFDV (SEQ ID NO: 51); and the VL1 domain comprises: a CDR-L1 sequence containing the amino acid sequence QNIYVW (SEQ ID NO: 52), a CDR-L2 sequence containing the amino acid sequence KAS (SEQ ID NO: 53), and a CDR-L3 sequence containing the amino acid sequence QQGQTYPY (SEQ ID NO: 54).

80. The method or binding protein for the stated purpose as described in claim 79, wherein the VH1 domain comprises the amino acid sequence QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYYIHWVRQAPGQGLEWIGSIYPGNVNTNYAQKFQGRATLTVDTSISTAYMELSRLRSDDTAVYYCTRSHYGLDWNFDVWGKGTTVTVSS (SEQ ID NO: 91), and / or the VL1 domain comprises the amino acid sequence DIQMTQSPSSLSASVGDRVTITCQASQNIYVWLNWYQQKPGKAPKLLIYKASNLHTGVPSRFSGSGSGTDFTLTISSLQPEDIATYYCQQGQTYPYTFGQGTKLEIK (SEQ ID NO: 92).

81. A method or binding protein for the purpose as claimed in any one of claims 51 to 80, wherein the CDR-L1 sequence of the VL2 domain comprises an amino acid sequence selected from the following: QSLVHQNAQTY (SEQ ID NO: 59), QSLVHENLQTY (SEQ ID NO: 60), QSLVHENLFTY (SEQ ID NO: 61), and QSLVHENLRTY (SEQ ID NO: 62).

82. The method or binding protein for the stated purpose as described in claim 81, wherein the VH2 domain comprises QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYADSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93) or QVQLVESGGGVVQPGRSLRLSCAASGFTFTKAWMHWVRQAPGKQLEWVAQIKDKSNSYATYYASSVKGRFTISRDDSKNTLYLQMNSLRAEDTAVYYCRGVYYALSPFDYWGQGTLVTVSS (SEQ ID NO: 93). The amino acid sequence of 302), and / or the VL2 domain comprising an amino acid sequence selected from the following: DIVMTQTPLSLSVTPGQPASISCKSSQSLVHQNAQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLQTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 95). 96), DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLFTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 97) and DIVMTQTPLSLSVTPGQPASISCKSSQSLVHENLRTYLSWYLQKPGQSPQSLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCGQGTQYPFTFGSGTKVEIK (SEQ ID NO: 98).

83. The method or binding protein for the said use as described in any one of claims 51 to 82, wherein: (a) The VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYTFTSYA (SEQ ID NO: 13), a CDR-H2 sequence containing the amino acid sequence IYPGQGGT (SEQ ID NO: 14), and a CDR-H3 sequence containing the amino acid sequence ARTGGLRRAYFTY (SEQ ID NO: 15); and the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSVSSYGQGF (SEQ ID NO: 16), a CDR-L2 sequence containing the amino acid sequence GAS (SEQ ID NO: 17), and a CDR-L3 sequence containing the amino acid sequence QQNKEDPWT (SEQ ID NO: 18); (b) The VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYTLTEFS (SEQ ID NO: 19), a CDR-H2 sequence containing the amino acid sequence FDPEDGET (SEQ ID NO: 18), and a CDR-H3 sequence containing the amino acid sequence GYTLTEFS (SEQ ID NO: 19). (c) The VL3 domain comprises: a CDR-H2 sequence containing the amino acid sequence QSVISRF (SEQ ID NO: 22), a CDR-H3 sequence containing the amino acid sequence TTGRFFDWF (SEQ ID NO: 21); and the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSVISRF (SEQ ID NO: 22), a CDR-L2 sequence containing the amino acid sequence GAS (SEQ ID NO: 23), and a CDR-L3 sequence containing the amino acid sequence QQDSNLPIT (SEQ ID NO: 24); and the VL3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GYAFTTYL (SEQ ID NO: 25), a CDR-H2 sequence containing the amino acid sequence INPGSGST (SEQ ID NO: 26), and a CDR-H3 sequence containing the amino acid sequence ARYAYGY (SEQ ID NO: 27); and the VL3 domain comprises: a CDR-H3 sequence containing the amino acid sequence QNVGTA (SEQ ID NO: 28). (d) The VH3 domain comprises: a CDR-L1 sequence containing the amino acid sequence of SEQ ID NO: 28), a CDR-L2 sequence containing the amino acid sequence of SAS (SEQ ID NO: 29), and a CDR-L3 sequence containing the amino acid sequence of QQYSTYPFT (SEQ ID NO: 30);The VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QSLVHSNGNTY (SEQ ID NO: 34), a CDR-L2 sequence containing the amino acid sequence KVS (SEQ ID NO: 35), and a CDR-L3 sequence containing the amino acid sequence SQSTHVPLT (SEQ ID NO: 36); (e) the VH3 domain comprises: a CDR-H1 sequence containing the amino acid sequence GFTFSSYG (SEQ ID NO: 37), a CDR-H2 sequence containing the amino acid sequence IWYDGSNK (SEQ ID NO: 38), and a CDR-H3 sequence containing the amino acid sequence ARDPGLRYFDGGMDV (SEQ ID NO: 39); and the VL3 domain comprises: a CDR-L1 sequence containing the amino acid sequence QGISSY (SEQ ID NO: 40), a CDR-L2 sequence containing the amino acid sequence AAS (SEQ ID NO: 39), and a CDR-L3 sequence containing the amino acid sequence AAS (SEQ ID NO: 39). 41) The CDR-L2 sequence of the amino acid sequence and the CDR-L3 sequence of the amino acid sequence containing QQLNSFPYT (SEQ ID NO: 42); or (f) the VH3 domain comprises: the CDR-H1 sequence of the amino acid sequence containing GFTFSSYG (SEQ ID NO: 43), the CDR-H2 sequence of the amino acid sequence containing IWYDGSNK (SEQ ID NO: 44), and the CDR-H3 sequence of the amino acid sequence containing ARMFRGAFDY (SEQ ID NO: 45); and the VL3 domain comprises: the CDR-L1 sequence of the amino acid sequence containing QGIRND (SEQ ID NO: 46), the CDR-L2 sequence of the amino acid sequence containing AAS (SEQ ID NO: 47), and the CDR-L3 sequence of the amino acid sequence containing LQDYIYYPT (SEQ ID NO: 48).

84. The method or binding protein for the said purpose as described in claim 83, wherein: (a) The VH3 domain contains the amino acid sequence QVQLVQSGAEVVKPGASVKVSCKASGYTFTSYAMHWVKEAPGQRLEWIGYIYPGQGGTNYNQKFQGRATLTADTSASTAYMELSSLRSEDTAVYFCARTGGLRRAYFTYWGQGTLVTVSS (SEQ ID NO: 79), and / or the VL3 domain contains the amino acid sequence DIVLTQSPATLSLSPGERATISCRASQSVSSYGQGFMHWYQQKPGQPPRLLIYGASSRATGIPARFSGSGSGTDFTLTISPLEPEDFAVYYCQQNKEDPWTFGGGTKLEIK (SEQ ID NO: 80); (b) The VH3 domain contains the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKVSGYTLTEFSIHWVRQAPGQGLEWMGGFDPEDGETIYAQKFQGRVIMTEDTSTDTAYMEMNSLRSEDTAIYYCTTGRFFDWFWGQGTLVTVSS (SEQ ID NO: 81), and / or the VL3 domain contains the amino acid sequence EIILTQSPAILSLSPGERATLSCRASQSVISRFLSWYQVKPGLAPRLLIYGASTRATGIPVRFSGSGSGTDFSLTISSLQPEDCAVYYCQQDSNLPITFGQGTRLEIK (SEQ ID NO: 82); (c) The VH3 domain contains the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYAFTTYLVEWIRQRPGQGLEWMGVINPGSGSTNYAQKFQGRVTMTVDRSSTTAYMELSRLRSDDTAVYYCARYAYGYWGQGTLVTVSS (SEQ ID NO: 83), and / or the VL3 domain contains the amino acid sequence DIQMTQSPSSLSASVGDRVTITCRASQNVGTAVAWYQQKPGKSPKQLIYSASNRYTGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQYSTYPFTFGQGTKLEIK (SEQ ID NO: 84);(d) The VH3 domain contains the amino acid sequence QVQLVQSGAEVKKPGASVKVSCKASGYSFTNYAVHWVRQAPGQGLEWMGVISPYYGDTTYAQKFQGRVTMTVDKSSSTAYMELSRLRSDDTAVYYCARRFEGFYYSMDYWGQGTLVTVSS (SEQ ID NO: 85), and / or the VL3 domain contains the amino acid sequence DVVMTQSPLSLPVTLGQPASISCRPSQSLVHSNGNTYLNWYQQRPGQSPKLLIYKVSKRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPLTFGGGTKVEIK (SEQ ID NO: 86); (e) The VH3 domain contains the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMYWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYHCARDPGLRYFDGGMDVWGQGTTVTVSS (SEQ ID NO: 87), and / or the VL3 domain contains the amino acid sequence DIQLTQSPSFLSASVGDRVTITCRASQGISSYLAWYQQKPGKAPKLLIFAASTLHSGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQLNSFPYTFGQGTKLEIK (SEQ ID NO: 88); or (f) The VH3 domain contains the amino acid sequence QVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWVRQAPGKGLEWVAVIWYDGSNKYYADSVKGRFTISGDNSKNTLYLQMNSLRAEDTAVYYCARMFRGAFDYWGQGTLVTVSS (SEQ ID NO: 89), and / or the VL3 domain contains the amino acid sequence AIQMTQSPSSLSASVGDRVTITCRASQGIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISGLQPEDSATYYCLQDYIYYPTFGQGTKVEIK (SEQ ID NO: 90).

85. The method or binding protein for the said use as claimed in any one of claims 51 to 82, wherein: (a) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 156 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 156; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 157 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 157; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 158 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 158; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 159 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 159; (b) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 160 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 161 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 160; The first polypeptide chain contains an amino acid sequence of SEQ ID NO: 161 that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; the third polypeptide chain contains an amino acid sequence of SEQ ID NO: 162 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 162; and the fourth polypeptide chain contains an amino acid sequence of SEQ ID NO: 163 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 163; (c) the first polypeptide chain contains an amino acid sequence of SEQ ID NO: 164 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; the second polypeptide chain contains an amino acid sequence of SEQ ID NO: 165 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 165; the third polypeptide chain contains an amino acid sequence of SEQ ID NO: 166 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; and the fourth polypeptide chain contains an amino acid sequence of SEQ ID NO: 161 that is at least 95% identical to the amino acid sequence of SEQ ID NO: 166; and the fourth polypeptide chain contains an amino acid sequence of SEQ ID NO: 161 that is at least 95% identical to the amino acid sequence of SEQ ID NO: 164; (d) The first polypeptide chain contains the amino acid sequence of SEQ ID NO: 167 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 167; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 169 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 169; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 170 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 170;The fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 171 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 171; (e) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 172 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 172; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 173 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 173; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 174 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 174; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 175 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 175; (f) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 176 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

175. The first polypeptide chain contains at least 95% identical amino acid sequences of SEQ ID NO: 176; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 177 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 177; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 178 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 178; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 179; (g) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 181 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 181; the second polypeptide chain contains the amino acid sequence of SEQ ID NO: 182 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 182; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 176; the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 177; the fifth polypeptide chain contains the amino acid sequence of SEQ ID NO: 178; the sixth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the seventh polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the eighth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the ninth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the tenth polypeptide chain contains the amino acid sequence of SEQ ID NO: 179; the eleven ... The fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 183 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 183; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 184 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 184; or (h) the first polypeptide chain contains the amino acid sequence of SEQ ID NO: 185 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 185;The second polypeptide chain contains the amino acid sequence of SEQ ID NO: 186 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 186; the third polypeptide chain contains the amino acid sequence of SEQ ID NO: 187 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 187; and the fourth polypeptide chain contains the amino acid sequence of SEQ ID NO: 188 or an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO:

188.

86. A vector system comprising one or more vectors encoding a first, second, third, and fourth polypeptide chain of a binding protein as described in any one of claims 1 to 27.

87. The vector system of claim 86, wherein the vector system comprises a first vector encoding the first polypeptide chain of the binding protein, a second vector encoding the second polypeptide chain of the binding protein, a third vector encoding the third polypeptide chain of the binding protein, and a fourth vector encoding the fourth polypeptide chain of the binding protein.

88. A polynucleotide bundle, the polynucleotide bundle comprising: (a) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 189, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 190, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 191, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 192; (b) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 193, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 194, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 195, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 196; (c) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 197, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 198, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 199, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 200; (d) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 201, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 199, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 199, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 190; (e) A second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 202, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 203, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 204; (f) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 209, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 210, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 211, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 212; (g) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 213, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 214, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 215, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 206; The fourth polynucleotide in the polynucleotide sequence of 216;(h) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 217, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 218, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 219, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 220; (i) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 221, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 222, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 223, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 224; (j) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 225, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 226, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 227, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 228; (k) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 229, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 229, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 220, a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 220, a fifth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 221, a sixth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 222, a seventh polynucleotide containing the polynucleotide sequence of SEQ ID NO: 223, and a fifth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 224; (j) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 225, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 226, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 227, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 228; (a) A second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 230, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 231, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 232; (b) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 233, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 234, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 235, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 236; (c) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 237, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 238, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 239, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 240; (d) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 241, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 242, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 243, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO:

234. The fourth polynucleotide in the polynucleotide sequence of 244;(o) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 245, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 246, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 247, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 248; (p) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 249, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 250, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 251, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 252; (q) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 253, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 254, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 255, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 256; (r) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 257, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 249, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 250, a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 251, and a fifth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 252; (s) A second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 258, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 259, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 260; (s) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 261, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 262, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 263, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 264; (t) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 265, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 266, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 267, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO: 268; (u) A first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 269, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 270, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 271, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO:

268. The fourth polynucleotide in the polynucleotide sequence of 272;Or (v) a first polynucleotide containing the polynucleotide sequence of SEQ ID NO: 273, a second polynucleotide containing the polynucleotide sequence of SEQ ID NO: 274, a third polynucleotide containing the polynucleotide sequence of SEQ ID NO: 275, and a fourth polynucleotide containing the polynucleotide sequence of SEQ ID NO:

276.

89. The kit as claimed in claim 88, wherein the first, second, third, and fourth polynucleotides are present on one or more expression vectors.