Wiskott-aldrich syndrome binding proteins and uses thereof

Abstract

The present disclosure relates to Wiskott-Aldrich Syndrome (WAS) binding proteins and uses thereof. The present disclosure further relates to WAS protein variants thereof and methods of producing WAS binding proteins thereof.

Description

[0001] WISKOTT-ALDRICH SYNDROME BINDING PROTEINS AND USES THEREOF

[0002] RELATED APPLICATION DATA

[0003] The present application claims priority from United States Patent Application No. 63 / 653,347 filed 30 May 2024 entitled “Wiskott-Aldrich syndrome binding proteins and uses thereof’. The entire contents of this application are hereby incorporated by reference.

[0004] SEQUENCE LISTING

[0005] The present application is filed together with a Sequence Listing in electronic form. The entire contents of the Sequence Listing is hereby incorporated by reference.

[0006] FIELD

[0007] The present disclosure relates to Wiskott-Aldrich Syndrome (WAS) binding proteins and uses thereof. The present disclosure further relates to WAS protein variants thereof and methods of producing WAS binding proteins thereof.

[0008] BACKGROUND

[0009] Wiskott-Aldrich Syndrome (WAS) is a rare, X-linked primary immunodeficiency disorder affecting around 1 in every 100,000 live births. It is seen almost exclusively in males and is characterized by recurrent infections, small platelets, microthrombocytopenia, eczema, and increased risk of autoimmune manifestations and tumors.

[0010] WAS is caused by mutations in the WAS gene, which encodes a protein that regulates the actin cytoskeleton leading to altered signaling function and / or development in multiple hematopoietic cell lineages. Mutations include missense / nonsense mutations, splicing, small deletions, small insertions, gross deletions, and gross insertions, and result in absent or mutated WAS protein.

[0011] The severity of the disease depends on the mutations present in the WAS protein. To date, four clinical forms of WAS have been identified. Classic WAS is the most severe form of WAS. Its main symptoms are having repeated bouts of infection, prolonged and severe bleeding leading to bruising easily, severe eczema and a higher incidence of leukaemia and lymphoma, and autoimmune disorders. Milder forms of WAS include X- linked thrombocytopenia, a condition with low platelet numbers but without many of the other symptoms of WAS, and X-linked neutropenia, a condition with low amounts of white blood cells but with normal levels of the WAS protein. The mildest form is known as intermittent thrombocytopenia where the platelet abnormalities are sporadic and there is no immunodeficiency.

[0012] Currently, therapies for individuals with WAS focus on the symptoms, including antibodies to prevent and treat infections, platelet and red blood cell infusions to treat excessive bleeding, moisturising and steroid creams to treat eczema, as well as immunoglobulin replacement therapy. The only available curative therapy for classic WAS or X-linked thrombocytopenia is bone marrow transplantation. Hematopoietic stem cell gene therapy using integrating viral vectors, such as lentiviral vectors, provides a new, potentially curative option for patients lacking matched donors for bone marrow transplantations. Whilst gene therapy offers advantages over allogeneic stem cell therapy, there is a need in the art for development of methods for assessing the safety and quality of therapeutic compounds and therapeutic genetic manipulations, including integrating gene therapy vectors, as well as methods for monitoring efficacy of treatment in patients.

[0013] SUMMARY

[0014] In work leading up to the invention, the inventors sought to produce an anti- Wiskott-Aldrich Syndrome (WAS) protein antibody for reliable detection and quantitation of WAS protein expression, e.g., for quality control assessment of integrating viral vectors encoding a WAS protein and / or quantification of WAS protein expression for patient monitoring post-treatment. Accordingly, the inventors produced a series of antibodies that bind to human WAS protein with high specificity and sensitivity and that do not cross-react with related protein, neuronal WAS protein (N-WASp).

[0015] In producing the present invention, the inventors also recognised the need for production of a human WAS protein capable of production in a mammalian expression system for use in phage library panning. The inventors recognised the absence of commercially available sources of WAS protein, with previous E.coli and insect cell expression systems resulting in low protein yields. Accordingly, the inventors produced a series of recombinant WAS protein constructs capable of production in a mammalian expression system at high yields.

[0016] Accordingly, the findings by the inventors provide the basis for a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that lacks at least one of a pleckstrin homology domain, a WASp homology 1 (WH1) domain, a proline-rich region, a WH2 domain and / or a verprolin homology domain, wherein the antibody variable region does not detectably bind to neuronal WAS protein.

[0017] In one example, the antibody variable region binds to human WAS protein and / or murine WAS protein. For example, the antibody variable region binds to human WAS protein. In another example, the antibody variable region binds to murine WAS protein. In a further example, the antibody variable region binds to human WAS protein and murine WAS protein.

[0018] In one example, the antibody variable region binds to a WAS protein variant that lacks a pleckstrin homology domain. In another example, the antibody variable region binds to a WAS protein variant that lacks a WH1 domain. In a further example, the antibody variable region binds to a WAS protein variant that lacks a proline -rich region. In one example, the antibody variable region binds to a WAS protein variant that lacks a WH2 domain. In another example, the antibody variable region binds to a WAS protein variant that lacks a verprolin homology domain. In a further example, the antibody variable region binds to a WAS protein variant that lacks a pleckstrin homology domain, a WASp homology 1 (WH1) domain, a proline-rich region, a WH2 domain and a verprolin homology domain.

[0019] In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal:

[0020] (i) a GTPase-binding domain; and

[0021] (ii) a cofilin-homology sequence.

[0022] In one example, the WAS protein variant comprises in order from N- to C- terminal:

[0023] (i) a GTPase-binding domain; and

[0024] (ii) a cofilin-homology sequence.

[0025] In one example, the WAS protein variant consists of in order from N- to C- terminal:

[0026] (i) a GTPase-binding domain; and

[0027] (ii) a cofilin-homology sequence.

[0028] In one example, the WAS protein variant comprises in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; and amino acid residues 461 to 492 of SEQ ID NO: 129.

[0029] In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal:

[0030] (i) a GTPase-binding domain;

[0031] (ii) a cofilin-homology sequence; and (iii) a C-terminal acid domain.

[0032] In one example, the WAS protein variant comprises in order from N- to C- terminal:

[0033] (i) a GTPase-binding domain;

[0034] (ii) a cofilin-homology sequence; and

[0035] (iii) a C-terminal acid domain.

[0036] In one example, the WAS protein variant consists of in order from N- to C- terminal:

[0037] (i) a GTPase-binding domain;

[0038] (ii) a cofilin-homology sequence; and

[0039] (iii) a C-terminal acid domain.

[0040] The present disclosure also provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that comprises, or consists of, in order from N- to C-terminal:

[0041] (i) a GTPase-binding domain; and

[0042] (ii) a cofilin-homology sequence.

[0043] The present disclosure also provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that comprises in order from N- to C- terminal:

[0044] (i) a GTPase-binding domain; and

[0045] (ii) a cofilin-homology sequence.

[0046] The present disclosure also provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that consists of in order from N- to C- terminal:

[0047] (i) a GTPase-binding domain; and

[0048] (ii) a cofilin-homology sequence.

[0049] The present disclosure further provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that comprises, or consists of, in order from N- to C-terminal:

[0050] (i) a GTPase-binding domain;

[0051] (ii) a cofilin-homology sequence; and

[0052] (iii) a C-terminal acid domain. The present disclosure further provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that comprises in order from N- to C -terminal:

[0053] (i) a GTPase-binding domain;

[0054] (ii) a cofilin-homology sequence; and

[0055] (iii)a C -terminal acid domain.

[0056] The present disclosure further provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that consists of in order from N- to C -terminal:

[0057] (i) a GTPase-binding domain;

[0058] (ii) a cofilin-homology sequence; and

[0059] (iii)a C -terminal acid domain.

[0060] In one example, the WAS protein variant comprises in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; and amino acid residues 461 to 502 of SEQ ID NO: 129.

[0061] The present disclosure further provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that comprises, or consists of, in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; and amino acid residues 461 to 502 of SEQ ID NO: 129.

[0062] In one example, the GTPase-binding domain, the cofilin-homology sequence and / or the C-terminal acid domain are directly or indirectly linked to each other. For example, each of the GTPase-binding domain, the cofilin-homology sequence and the C- terminal acid domain are directly linked to each other (e.g., without an intervening linker). In another example, each of the GTPase-binding domain, the cofilin-homology sequence and the C-terminal acid domain are indirectly linked to each other. In a further example, the GTPase-binding and the cofilin-homology sequence are indirectly linked to each other and the cofilin-homology sequence and the C-terminal acid domain are directly linked to each other.

[0063] In one example, the GTPase-binding domain, the cofilin-homology sequence and / or the C-terminal acid domain are indirectly linked to each other via a linker.

[0064] In one example, the GTPase-binding and the cofilin-homology sequence are indirectly linked to each other via a linker. In one example, the linker is a peptide or a polypeptide. For example, the linker is a peptide linker comprising at least 2 amino acids in length. In one example, the linker comprises between 2 and 70 amino acids.

[0065] In one example, the linker is a rigid or a flexible linker.

[0066] In one example, the linker is selected from the group consisting of a (GS)nlinker, wherein n=l, 2, 3, 4, 5 or 6, a GSGGS linker, a GGSSG linker, a GGGGS linker, a GSGSG linker, a (Gly)s linker, a (Gly)e linker, a (GGGS)nlinker, wherein n=l, 2, 3 or 4, a (EAAAK)n linker, wherein n=l, 2 or 3, a A(EAAAK)4ALEA(EAAAK4)A linker, a AEAAAKEAAAKA linker, a (Ala-Pro)nlinker, wherein n=10-34, and a PAPAP linker.

[0067] In one example, the linker is a flexible linker. In one example, the linker comprises glycine or glycine and serine. In one example, the flexible linker is selected from the group consisting of a (GS)nlinker, wherein n=l, 2, 3, 4, 5 or 6, a GSGGS linker, a GGSSG linker, a GGGGS linker, a GSGSG linker, a (Gly)s linker, a (Gly)6linker, a (GGGS)n linker, wherein n=l, 2, 3 or 4. For example, the linker is a GS6 linker as set forth in SEQ ID NO: 136 (GGSGGS).

[0068] In one example, the linker is a rigid linker. In one example, the rigid linker is selected from the group consisting of a (EAAAK)nlinker, wherein n=l, 2 or 3, a A(EAAAK)4ALEA(EAAAK4)A linker, a AEAAAKEAAAKA linker, a (Ala-Pro)nlinker, wherein n= 10-34, and a PAPAP linker.

[0069] In one example, the WAS protein variant further comprises a purification tag located at the C-terminus of the protein variant. For example, the purification tag is directly or indirectly linked to the C-terminus of the protein variant. In one example, the purification tag is directly linked to the C-terminus of the protein variant. In another example, the purification tag is indirectly linked to the C-terminus of the protein variant. Suitable linkers for linking the purification tag to the C-terminus of the protein variant will be apparent to the skilled person and / or described herein (e.g., in the above four paragraphs).

[0070] In one example, the purification tag is selected from the group consisting of a hexahistidine tag, a FLAG-tag, a calmodulin binding peptide (CBP) tag, a poly-glutamate tag, a polycysteine (Cys) tag, a polyhistidine (His) tag, a Myc-tag, a streptavidin-binding peptide (SBP) tag, a streptavidin (Strep) tag, an avidin tag, a bacteriophage V5 epitope (V5) tag, an isopeptag, a SpyTag, a biotin-carboxyl carrier protein (BCCP) tag, a Halotag, a thioredoxin (Trx) tag, a small ubiquitin-like molecule (SUMO) tag, and a maltose binding protein (MBP) tag.

[0071] In one example, the purification tag comprises a hexahistidine tag.

[0072] In one example, the purification tag comprises a FLAG-tag. In one example, the purification tag comprises a calmodulin binding peptide (CBP) tag.

[0073] In one example, the purification tag comprises a poly-glutamate tag.

[0074] In one example, the purification tag comprises a polycysteine (Cys) tag.

[0075] In one example, the purification tag comprises a polyhistidine (His) tag. For example, the purification tag is a His8 tag as set forth in SEQ ID NO: 137 (HHHHHHHH).

[0076] In one example, the purification tag comprises a Myc-tag.

[0077] In one example, the purification tag comprises a streptavidin-binding peptide (SBP) tag.

[0078] In one example, the purification tag comprises a streptavidin (Strep) tag.

[0079] In one example, the purification tag comprises an avidin tag.

[0080] In one example, the purification tag comprises a bacteriophage V5 epitope (V5) tag.

[0081] In one example, the purification tag comprises an isopeptag. For example, a peptide which binds covalently to pilin-C protein.

[0082] In one example, the purification tag comprises a SpyTag. For example, a peptide which binds covalently to SpyCatcher protein.

[0083] In one example, the purification tag comprises a biotin-carboxyl carrier protein (BCCP) tag.

[0084] In one example, the purification tag comprises a Halo-tag. For example, the purification tag comprises a modified haloalkane dehalogenase which covalently binds to synthetic ligands comprising a chloroalkane linker.

[0085] In one example, the purification tag comprises a thioredoxin (Trx) tag.

[0086] In one example, the purification tag comprises a small ubiquitin-like molecule (SUMO) tag.

[0087] In one example, the purification tag comprises a maltose binding protein (MBP) tag.

[0088] In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal:

[0089] (i) a GTPase-binding domain;

[0090] (ii) a (GS)6 linker;

[0091] (iii) a cofilin-homology sequence;

[0092] (iv) a C-terminal acid domain; and

[0093] (v) a His8 tag. In one example, the WAS protein variant comprises, in order form N- to C- terminal:

[0094] (i) a GTPase-binding domain;

[0095] (ii) a (GS)6 linker;

[0096] (iii) a cofilin-homology sequence;

[0097] (iv) a C-terminal acid domain; and

[0098] (v) a His8 tag.

[0099] In one example, the WAS protein variant consists of, in order form N- to C- terminal:

[0100] (i) a GTPase-binding domain;

[0101] (ii) a (GS)6 linker;

[0102] (iii) a cofilin-homology sequence;

[0103] (iv) a C-terminal acid domain; and

[0104] (v) a His8 tag.

[0105] In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137).

[0106] In one example, the WAS protein variant comprises in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137).

[0107] In one example, the WAS protein variant consists of in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137.

[0108] In one example, the WAS protein variant comprises a sequence set forth in SEQ ID NO: 130. For example, the WAS protein variant comprises a sequence set forth in SEQ ID NO: 130 lacking amino acids 1 to 19 (i.e., the signal peptide).

[0109] In one example, the human WAS protein comprises a sequence set forth in SEQ ID NO: 129 and / or the murine WAS protein comprises a sequence set forth in SEQ ID NO: 135. In one example, the human WAS protein comprises a sequence set forth in SEQ ID NO: 129. In another example, the murine WAS protein comprises a sequence set forth in SEQ ID NO: 135. In a further example, the human WAS protein comprises a sequence set forth in SEQ ID NO: 129 and the murine WAS protein comprises a sequence set forth in SEQ ID NO: 135. In one example, the human WAS protein comprises a sequence set forth in SEQ ID NO: 129 or the murine WAS protein comprises a sequence set forth in SEQ ID NO: 135.

[0110] In one example, the antibody variable region comprises:

[0111] (i) a heavy chain variable region (VH) comprising a sequence set forth in any one of SEQ ID NOs: 1 or 2 or 6 to 15; and a light chain variable region (VL) comprising a sequence set forth in any one of SEQ ID NOs: 3 to 5 or 16 to 25; or

[0112] (ii) a VH comprising three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 1 or 2 or 6 to 15; and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 3 to 5 or 16 to 25.

[0113] In one example, the antibody variable region comprises a VH comprising a sequence set forth in any one of SEQ ID NOs: 1 or 2 or 6 to 15; and a VL comprising a sequence set forth in any one of SEQ ID NOs: 3 to 5 or 16 to 25.

[0114] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises Q or E at position 6 and / or W or S at position 7 and / or A or P at position 9 and / or L or V at position 12 and / or E or G at position 16 and / or Y or S at position 25 and / or F or I at position 29 and / or G or S at position 31 and / or Y or S at position 32 and / or Y or N at position 33 and / or W or absent at position 34 and / or I or V at position 38 and / or N or Y at position 53 and / or T or K at position 74 and / or G or R at position 98 and / or V or D at position 99 and / or G or S at position 100 and / or A or E or R at position 101 and / or H or Q at position 102 and / or T or absent at position 104 and / or V or absent at position 105 and / or R or absent at position 106 and / or G or absent at position 107 and / or V or absent at position

[0115] 108 and / or I or absent at position 109 and / or N or absent at position 110 and / or N or absent at position 111 and / or T or absent at position 112 and / or P or absent at position 113 and / or A or absent at position 114 and / or C or absent at position 115.

[0116] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and V at position 99 and G at position 100 and E at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position

[0117] 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115. In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises Q at position 6 and W at position 7 and A at position 9 and L at position 12 and E at position 16 and Y at position 25 and F at position 29 and G at position 31 and Y at position 32 and Y at position 33 and absent at position 34 and I at position 38 and N at position 53 and T at position 74 and G at position 98 and V at position 99 and G at position 100 and A at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115.

[0118] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and D at position 99 and S at position 100 and R at position 101 and

[0119] Q at position 102 and T at position 104 and V at position 105 and R at position 106 and

[0120] G at position 107 and V at position 108 and I at position 109 and N at position 110 and

[0121] N at position 111 and T at position 112 and P at position 113 and A at position 114 and

[0122] C at position 115.

[0123] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q or K at position 12 and / or M or K at position 23 and / or S or A at position 24 and / or S or Y at position 32 and / or N or Y at position 33 and / or I or M at position 34 and / or N or H at position 35 and / or I or V at position 37 and / or T or P at position 41 and / or L or M at position 48 and / or W or I at position 50 and / or M or I at position 51 and / or N or S at position 54 and / or T or G at position 55 and / or N or S at position 57 and / or G or S at position 59 and / or N or D at position 73 and / or I or T at position 76 and / or N or S at position 77 and / or A or V at position 79 and / or G or A at position 99 and / or S or I at position 101 and / or E or absent at position 102 and / or G or absent at position 103 and / or Y or absent and / or Y or absent at position 105 and / or Y or absent at position 106 and / or Y or absent at position 107 and / or Y or absent at position 108 and / or Y or absent at position 109.

[0124] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109.

[0125] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109.

[0126] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises K at position 12 and K at position 23 and A at position 24 and Y at position 32 and Y at position 33 and M at position 34 and H at position 35 and V at position 37 and P at position 41 and M at position 48 and I at position 50 and I at position 51 and S at position 54 and G at position 55 and S at position 57 and S at position 59 and D at position 73 and T at position 76 and S at position 77 and V at position 79 and A at position 99 and I at position 101 and E at position 102 and G at position 103 and Y and Y at position 105 and Y at position 106 and Y at position 107 and Y at position 108 and Y at position 109.

[0127] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N or S at position 31 and / or Y or H at position 33 and / or L or V at position 40 and / or P or A at position 41 and / or A or T or S at position 43 and / or I or V at position 49 and / or N or S or D at position 53 and / or I or E or R at position 54 and / or P or H at position 56 and / or D or A at position 61 and / or G or A at position 65 and / or G or D or V at position 75 and / or S or N at position 94 and / or S or T at position 97 and / or S or H or V at position 98 and / or E or absent at position 99 and / or T or G at position 103 and / or K or T or S at position 106 and / or V or L at position 107. In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises S at position 31 and H at position 33 and V at position 40 and A at position 41 and S at position 43 and

[0128] V at position 49 and D at position 53 and R at position 54 and H at position 56 and A at position 61 and A at position 65 and V at position 75 and N at position 94 and S at position 97 and V at position 98 and E at position 99 and G at position 103 and S at position 106 and L at position 107.

[0129] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and A at position 43 and I at position 49 and N at position 53 and I at position 54 and P at position 56 and D at position 61 and G at position 65 and G at position 75 and S at position 94 and S at position 97 and S at position 98 and absent at position 99 and T at position 103 and K at position 106 and V at position 107.

[0130] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and T at position 43 and I at position 49 and S at position 53 and E at position 54 and P at position 56 and D at position 61 and G at position 65 and D at position 75 and N at position 94 and T at position 97 and H at position 98 and absent at position 99 and T at position 103 and T at position 106 and V at position 107.

[0131] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A or P at position 8 and / or V or A at position 10 and / or I or V at position 18 and / or S or N at position 26 and / or G or Y at position 31 and / or N or D at position 33 and / or M or I at position 49 and / or E or D at position 52 and / or S or T at position 54 and / or N or K at position 55 and / or S or P at position 61 and / or N or D at position 62 and / or I or V at position 77 and / or A or P at position 82 and / or E or D at position 83 and / or R or I at position 94 and / or S or G at position 95 and / or G or Y at position 96 and / or S or N at position 97 and / or T or L at position 98 and / or L or Y at position 99 and / or G or T at position 103 and / or L or V at position 107 and / or T or I at position 108.

[0132] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A at position 8 and

[0133] V at position 10 and I at position 18 and S at position 26 and G at position 31 and N at position 33 and M at position 49 and E at position 52 and S at position 54 and N at position 55 and S at position 61 and N at position 62 and I at position 77 and A at position 82 and E at position 83 and R at position 94 and S at position 95 and G at position 96 and S at position 97 and T at position 98 and L at position 99 and G at position 103 and L at position 107 and T at position 108.

[0134] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises P at position 8 and A at position 10 and V at position 18 and N at position 26 and Y at position 31 and D at position 33 and I at position 49 and D at position 52 and T at position 54 and K at position 55 and P at position 61 and D at position 62 and V at position 77 and P at position 82 and D at position 83 and I at position 94 and G at position 95 and Y at position 96 and N at position 97 and L at position 98 and Y at position 99 and T at position 103 and V at position 107 and I at position 108.

[0135] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L or M at position 4 and / or D or A at position 17 and / or Q or R at position 24 and / or H or Q at position 27 and / or D or T at position 28 and / or N or T at position 31 and / or Q or H at position 38 and / or N or G at position 41 and / or K or Q at position 42 and / or L or V at position 46 and / or D or A at position 50 and / or N or S at position 53 and / or E or Q at position 55 and / or A or S at position 56 and / or F or L at position 73 and / or N or S at position 77 and / or D or E at position 81 and / or I or F at position 83 and / or H or Q at position 90 and / or H or S at position 91 and / or Y or E at position 92 and / or N or S at position 93 and / or L or T at position 94.

[0136] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises M at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and G at position 41 and Q at position 42 and V at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and S at position 77 and D at position 81 and I at position

[0137] 83 and Q at position 90 and H at position 91 and E at position 92 and N at position 93 and L at position 94.

[0138] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and N at position 41 and K at position 42 and L at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and N at position 77 and D at position 81 and I at position 83 and H at position 90 and H at position 91 and Y at position 92 and N at position 93 and L at position 94.

[0139] In one example, the antibody variable region comprises a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and A at position 17 and R at position 24 and Q at position 27 and T at position 28 and T at position 31 and H at position 38 and G at position 41 and K at position 42 and L at position 46 and A at position 50 and S at position 53 and Q at position 55 and S at position 56 and L at position 73 and S at position 77 and E at position 81 and F at position 83 and Q at position 90 and S at position 91 and Y at position 92 and S at position 93 and T at position 94.

[0140] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the VH comprises a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and V at position 99 and G at position 100 and E at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and the VL comprises a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and A at position 43 and I at position 49 and N at position 53 and I at position 54 and P at position 56 and D at position 61 and G at position 65 and G at position 75 and S at position 94 and S at position 97 and S at position 98 and absent at position 99 and T at position 103 and K at position 106 and V at position 107.

[0141] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the VH comprises a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises Q at position 6 and W at position 7 and A at position 9 and L at position 12 and E at position 16 and Y at position 25 and F at position 29 and G at position 31 and Y at position 32 and Y at position 33 and absent at position 34 and I at position 38 and N at position 53 and T at position 74 and G at position 98 and V at position 99 and G at position 100 and A at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and the VL comprises a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and T at position 43 and I at position 49 and S at position 53 and E at position 54 and P at position 56 and D at position 61 and G at position 65 and D at position 75 and N at position 94 and T at position 97 and H at position 98 and absent at position 99 and T at position 103 and T at position 106 and V at position 107.

[0142] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the VH comprises a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and D at position 99 and S at position 100 and R at position 101 and Q at position 102 and T at position 104 and V at position 105 and R at position 106 and G at position 107 and V at position 108 and I at position 109 and N at position 110 and N at position 111 and T at position 112 and P at position 113 and A at position 114 and C at position 115; and the VL comprises a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and A at position 17 and R at position 24 and Q at position 27 and T at position 28 and T at position 31 and H at position 38 and G at position 41 and K at position 42 and L at position 46 and A at position 50 and S at position 53 and Q at position 55 and S at position 56 and L at position 73 and S at position 77 and E at position 81 and F at position 83 and Q at position 90 and S at position 91 and Y at position 92 and S at position 93 and T at position 9.

[0143] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the VH comprises a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and the VL comprises a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises M at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and G at position 41 and Q at position 42 and V at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and S at position 77 and D at position 81 and I at position 83 and Q at position 90 and H at position 91 and E at position 92 and N at position 93 and L at position 9.

[0144] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the VH comprises a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and the VL comprises a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and N at position 41 and K at position 42 and L at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and N at position 77 and D at position 81 and I at position 83 and H at position 90 and H at position 91 and Y at position 92 and N at position 93 and L at position 94.

[0145] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising a sequence set forth in SEQ ID NO: 21. For example, the VH comprises a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises K at position 12 and K at position 23 and A at position 24 and Y at position 32 and Y at position 33 and M at position 34 and H at position 35 and V at position 37 and P at position 41 and M at position 48 and I at position 50 and I at position 51 and S at position 54 and G at position 55 and S at position 57 and S at position 59 and D at position 73 and T at position 76 and S at position 77 and V at position 79 and A at position 99 and I at position 101 and E at position 102 and G at position 103 and Y and

[0146] Y at position 105 and Y at position 106 and Y at position 107 and Y at position 108 and

[0147] Y at position 109; and the VL comprises a sequence set forth in SEQ ID NO: 21.

[0148] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the VH comprises a sequence set forth in SEQ ID NO: 9; and the VL comprises a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises S at position 31 and H at position 33 and V at position 40 and A at position 41 and S at position 43 and V at position 49 and D at position 53 and R at position 54 and H at position 56 and A at position 61 and A at position 65 and V at position 75 and N at position 94 and S at position 97 and V at position 98 and E at position 99 and G at position 103 and S at position 106 and L at position 107.

[0149] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 4. For example, the VH comprises a sequence set forth in SEQ ID NO: 8; and the VL comprises a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A at position 8 and V at position 10 and I at position 18 and S at position 26 and G at position 31 and N at position 33 and M at position 49 and E at position 52 and S at position 54 and N at position 55 and S at position 61 and N at position 62 and I at position 77 and A at position 82 and E at position 83 and R at position 94 and S at position 95 and G at position 96 and S at position 97 and T at position 98 and L at position 99 and G at position 103 and L at position 107 and T at position 108.

[0150] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 4. For example, the VH comprises a sequence set forth in SEQ ID NO: 12; and the VL comprises a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises P at position 8 and A at position 10 and V at position 18 and N at position 26 and Y at position 31 and D at position 33 and I at position 49 and D at position 52 and T at position 54 and K at position 55 and P at position 61 and D at position 62 and V at position 77 and P at position 82 and D at position 83 and I at position 94 and G at position 95 and Y at position 96 and N at position 97 and L at position 98 and Y at position 99 and T at position 103 and V at position 107 and I at position 108.

[0151] In one example, the antibody variable region comprises a VH comprising a sequence set forth in any one of SEQ ID NOs: 6 to 15; and a VL comprising a sequence set forth in any one of SEQ ID NOs: 16 to 25. In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 6; and a VL comprising a sequence set forth in SEQ ID NO: 16.

[0152] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 7; and a VL comprising a sequence set forth in SEQ ID NO: 17.

[0153] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 8; and a VL comprising a sequence set forth in SEQ ID NO: 18.

[0154] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 9; and a VL comprising a sequence set forth in SEQ ID NO: 19.

[0155] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 10; and a VL comprising a sequence set forth in SEQ ID NO: 20.

[0156] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 11; and a VL comprising a sequence set forth in SEQ ID NO: 21.

[0157] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 12; and a VL comprising a sequence set forth in SEQ ID NO: 22.

[0158] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 13; and a VL comprising a sequence set forth in SEQ ID NO: 23.

[0159] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 14; and a VL comprising a sequence set forth in SEQ ID NO: 24.

[0160] In one example, the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 15; and a VL comprising a sequence set forth in SEQ ID NO: 25.

[0161] In one example, the antibody variable region comprises a VH comprising three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 1 or 2 or 6 to 15; and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 3 to 5 or 16 to 25.

[0162] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and V at position 99 and G at position 100 and E at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and A at position 43 and I at position 49 and N at position 53 and I at position 54 and P at position 56 and D at position 61 and G at position 65 and G at position 75 and S at position 94 and S at position 97 and S at position 98 and absent at position 99 and T at position 103 and K at position 106 and V at position 107.

[0163] In one example, the antibody variable region comprises:

[0164] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 36 of SEQ ID

[0165] NO: 1; a CDR2 comprising amino acid residues 51 to 66 of SEQ ID NO: 1 and a CDR3 comprising amino acid residues 99 to 119 of SEQ ID NO: 1, wherein SEQ ID NO: 1 comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and V at position 99 and G at position 100 and E at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and

[0166] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 35 of SEQ ID NO:

[0167] 3; a CDR2 comprising amino acid residues 51 to 57 of SEQ ID NO: 3; and a CDR3 comprising amino acid residues 90 to 100 of SEQ ID NO: 3, wherein SEQ ID NO: 3 comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and A at position 43 and I at position 49 and N at position 53 and I at position 54 and P at position 56 and D at position 61 and G at position 65 and G at position 75 and S at position 94 and S at position 97 and S at position 98 and absent at position 99 and T at position 103 and K at position 106 and V at position 107.

[0168] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises Q at position 6 and W at position 7 and A at position 9 and L at position 12 and E at position 16 and Y at position 25 and F at position 29 and G at position 31 and Y at position 32 and Y at position 33 and absent at position 34 and I at position 38 and N at position 53 and T at position 74 and G at position 98 and V at position 99 and G at position 100 and A at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and T at position 43 and I at position 49 and S at position 53 and E at position 54 and P at position 56 and D at position 61 and G at position 65 and D at position 75 and N at position 94 and T at position 97 and H at position 98 and absent at position 99 and T at position 103 and T at position 106 and V at position 107.

[0169] In one example, the antibody variable region comprises:

[0170] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 36 of SEQ ID NO: 1; a CDR2 comprising amino acid residues 51 to 66 of SEQ ID NO: 1 and a CDR3 comprising amino acid residues 99 to 119 of SEQ ID NO: 1, wherein SEQ ID NO: 1 comprises Q at position 6 and W at position 7 and A at position 9 and L at position 12 and E at position 16 and Y at position 25 and F at position 29 and G at position 31 and Y at position 32 and Y at position 33 and absent at position 34 and I at position 38 and N at position 53 and T at position 74 and G at position 98 and V at position 99 and G at position 100 and A at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and

[0171] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 35 of SEQ ID NO: 3; a CDR2 comprising amino acid residues 51 to 57 of SEQ ID NO: 3; and a CDR3 comprising amino acid residues 90 to 100 of SEQ ID NO: 3, wherein SEQ ID NO: 3 comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and T at position 43 and I at position 49 and S at position 53 and E at position 54 and P at position 56 and D at position 61 and G at position 65 and D at position 75 and N at position 94 and T at position 97 and H at position 98 and absent at position 99 and T at position 103 and T at position 106 and V at position 107.

[0172] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and D at position 99 and S at position 100 and R at position 101 and Q at position 102 and T at position 104 and V at position 105 and R at position 106 and G at position 107 and V at position 108 and I at position 109 and N at position 110 and N at position 111 and T at position 112 and P at position 113 and A at position 114 and C at position 115; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and A at position 17 and R at position 24 and Q at position 27 and T at position 28 and T at position 31 and H at position 38 and G at position 41 and K at position 42 and L at position 46 and A at position 50 and S at position 53 and Q at position 55 and S at position 56 and L at position 73 and S at position 77 and E at position 81 and F at position 83 and Q at position 90 and S at position 91 and Y at position 92 and S at position 93 and T at position 94.

[0173] In one example, the antibody variable region comprises:

[0174] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 36 of SEQ ID NO: 1; a CDR2 comprising amino acid residues 51 to 66 of SEQ ID NO: 1 and a CDR3 comprising amino acid residues 99 to 119 of SEQ ID NO: 1, wherein SEQ ID NO: 1 comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and D at position 99 and S at position 100 and R at position 101 and Q at position 102 and T at position 104 and V at position 105 and R at position 106 and G at position 107 and V at position 108 and I at position 109 and N at position 110 and N at position 111 and T at position 112 and P at position 113 and A at position 114 and C at position 115; and

[0175] (ii) a VL comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 5; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 5; and a CDR3 comprising amino acid residues 99 to 112 of SEQ ID NO: 5, wherein SEQ ID NO: 5 comprises L at position 4 and A at position 17 and R at position 24 and Q at position 27 and T at position 28 and T at position 31 and H at position 38 and G at position 41 and K at position 42 and L at position 46 and A at position 50 and S at position 53 and Q at position 55 and S at position 56 and L at position 73 and S at position 77 and E at position 81 and F at position 83 and Q at position 90 and S at position 91 and Y at position 92 and S at position 93 and T at position 94.

[0176] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises M at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and G at position 41 and Q at position 42 and V at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and S at position 77 and D at position 81 and I at position 83 and Q at position 90 and H at position 91 and E at position 92 and N at position 93 and L at position 94. In one example, the antibody variable region comprises:

[0177] (i) a VH comprising a CDR1 comprising amino acid residues 30 to 34 of SEQ ID NO: 2; a CDR2 comprising amino acid residues 49 to 65 of SEQ ID NO: 2 and a CDR3 comprising amino acid residues 98 to 112 of SEQ ID NO: 2, wherein SEQ ID NO: 2 comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and

[0178] (ii) a VL comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 5; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 5; and a CDR3 comprising amino acid residues 99 to 112 of SEQ ID NO: 5, wherein SEQ ID NO: 5 comprises M at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and G at position 41 and Q at position 42 and V at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and S at position 77 and D at position 81 and I at position 83 and Q at position 90 and H at position 91 and E at position 92 and N at position 93 and L at position 94.

[0179] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and N at position 41 and K at position 42 and L at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and N at position 77 and D at position 81 and I at position 83 and H at position 90 and H at position 91 and Y at position 92 and N at position 93 and L at position 94.

[0180] In one example, the antibody variable region comprises:

[0181] (i) a VH comprising a CDR1 comprising amino acid residues 30 to 34 of SEQ ID NO: 2; a CDR2 comprising amino acid residues 49 to 65 of SEQ ID NO: 2 and a CDR3 comprising amino acid residues 98 to 112 of SEQ ID NO: 2, wherein SEQ ID NO: 2 comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and

[0182] (ii) a VL comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 5; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 5; and a CDR3 comprising amino acid residues 99 to 112 of SEQ ID NO: 5, wherein SEQ ID NO: 5 comprises L at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and N at position 41 and K at position 42 and L at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and N at position 77 and D at position 81 and I at position 83 and H at position 90 and H at position 91 and Y at position 92 and N at position 93 and L at position 94.

[0183] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises K at position 12 and K at position 23 and A at position 24 and Y at position 32 and Y at position 33 and M at position 34 and H at position 35 and V at position 37 and P at position 41 and M at position 48 and I at position 50 and I at position 51 and S at position 54 and G at position 55 and S at position 57 and S at position 59 and D at position 73 and T at position 76 and S at position 77 and V at position 79 and A at position 99 and I at position 101 and E at position 102 and G at position 103 and Y and Y at position 105 and Y at position 106 and Y at position 107 and Y at position 108 and Y at position 109; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21.

[0184] In one example, the antibody variable region comprises:

[0185] (i) a VH comprising a CDR1 comprising amino acid residues 30 to 34 of SEQ ID NO: 2; a CDR2 comprising amino acid residues 49 to 65 of SEQ ID NO: 2 and a CDR3 comprising amino acid residues 98 to 112 of SEQ ID NO: 2, wherein SEQ ID NO: 2 comprises K at position 12 and K at position 23 and A at position 24 and Y at position 32 and Y at position 33 and M at position 34 and H at position 35 and V at position 37 and P at position 41 and M at position 48 and I at position 50 and I at position 51 and S at position 54 and G at position 55 and S at position 57 and S at position 59 and D at position 73 and T at position 76 and S at position 77 and V at position 79 and A at position 99 and I at position 101 and E at position 102 and G at position 103 and Y and Y at position 105 and Y at position 106 and Y at position 107 and Y at position 108 and Y at position 109

[0186] (ii) a VL comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 21; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 21; and a CDR3 comprising amino acid residues 99 to 112 of SEQ ID NO: 21.

[0187] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises S at position 31 and H at position 33 and V at position 40 and A at position 41 and S at position 43 and V at position 49 and D at position 53 and R at position 54 and H at position 56 and A at position 61 and A at position 65 and V at position 75 and N at position 94 and S at position 97 and V at position 98 and E at position 99 and G at position 103 and S at position 106 and L at position 107.

[0188] In one example, the antibody variable region comprises:

[0189] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 9; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 9 and a CDR3 comprising amino acid residues 100 to 109 of SEQ ID NO: 9; and (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 35 of SEQ ID NO: 3; a CDR2 comprising amino acid residues 51 to 57 of SEQ ID NO: 3; and a CDR3 comprising amino acid residues 90 to 100 of SEQ ID NO: 3, wherein SEQ ID NO: 3 comprises S at position 31 and H at position 33 and V at position 40 and A at position 41 and S at position 43 and V at position 49 and D at position 53 and R at position 54 and H at position 56 and A at position 61 and A at position 65 and V at position 75 and N at position 94 and S at position 97 and V at position 98 and E at position 99 and G at position 103 and S at position 106 and L at position 107.

[0190] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A at position 8 and V at position 10 and I at position 18 and S at position 26 and G at position 31 and N at position 33 and M at position 49 and E at position 52 and S at position 54 and N at position 55 and S at position 61 and N at position 62 and I at position 77 and A at position 82 and E at position 83 and R at position 94 and S at position 95 and G at position 96 and S at position 97 and T at position 98 and L at position 99 and G at position 103 and L at position 107 and T at position 108.

[0191] In one example, the antibody variable region comprises:

[0192] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 8; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 8 and a CDR3 comprising amino acid residues 99 to 118 of SEQ ID NO: 8; and

[0193] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 36 of SEQ ID NO: 4; a CDR2 comprising amino acid residues 52 to 58 of SEQ ID NO: 4; and a CDR3 comprising amino acid residues 91 to 100 of SEQ ID NO: 4, wherein SEQ ID NO: 4 comprises A at position 8 and V at position 10 and I at position 18 and S at position 26 and G at position 31 and N at position 33 and M at position 49 and E at position 52 and S at position 54 and N at position 55 and S at position 61 and N at position 62 and I at position 77 and A at position 82 and E at position 83 and R at position 94 and S at position 95 and G at position 96 and S at position 97 and T at position 98 and L at position 99 and G at position 103 and L at position 107 and T at position 108.

[0194] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4. For example, the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12; and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises P at position 8 and A at position 10 and V at position 18 and N at position 26 and Y at position 31 and D at position 33 and I at position 49 and D at position 52 and T at position 54 and K at position 55 and P at position 61 and D at position 62 and V at position 77 and P at position 82 and D at position 83 and I at position 94 and G at position 95 and Y at position 96 and N at position 97 and L at position 98 and Y at position 99 and T at position 103 and V at position 107 and I at position 108.

[0195] In one example, the antibody variable region comprises:

[0196] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 12; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 12 and a CDR3 comprising amino acid residues 99 to 104 of SEQ ID NO: 12; and

[0197] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 36 of SEQ ID NO: 4; a CDR2 comprising amino acid residues 52 to 58 of SEQ ID NO: 4; and a CDR3 comprising amino acid residues 91 to 100 of SEQ ID NO: 4, wherein SEQ ID NO: 4 comprises P at position 8 and A at position 10 and V at position 18 and N at position 26 and Y at position 31 and D at position 33 and I at position 49 and D at position 52 and T at position 54 and K at position 55 and P at position 61 and D at position 62 and V at position 77 and P at position 82 and D at position 83 and I at position 94 and G at position 95 and Y at position 96 and N at position 97 and L at position 98 and Y at position 99 and T at position 103 and V at position 107 and I at position 108.

[0198] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6 to 15; and a VL comprising a sequence set forth in any one of SEQ ID NOs: 16 to 25.

[0199] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16.

[0200] In one example, the antibody variable region comprises:

[0201] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 6; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 6 and a CDR3 comprising amino acid residues 99 to 104 of SEQ ID NO: 6; and (ii) a VL comprising a CDR1 comprising amino acid residues 24 to 34 of SEQ ID NO: 16; a CDR2 comprising amino acid residues 50 to 56 of SEQ ID NO: 16; and a CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 16.

[0202] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17.

[0203] In one example, the antibody variable region comprises:

[0204] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 7; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 7 and a CDR3 comprising amino acid residues 99 to 104 of SEQ ID NO: 7; and

[0205] (ii) a VL comprising a CDR1 comprising amino acid residues 24 to 34 of SEQ ID NO: 17; a CDR2 comprising amino acid residues 50 to 56 of SEQ ID NO: 17; and a CDR3 comprising amino acid residues 89 to 97 of SEQ ID NO: 17.

[0206] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18.

[0207] In one example, the antibody variable region comprises:

[0208] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 8; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 8 and a CDR3 comprising amino acid residues 99 to 118 of SEQ ID NO: 8; and

[0209] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 36 of SEQ ID NO: 18; a CDR2 comprising amino acid residues 52 to 58 of SEQ ID NO: 18; and a CDR3 comprising amino acid residues 91 to 100 of SEQ ID NO: 18.

[0210] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19.

[0211] In one example, the antibody variable region comprises:

[0212] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 9; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 9 and a CDR3 comprising amino acid residues 100 to 109 of SEQ ID NO: 9; and

[0213] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 35 of SEQ ID NO: 19; a CDR2 comprising amino acid residues 51 to 57 of SEQ ID NO: 19; and a CDR3 comprising amino acid residues 90 to 100 of SEQ ID NO: 19.

[0214] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20. In one example, the antibody variable region comprises:

[0215] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 36 of SEQ ID NO: 10; a CDR2 comprising amino acid residues 51 to 66 of SEQ ID NO: 10 and a CDR3 comprising amino acid residues 99 to 107 of SEQ ID NO: 10; and

[0216] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 35 of SEQ ID NO: 20; a CDR2 comprising amino acid residues 51 to 57 of SEQ ID NO: 20; and a CDR3 comprising amino acid residues 90 to 99 of SEQ ID NO: 20.

[0217] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21.

[0218] In one example, the antibody variable region comprises:

[0219] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 11; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 11 and a CDR3 comprising amino acid residues 99 to 112 of SEQ ID NO: 11; and

[0220] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 36 of SEQ ID NO: 21; a CDR2 comprising amino acid residues 52 to 58 of SEQ ID NO: 21; and a CDR3 comprising amino acid residues 91 to 101 of SEQ ID NO: 21.

[0221] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22.

[0222] In one example, the antibody variable region comprises:

[0223] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 12; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 12 and a CDR3 comprising amino acid residues 99 to 104 of SEQ ID NO: 12; and

[0224] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 36 of SEQ ID NO: 22; a CDR2 comprising amino acid residues 52 to 58 of SEQ ID NO: 22; and a CDR3 comprising amino acid residues 91 to 100 of SEQ ID NO: 22.

[0225] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23.

[0226] In one example, the antibody variable region comprises:

[0227] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 13; a CDR2 comprising amino acid residues 50 to 65 of SEQ ID NO: 13 and a CDR3 comprising amino acid residues 98 to 105 of SEQ ID NO: 13; and (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 35 of SEQ ID NO: 23; a CDR2 comprising amino acid residues 51 to 57 of SEQ ID NO: 23; and a CDR3 comprising amino acid residues 90 to 99 of SEQ ID NO: 23.

[0228] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24.

[0229] In one example, the antibody variable region comprises:

[0230] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 35 of SEQ ID NO: 14; a CDR2 comprising amino acid residues 50 to 66 of SEQ ID NO: 14 and a CDR3 comprising amino acid residues 99 to 108 of SEQ ID NO: 14; and

[0231] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 33 of SEQ ID NO: 24; a CDR2 comprising amino acid residues 49 to 55 of SEQ ID NO: 24; and a CDR3 comprising amino acid residues 88 to 96 of SEQ ID NO: 24.

[0232] In one example, the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25.

[0233] In one example, the antibody variable region comprises:

[0234] (i) a VH comprising a CDR1 comprising amino acid residues 31 to 36 of SEQ ID NO: 15; a CDR2 comprising amino acid residues 51 to 66 of SEQ ID NO: 15 and a CDR3 comprising amino acid residues 99 to 119 of SEQ ID NO: 15; and

[0235] (ii) a VL comprising a CDR1 comprising amino acid residues 23 to 33 of SEQ ID NO: 25; a CDR2 comprising amino acid residues 49 to 55 of SEQ ID NO: 25; and a CDR3 comprising amino acid residues 88 to 96 of SEQ ID NO: 25.

[0236] In one example, the binding protein is selected from the group consisting of:

[0237] (i) a single chain Fv fragment (scFv);

[0238] (ii) a dimeric scFv (di-scFv);

[0239] (iii) a diabody;

[0240] (iv) a triabody;

[0241] (v) a tetrabody;

[0242] (vi) a Fab;

[0243] (vii) a F(ab’)2;

[0244] (viii) a Fv;

[0245] (ix) one of (i) to (viii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and / or CH3; and

[0246] (x) an antibody.

[0247] In one example, the binding protein is an antibody and comprises: (i) a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25; or

[0248] (ii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25; or

[0249] (iii)a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21; or

[0250] (iv)a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21; or

[0251] (v) a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising a sequence set forth in SEQ ID NO: 3; or

[0252] (vi)a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3; or

[0253] (vii) a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising a sequence set forth in SEQ ID NO: 4; or

[0254] (viii) a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4; or

[0255] (ix)a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising a sequence set forth in SEQ ID NO: 5; or

[0256] (x) a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5.

[0257] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25. In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises wherein the sequence comprises Q or E at position 6 and / or W or S at position 7 and / or A or P at position 9 and / or L or V at position 12 and / or E or G at position 16 and / or Y or S at position 25 and / or F or I at position 29 and / or G or S at position 31 and / or Y or S at position 32 and / or Y or N at position 33 and / or W or absent at position 34 and / or I or V at position 38 and / or N or Y at position 53 and / or T or K at position 74 and / or G or R at position 98 and / or V or D at position 99 and / or G or S at position 100 and / or A or E or R at position 101 and / or H or Q at position 102 and / or T or absent at position 104 and / or V or absent at position 105 and / or R or absent at position 106 and / or G or absent at position 107 and / or V or absent at position 108 and / or I or absent at position 109 and / or N or absent at position 110 and / or N or absent at position 111 and / or T or absent at position 112 and / or P or absent at position 113 and / or A or absent at position 114 and / or C or absent at position 115; and a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25.

[0258] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and V at position 99 and G at position 100 and E at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and a VL comprising a sequence set forth in SEQ ID NO: 20.

[0259] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises Q at position 6 and W at position 7 and A at position 9 and L at position 12 and E at position 16 and Y at position 25 and F at position 29 and G at position 31 and Y at position 32 and Y at position 33 and absent at position 34 and I at position 38 and N at position 53 and T at position 74 and G at position 98 and V at position 99 and G at position 100 and A at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and a VL comprising a sequence set forth in SEQ ID NO: 23.

[0260] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and D at position 99 and S at position 100 and R at position 101 and Q at position 102 and T at position 104 and V at position 105 and R at position 106 and G at position 107 and V at position 108 and I at position 109 and N at position 110 and N at position 111 and T at position 112 and P at position 113 and A at position 114 and C at position 115; and a VL comprising a sequence set forth in SEQ ID NO: 25.

[0261] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25. For example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises Q or E at position 6 and / or W or S at position 7 and / or A or P at position 9 and / or L or V at position 12 and / or E or G at position 16 and / or Y or S at position 25 and / or F or I at position 29 and / or G or S at position 31 and / or Y or S at position 32 and / or Y or N at position 33 and / or W or absent at position 34 and / or I or V at position 38 and / or N or Y at position 53 and / or T or K at position 74 and / or G or R at position 98 and / or V or D at position 99 and / or G or S at position 100 and / or A or E or R at position 101 and / or H or Q at position 102 and / or T or absent at position 104 and / or V or absent at position 105 and / or R or absent at position 106 and / or G or absent at position 107 and / or V or absent at position 108 and / or I or absent at position 109 and / or N or absent at position 110 and / or N or absent at position 111 and / or T or absent at position 112 and / or P or absent at position 113 and / or A or absent at position 114 and / or C or absent at position 115; and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25.

[0262] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and V at position 99 and G at position 100 and E at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20.

[0263] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises Q at position 6 and W at position 7 and A at position 9 and L at position 12 and E at position 16 and Y at position 25 and F at position 29 and G at position 31 and Y at position 32 and Y at position 33 and absent at position 34 and I at position 38 and N at position 53 and T at position 74 and G at position 98 and V at position 99 and G at position 100 and A at position 101 and H at position 102 and absent at position 104 and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and absent at position 110 and absent at position 111 and absent at position 112 and absent at position 113 and absent at position 114 and absent at position 115; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23.

[0264] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1, wherein the sequence comprises E at position 6 and S at position 7 and P at position 9 and V at position 12 and G at position 16 and S at position 25 and I at position 29 and S at position 31 and S at position 32 and N at position 33 and W at position 34 and V at position 38 and Y at position 53 and K at position 74 and R at position 98 and D at position 99 and S at position 100 and R at position 101 and Q at position 102 and T at position 104 and

[0265] V at position 105 and R at position 106 and G at position 107 and V at position 108 and I at position 109 and N at position 110 and N at position 111 and T at position 112 and P at position 113 and A at position 114 and C at position 115; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25.

[0266] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21. For example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q or K at position 12 and / or M or K at position 23 and / or S or A at position 24 and / or S or Y at position 32 and / or N or Y at position 33 and / or I or M at position 34 and / or N or H at position 35 and / or I or V at position 37 and / or T or P at position 41 and / or L or M at position 48 and / or W or I at position 50 and / or M or I at position 51 and / or N or S at position 54 and / or T or G at position 55 and / or N or S at position 57 and / or G or S at position 59 and / or N or D at position 73 and / or I or T at position 76 and / or N or S at position 77 and / or A or V at position 79 and / or G or A at position 99 and / or S or I at position 101 and / or E or absent at position 102 and / or G or absent at position 103 and / or Y or absent and / or Y or absent at position 105 and / or Y or absent at position 106 and / or Y or absent at position 107 and / or Y or absent at position 108 and / or

[0267] Y or absent at position 109 and a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21. In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109and a VL comprising a sequence set forth in SEQ ID NO: 16.

[0268] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109 and a VL comprising a sequence set forth in SEQ ID NO: 17.

[0269] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises K at position 12 and K at position 23 and A at position 24 and Y at position 32 and Y at position 33 and M at position 34 and H at position 35 and V at position 37 and P at position 41 and M at position 48 and I at position 50 and I at position 51 and S at position 54 and G at position 55 and S at position 57 and S at position 59 and D at position 73 and T at position 76 and S at position 77 and V at position 79 and A at position 99 and I at position 101 and E at position 102 and G at position 103 and Y and Y at position 105 and Y at position 106 and Y at position 107 and Y at position 108 and Y at position 109 and a VL comprising a sequence set forth in SEQ ID NO: 21.

[0270] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21. For example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q or K at position 12 and / or M or K at position 23 and / or S or A at position 24 and / or S or Y at position 32 and / or N or Y at position 33 and / or I or M at position 34 and / or N or H at position 35 and / or I or V at position 37 and / or T or P at position 41 and / or L or M at position 48 and / or W or I at position 50 and / or M or I at position 51 and / or N or S at position 54 and / or T or G at position 55 and / or N or S at position 57 and / or G or S at position 59 and / or N or D at position 73 and / or I or T at position 76 and / or N or S at position 77 and / or A or V at position 79 and / or G or A at position 99 and / or S or I at position 101 and / or E or absent at position 102 and / or G or absent at position 103 and / or Y or absent and / or Y or absent at position 105 and / or Y or absent at position 106 and / or Y or absent at position 107 and / or Y or absent at position 108 and / or Y or absent at position 109; and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21.

[0271] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16.

[0272] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises Q at position 12 and M at position 23 and S at position 24 and S at position 32 and N at position 33 and I at position 34 and N at position 35 and I at position 37 and T at position 41 and L at position 48 and W at position 50 and M at position 51 and N at position 54 and T at position 55 and N at position 57 and G at position 59 and N at position 73 and I at position 76 and N at position 77 and A at position 79 and G at position 99 and S at position 101 and absent at position 102 and absent at position 103 and absent and absent at position 105 and absent at position 106 and absent at position 107 and absent at position 108 and absent at position 109; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17.

[0273] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2, wherein the sequence comprises K at position 12 and K at position 23 and A at position 24 and Y at position 32 and Y at position 33 and M at position 34 and H at position 35 and V at position 37 and P at position 41 and M at position 48 and I at position 50 and I at position 51 and S at position 54 and G at position 55 and S at position 57 and S at position 59 and D at position 73 and T at position 76 and S at position 77 and V at position 79 and A at position 99 and I at position 101 and E at position 102 and G at position 103 and Y and

[0274] Y at position 105 and Y at position 106 and Y at position 107 and Y at position 108 and

[0275] Y at position 109; and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21.

[0276] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N or S at position 31 and / or Y or H at position 33 and / or L or V at position 40 and / or P or A at position 41 and / or A or T or S at position 43 and / or I or V at position 49 and / or N or S or D at position 53 and / or I or E or R at position 54 and / or P or H at position 56 and / or D or A at position 61 and / or G or A at position 65 and / or G or D or V at position 75 and / or S or N at position 94 and / or S or T at position 97 and / or S or H or V at position 98 and / or E or absent at position 99 and / or T or G at position 103 and / or K or T or S at position 106 and / or V or L at position 107.

[0277] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises S at position 31 and H at position 33 and V at position 40 and A at position 41 and S at position 43 and V at position 49 and D at position 53 and R at position 54 and H at position 56 and A at position 61 and A at position 65 and V at position 75 and N at position 94 and S at position 97 and V at position 98 and E at position 99 and G at position 103 and S at position 106 and L at position 107.

[0278] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and A at position 43 and I at position 49 and N at position 53 and I at position 54 and P at position 56 and D at position 61 and G at position 65 and G at position 75 and S at position 94 and S at position 97 and S at position 98 and absent at position 99 and T at position 103 and K at position 106 and V at position 107. In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and T at position 43 and I at position 49 and S at position 53 and E at position 54 and P at position 56 and D at position 61 and G at position 65 and D at position 75 and N at position 94 and T at position 97 and H at position 98 and absent at position 99 and T at position 103 and T at position 106 and V at position 107.

[0279] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3. For example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N or S at position 31 and / or Y or H at position 33 and / or L or V at position 40 and / or P or A at position 41 and / or A or T or S at position 43 and / or I or V at position 49 and / or N or S or D at position 53 and / or I or E or R at position 54 and / or P or H at position 56 and / or D or A at position 61 and / or G or A at position 65 and / or G or D or V at position 75 and / or S or N at position 94 and / or S or T at position 97 and / or S or H or V at position 98 and / or E or absent at position 99 and / or T or G at position 103 and / or K or T or S at position 106 and / or V or L at position 107.

[0280] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises S at position 31 and H at position 33 and V at position 40 and A at position 41 and S at position 43 and V at position 49 and D at position 53 and R at position 54 and H at position 56 and A at position 61 and A at position 65 and V at position 75 and N at position 94 and S at position 97 and V at position 98 and E at position 99 and G at position 103 and S at position 106 and L at position 107.

[0281] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and A at position 43 and I at position 49 and N at position 53 and I at position 54 and P at position 56 and D at position 61 and G at position 65 and G at position 75 and S at position 94 and S at position 97 and S at position 98 and absent at position 99 and T at position 103 and K at position 106 and V at position 107.

[0282] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3, wherein the sequence comprises N at position 31 and Y at position 33 and L at position 40 and P at position 41 and T at position 43 and I at position 49 and S at position 53 and E at position 54 and P at position 56 and D at position 61 and G at position 65 and D at position 75 and N at position 94 and T at position 97 and H at position 98 and absent at position 99 and T at position 103 and T at position 106 and V at position 107.

[0283] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising a sequence set forth in SEQ ID NO: 4. For example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A or P at position 8 and / or V or A at position 10 and / or I or V at position 18 and / or S or N at position 26 and / or G or Y at position 31 and / or N or D at position 33 and / or M or I at position 49 and / or E or D at position 52 and / or S or T at position 54 and / or N or K at position 55 and / or S or P at position 61 and / or N or D at position 62 and / or I or V at position 77 and / or A or P at position 82 and / or E or D at position 83 and / or R or I at position 94 and / or S or G at position 95 and / or G or Y at position 96 and / or S or N at position 97 and / or T or L at position 98 and / or L or Y at position 99 and / or G or T at position 103 and / or L or V at position 107 and / or T or I at position 108.

[0284] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A at position 8 and V at position 10 and I at position 18 and S at position 26 and G at position 31 and N at position 33 and M at position 49 and E at position 52 and S at position 54 and N at position 55 and S at position 61 and N at position 62 and I at position 77 and A at position 82 and E at position 83 and R at position 94 and S at position 95 and G at position 96 and S at position 97 and T at position 98 and L at position 99 and G at position 103 and L at position 107 and T at position 108.

[0285] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises P at position 8 and A at position 10 and V at position 18 and N at position 26 and Y at position 31 and D at position 33 and I at position 49 and D at position 52 and T at position 54 and K at position 55 and P at position 61 and D at position 62 and V at position 77 and P at position 82 and D at position 83 and I at position 94 and G at position 95 and Y at position 96 and N at position 97 and L at position 98 and Y at position 99 and T at position 103 and V at position 107 and I at position 108.

[0286] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4. For example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A or P at position 8 and / or V or A at position 10 and / or I or V at position 18 and / or S or N at position 26 and / or G or Y at position 31 and / or N or D at position 33 and / or M or I at position 49 and / or E or D at position 52 and / or S or T at position 54 and / or N or K at position 55 and / or S or P at position 61 and / or N or D at position 62 and / or I or V at position 77 and / or A or P at position 82 and / or E or D at position 83 and / or R or I at position 94 and / or S or G at position 95 and / or G or Y at position 96 and / or S or N at position 97 and / or T or L at position 98 and / or L or Y at position 99 and / or G or T at position 103 and / or L or V at position 107 and / or T or I at position 108.

[0287] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises A at position 8 and V at position 10 and I at position 18 and S at position 26 and G at position 31 and N at position 33 and M at position 49 and E at position 52 and S at position 54 and N at position 55 and S at position 61 and N at position 62 and I at position 77 and A at position 82 and E at position 83 and R at position 94 and S at position 95 and G at position 96 and S at position 97 and T at position 98 and L at position 99 and G at position 103 and L at position 107 and T at position 108.

[0288] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4, wherein the sequence comprises P at position 8 and A at position 10 and V at position 18 and N at position 26 and Y at position 31 and D at position 33 and I at position 49 and D at position 52 and T at position 54 and K at position 55 and P at position 61 and D at position 62 and V at position 77 and P at position 82 and D at position 83 and I at position 94 and G at position 95 and Y at position 96 and N at position 97 and L at position 98 and Y at position 99 and T at position 103 and V at position 107 and I at position 108.

[0289] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L or M at position 4 and / or D or A at position 17 and / or Q or R at position 24 and / or H or Q at position 27 and / or D or T at position 28 and / or N or T at position 31 and / or Q or H at position 38 and / or N or G at position 41 and / or K or Q at position 42 and / or L or V at position 46 and / or D or A at position 50 and / or N or S at position 53 and / or E or Q at position 55 and / or A or S at position 56 and / or F or L at position 73 and / or N or S at position 77 and / or D or E at position 81 and / or I or F at position 83 and / or H or Q at position 90 and / or H or S at position 91 and / or Y or E at position 92 and / or N or S at position 93 and / or L or T at position 94.

[0290] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises M at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and G at position 41 and Q at position 42 and V at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and S at position 77 and D at position 81 and I at position 83 and Q at position 90 and H at position 91 and E at position 92 and N at position 93 and L at position 94.

[0291] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and N at position 41 and K at position 42 and L at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and N at position 77 and D at position 81 and I at position 83 and H at position 90 and H at position 91 and Y at position 92 and N at position 93 and L at position 94.

[0292] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and A at position 17 and R at position 24 and Q at position 27 and T at position 28 and T at position 31 and H at position 38 and G at position 41 and K at position 42 and L at position 46 and A at position 50 and S at position 53 and Q at position 55 and S at position 56 and L at position 73 and S at position 77 and E at position 81 and F at position 83 and Q at position 90 and S at position 91 and Y at position 92 and S at position 93 and T at position 94.

[0293] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5. For example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L or M at position 4 and / or D or A at position 17 and / or Q or R at position 24 and / or H or Q at position 27 and / or D or T at position 28 and / or N or T at position 31 and / or Q or H at position 38 and / or N or G at position 41 and / or K or Q at position 42 and / or L or V at position 46 and / or D or A at position 50 and / or N or S at position 53 and / or E or Q at position 55 and / or A or S at position 56 and / or F or L at position 73 and / or N or S at position 77 and / or D or E at position 81 and / or I or F at position 83 and / or H or Q at position 90 and / or H or S at position 91 and / or Y or E at position 92 and / or N or S at position 93 and / or L or T at position 94.

[0294] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises M at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and G at position 41 and Q at position 42 and V at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and S at position 77 and D at position 81 and I at position 83 and Q at position 90 and H at position 91 and E at position 92 and N at position 93 and L at position 94.

[0295] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and D at position 17 and Q at position 24 and H at position 27 and D at position 28 and N at position 31 and Q at position 38 and N at position 41 and K at position 42 and L at position 46 and D at position 50 and N at position 53 and E at position 55 and A at position 56 and F at position 73 and N at position 77 and D at position 81 and I at position 83 and H at position 90 and H at position 91 and Y at position 92 and N at position 93 and L at position 94. In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5, wherein the sequence comprises L at position 4 and A at position 17 and R at position 24 and Q at position 27 and T at position 28 and T at position 31 and H at position 38 and G at position 41 and K at position 42 and L at position 46 and A at position 50 and S at position 53 and Q at position 55 and S at position 56 and L at position 73 and S at position 77 and E at position 81 and F at position 83 and Q at position 90 and S at position 91 and Y at position 92 and S at position 93 and T at position 94.

[0296] In one example, the binding protein is an antibody and comprises:

[0297] (i) a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising a sequence set forth in SEQ ID NO: 16; or

[0298] (ii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16; or

[0299] (iii)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising a sequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44; or

[0300] (iv)a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising a sequence set forth in SEQ ID NO: 17; or

[0301] (v) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17; or

[0302] (vi)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 50; or

[0303] (vii) a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 18; or (viii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18; or

[0304] (ix)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56; or

[0305] (x) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 19; or

[0306] (xi)a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19; or

[0307] (xii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62; or

[0308] (xiii) a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO: 20; or

[0309] (xiv) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20; or

[0310] (xv) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68; or

[0311] (xvi) a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO: 21; or

[0312] (xvii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21; or (xviii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74; or

[0313] (xix) a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 22; or

[0314] (xx) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22; or

[0315] (xxi) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80; or

[0316] (xxii) a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising a sequence set forth in SEQ ID NO: 23; or

[0317] (xxiii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23; or

[0318] (xxiv) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 81, a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86; or

[0319] (xxv) a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO: 24; or

[0320] (xxvi) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24; or

[0321] (xxvii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92; or

[0322] (xxviii) a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising a sequence set forth in SEQ ID NO: 25; or

[0323] (xxix) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25; or

[0324] (xxx) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

[0325] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising a sequence set forth in SEQ ID NO: 16.

[0326] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16.

[0327] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising a sequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44.

[0328] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising a sequence set forth in SEQ ID NO: 17.

[0329] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17.

[0330] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 5.

[0331] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 18.

[0332] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18.

[0333] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56.

[0334] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 19.

[0335] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19.

[0336] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62.

[0337] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO: 20.

[0338] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20.

[0339] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68.

[0340] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO: 21.

[0341] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21.

[0342] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74.

[0343] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 22.

[0344] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22.

[0345] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80.

[0346] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising a sequence set forth in SEQ ID NO: 23.

[0347] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23.

[0348] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 81, a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86.

[0349] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO: 24.

[0350] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24.

[0351] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92.

[0352] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising a sequence set forth in SEQ ID NO: 25.

[0353] In one example, the binding protein is an antibody and comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25.

[0354] In one example, the binding protein is an antibody and comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

[0355] In one example, the binding protein is an antibody and further comprises a light chain constant domain comprising a sequence set forth in any one of SEQ ID NO: 36, 37 or 38. For example, the binding protein is an antibody and further comprises a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36. In one example, the binding protein is an antibody and further comprises a light chain constant domain comprising a sequence set forth in SEQ ID NO: 37. In another example, the binding protein is an antibody and further comprises a light chain constant domain comprising a sequence set forth in SEQ ID NO: 38.

[0356] In one example, the binding protein is an antibody and comprises a VH and a VL of the present disclosure, wherein the VH is linked to a human heavy chain constant region and the VL is linked to a human light chain constant region. For example, the binding protein comprises a heavy chain constant region of isotype IgG4 and a light chain constant region of isotype lambda or kappa. In one example, the binding protein comprises an IgG4 heavy chain and a lambda light chain. In one example, the binding protein comprises an IgG4 heavy chain and a kappa light chain.

[0357] In one example, the binding protein is an antibody and comprises:

[0358] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in any one of SEQ ID NO: 1 or 2 or 6 to 15; and

[0359] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in any one of SEQ ID NO: 3 to 5 or 16 to 25.

[0360] In one example, the binding protein is an antibody and comprises:

[0361] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in any one of SEQ ID NO: 1 or 2 or 6 to 15; and

[0362] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in any one of SEQ ID NO: 3 to 5 or 16 to 25.

[0363] In one example, the binding protein is an antibody and comprises:

[0364] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 6; and

[0365] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth SEQ ID NO: 16.

[0366] In one example, the binding protein is an antibody and comprises:

[0367] (iii)an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 6; and

[0368] (iv) a kappa light chain comprising a VL comprising an amino acid sequence set forth SEQ ID NO: 16.

[0369] In one example, the binding protein is an antibody and comprises:

[0370] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 7; and

[0371] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth SEQ ID NO: 17.

[0372] In one example, the binding protein is an antibody and comprises:

[0373] (iii)an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 7; and

[0374] (iv) a kappa light chain comprising a VL comprising an amino acid sequence set forth SEQ ID NO: 17.

[0375] In one example, the binding protein is an antibody and comprises: (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 8; and

[0376] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 18.

[0377] In one example, the binding protein is an antibody and comprises:

[0378] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 8; and

[0379] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 18.

[0380] In one example, the binding protein is an antibody and comprises:

[0381] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 9; and

[0382] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 19.

[0383] In one example, the binding protein is an antibody and comprises:

[0384] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 9; and

[0385] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 19.

[0386] In one example, the binding protein is an antibody and comprises:

[0387] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 10; and

[0388] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 20.

[0389] In one example, the binding protein is an antibody and comprises:

[0390] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 10; and

[0391] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 20.

[0392] In one example, the binding protein is an antibody and comprises:

[0393] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 11; and

[0394] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 21.

[0395] In one example, the binding protein is an antibody and comprises: (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 11; and

[0396] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 21.

[0397] In one example, the binding protein is an antibody and comprises:

[0398] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 12; and

[0399] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 22.

[0400] In one example, the binding protein is an antibody and comprises:

[0401] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 12; and

[0402] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 22.

[0403] In one example, the binding protein is an antibody and comprises:

[0404] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 13; and

[0405] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 23.

[0406] In one example, the binding protein is an antibody and comprises:

[0407] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 13; and

[0408] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 23.

[0409] In one example, the binding protein is an antibody and comprises:

[0410] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 14; and

[0411] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 24.

[0412] In one example, the binding protein is an antibody and comprises:

[0413] (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 14; and

[0414] (ii) a kappa light chain comprising a VL comprising an amino acid sequence set forth in SEQ ID NO: 24.

[0415] In one example, the binding protein is an antibody and comprises: (i) an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 15; and

[0416] (ii) a lambda light chain comprising a VL comprising an amino acid sequence set forth SEQ ID NO: 25.

[0417] In one example, the binding protein is an antibody and comprises:

[0418] (iii)an IgG4 heavy chain comprising a VH comprising an amino acid sequence set forth in SEQ ID NO: 15; and

[0419] (iv) a kappa light chain comprising a VL comprising an amino acid sequence set forth SEQ ID NO: 25.

[0420] In one example, the binding protein is an antibody and comprises:

[0421] (i) a VH comprising a sequence set forth in SEQ ID NO: 6, a VL comprising a sequence set forth in SEQ ID NO: 16; and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 37; or

[0422] (ii) a VH comprising a sequence set forth in SEQ ID NO: 6, a light chain comprising a sequence set forth in SEQ ID NO: 26; or

[0423] (iii)a VH comprising a sequence set forth in SEQ ID NO: 7, a VL comprising a sequence set forth in SEQ ID NO: 17 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 37; or

[0424] (iv)a VH comprising a sequence set forth in SEQ ID NO: 7 and a light chain comprising a sequence set forth in SEQ ID NO: 27; or

[0425] (v) a VH comprising a sequence set forth in SEQ ID NO: 8, a VL comprising a sequence set forth in SEQ ID NO: 18 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or

[0426] (vi)a VH comprising a sequence set forth in SEQ ID NO: 8 and a light chain comprising a sequence set forth in SEQ ID NO: 28; or

[0427] (vii) a VH comprising a sequence set forth in SEQ ID NO: 9, a VL comprising a sequence set forth in SEQ ID NO: 19 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or

[0428] (viii) a VH comprising a sequence set forth in SEQ ID NO: 9 and a light chain comprising a sequence set forth in SEQ ID NO: 29; or

[0429] (ix)a VH comprising a sequence set forth in SEQ ID NO: 10, a VL comprising a sequence set forth in SEQ ID NO: 20 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or

[0430] (x) a VH comprising a sequence set forth in SEQ ID NO: 10 and a light chain comprising a sequence set forth in SEQ ID NO: 30; or (xi)a VH comprising a sequence set forth in SEQ ID NO: 11, a VL comprising a sequence set forth in SEQ ID NO: 21 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or

[0431] (xii) a VH comprising a sequence set forth in SEQ ID NO: 11 and a light chain comprising a sequence set forth in SEQ ID NO: 31; or

[0432] (xiii) a VH comprising a sequence set forth in SEQ ID NO: 12, a VL comprising a sequence set forth in SEQ ID NO: 22 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or

[0433] (xiv) a VH comprising a sequence set forth in SEQ ID NO: 12 and a light chain comprising a sequence set forth in SEQ ID NO: 32; or

[0434] (xv) a VH comprising a sequence set forth in SEQ ID NO: 13, a VL comprising a sequence set forth in SEQ ID NO: 23 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or

[0435] (xvi) a VH comprising a sequence set forth in SEQ ID NO: 13 and a light chain comprising a sequence set forth in SEQ ID NO: 33; or

[0436] (xvii) a VH comprising a sequence set forth in SEQ ID NO: 14, a VL comprising a sequence set forth in SEQ ID NO: 24 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or

[0437] (xviii) a VH comprising a sequence set forth in SEQ ID NO: 14 and a light chain comprising a sequence set forth in SEQ ID NO: 34; or

[0438] (xix) a VH comprising a sequence set forth in SEQ ID NO: 15, a VL comprising a sequence set forth in SEQ ID NO: 25 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 38; or

[0439] (xx) a VH comprising a sequence set forth in SEQ ID NO: 15 and a light chain comprising a sequence set forth in SEQ ID NO: 35.

[0440] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 6, a VL comprising a sequence set forth in SEQ ID NO: 16; and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 37.

[0441] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 6, a light chain comprising a sequence set forth in SEQ ID NO: 26.

[0442] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 7, a VL comprising a sequence set forth in SEQ ID NO: 17 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 37. In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 7 and a light chain comprising a sequence set forth in SEQ ID NO: 27.

[0443] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 8, a VL comprising a sequence set forth in SEQ ID NO: 18 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36.

[0444] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 8 and a light chain comprising a sequence set forth in SEQ ID NO: 28.

[0445] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 9, a VL comprising a sequence set forth in SEQ ID NO: 19 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36.

[0446] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 9 and a light chain comprising a sequence set forth in SEQ ID NO: 29.

[0447] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 10, a VL comprising a sequence set forth in SEQ ID NO: 20 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36.

[0448] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 10 and a light chain comprising a sequence set forth in SEQ ID NO: 30.

[0449] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 11, a VL comprising a sequence set forth in SEQ ID NO: 21 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36.

[0450] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 11 and a light chain comprising a sequence set forth in SEQ ID NO: 31.

[0451] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 12, a VL comprising a sequence set forth in SEQ ID NO: 22 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36. In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 12 and a light chain comprising a sequence set forth in SEQ ID NO: 32.

[0452] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 13, a VL comprising a sequence set forth in SEQ ID NO: 23 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36.

[0453] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 13 and a light chain comprising a sequence set forth in SEQ ID NO: 33.

[0454] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 14, a VL comprising a sequence set forth in SEQ ID NO: 24 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36.

[0455] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 14 and a light chain comprising a sequence set forth in SEQ ID NO: 34.

[0456] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 15, a VL comprising a sequence set forth in SEQ ID NO: 25 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 38.

[0457] In one example, the binding protein is an antibody and comprises a VH comprising a sequence set forth in SEQ ID NO: 15 and a light chain comprising a sequence set forth in SEQ ID NO: 35.

[0458] In one example, the protein or antibody is any form of the protein or antibody encoded by a nucleic acid encoding any of the foregoing proteins or antibodies.

[0459] In one example, the binding protein is an antibody and comprises:

[0460] (i) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0461] NO: 99 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109; or

[0462] (ii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0463] NO: 99, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 119; or (iii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0464] NO: 100 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110; or

[0465] (iv) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0466] NO: 100, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 120; or

[0467] (v) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0468] NO: 101 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111; or

[0469] (vi) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0470] NO: 101, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 121; or

[0471] (vii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0472] NO: 102 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112; or

[0473] (viii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 102, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 122; or

[0474] (ix) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0475] NO: 103 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113; or

[0476] (x) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0477] NO: 103, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 123; or

[0478] (xi) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0479] NO: 104 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114; or (xii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 104, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 124; or

[0480] (xiii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 105 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115; or

[0481] (xiv) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0482] NO: 105, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 125; or

[0483] (xv) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0484] NO: 106 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116; or

[0485] (xvi) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0486] NO: 106, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 126; or

[0487] (xvii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 107 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117; or

[0488] (xviii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 107, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 127; or

[0489] (xix) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0490] NO: 108 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118; or

[0491] (xx) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0492] NO: 108, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 128.

[0493] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 99 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109.

[0494] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 99, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 119.

[0495] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 100 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110.

[0496] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 100, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 120.

[0497] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 101 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111.

[0498] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 101, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 121.

[0499] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 102 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112.

[0500] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 102, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 122. In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 103 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113.

[0501] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 103, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 123.

[0502] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 104 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114.

[0503] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 104, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 124.

[0504] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 105 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115.

[0505] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 105, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 125.

[0506] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 106 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116.

[0507] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 106, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 126.

[0508] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 107 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117. In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 107, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 127.

[0509] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 108 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118.

[0510] In one example, the binding protein is an antibody and comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 108, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 128.

[0511] In one example, the WAS binding protein is conjugated to a detectable label. Detectable labels suitable for use in the present disclosure will be apparent to the skilled person and / or are described herein. For example, the detectable label is selected from the group consisting of an enzyme, a radiolabel, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, a prosthetic group and a contrast agent.

[0512] In one example, the detectable label is a radiolabel. For example, the radiolabel can be, but is not limited to, radioiodine (1251, 1311); technetium; yttrium; 35S or 3H.

[0513] In one example, the detectable label is an enzyme. For example, the enzyme can be, but is not limited to, horseradish peroxidase, alkaline phosphatase, P-galactosidase, or acetylcholinesterase.

[0514] In one example, the detectable label is a fluorescent label. For example, the fluorescent label can be, but is not limited to, umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylamine fluorescein, dansyl chloride or phycoerythrin.

[0515] In one example, the detectable label is a luminescent label. For example, the luminescent label can be, but is not limited to, luminol.

[0516] In one example, the detectable label is a bioluminescent label. For example, the bioluminescent label can be, but is not limited to, luciferase, luciferin or aequorin.

[0517] In one example, the detectable label is a magnetic label. For example, the magnetic label can be, but is not limited to, gadolinium or iron-oxide chelate.

[0518] In one example, the detectable label is a prosthetic group. For example, the prosthetic group can be, but is not limited to, streptavidin / biotin or avidin / biotin.

[0519] In one example, the detectable label is a contrast agent. The present disclosure provides a nucleic acid encoding the Wiskott-Aldrich Syndrome (WAS) binding protein of the present disclosure.

[0520] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises:

[0521] (i) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0522] NO: 99 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109; or

[0523] (ii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0524] NO: 100 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110; or

[0525] (iii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0526] NO: 101 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111; or

[0527] (iv) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0528] NO: 102 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112; or

[0529] (v) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0530] NO: 103 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113; or

[0531] (vi) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0532] NO: 104 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114; or

[0533] (vii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0534] NO: 105 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115; or

[0535] (viii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 106 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116; or

[0536] (ix) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0537] NO: 107 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117; or

[0538] (x) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID

[0539] NO: 108 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118. The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 99 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109.

[0540] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 100 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110.

[0541] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 101 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111.

[0542] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 102 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112.

[0543] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 103 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113.

[0544] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 104 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114.

[0545] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 105 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115. The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 106 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116.

[0546] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 107 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117.

[0547] The present disclosure provides a nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 108 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118.

[0548] In one example, the VH and VL are in a single polypeptide chain encoded by a single nucleic acid or wherein the VH and VL are in separate polypeptide chains, wherein each polypeptide chain is encoded by a separate nucleic acid. For example, the VH and VL are in a single polypeptide chain encoded by a single nucleic acid. In another example, the VH and VL are in separate polypeptide chains, wherein each polypeptide chain is encoded by a separate nucleic acid.

[0549] In one example, if the VH and VL are in the same polypeptide chain, the protein is:

[0550] (i) a single chain Fv fragment (scFv);

[0551] (ii) a dimeric scFv (di-scFv); or

[0552] (iii) at least one of (i) and / or (ii) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (CH) 2 and / or CH3; or if the VH and VL are in separate polypeptide chains, the protein is:

[0553] (i) a diabody;

[0554] (ii) a triabody;

[0555] (iii) a tetrabody;

[0556] (iv) a Fab;

[0557] (v) a F(ab')2;

[0558] (vi) a Fv;

[0559] (vii) an antibody; or (viii) one of (i) to (vi) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (CH)2 and / or CH3.

[0560] In one example, if the VH and VL are in the same polypeptide chain, the protein is:

[0561] (i) a single chain Fv fragment (scFv);

[0562] (ii) a dimeric scFv (di-scFv); or

[0563] (iii) at least one of (i) and / or (ii) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (CH) 2 and / or CH3.

[0564] In one example, if the VH and VL are in separate polypeptide chains, the protein is:

[0565] (i) a diabody;

[0566] (ii) a triabody;

[0567] (iii) a tetrabody;

[0568] (iv) a Fab;

[0569] (v) a F(ab')2;

[0570] (vi) a Fv;

[0571] (vii) an antibody; or

[0572] (viii) one of (i) to (vi) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (CH)2 and / or CH3.

[0573] In one example, the binding protein is selected from the group consisting of:

[0574] (i) a single chain Fv fragment (scFv);

[0575] (ii) a dimeric scFv (di-scFv);

[0576] (iii) a diabody;

[0577] (iv) a triabody;

[0578] (v) a tetrabody;

[0579] (vi) a Fab;

[0580] (vii) a F(ab’)2;

[0581] (viii) a Fv;

[0582] (ix) one of (i) to (ix) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and / or CH3; and

[0583] (x) an antibody.

[0584] The foregoing binding proteins (described in the previous three lists) can also be referred to as antigen binding domains of antibodies.

[0585] In one example, the binding protein is an antibody. In one example, the antibody is a naked antibody. In one example, the binding protein is chimeric, de-immunized, humanized, human or primatized.

[0586] In one example, the binding protein or antibody is human.

[0587] In one example, the binding protein comprises:

[0588] (i) a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising a sequence set forth in SEQ ID NO: 16; or

[0589] (ii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16; or

[0590] (iii)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising a sequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44; or

[0591] (iv)a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising a sequence set forth in SEQ ID NO: 17; or

[0592] (v) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17; or

[0593] (vi)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 50; or

[0594] (vii) a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 18; or

[0595] (viii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18; or

[0596] (ix)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56; or

[0597] (x) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 19; or

[0598] (xi)a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19; or

[0599] (xii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62; or

[0600] (xiii) a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO: 20; or

[0601] (xiv) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20; or

[0602] (xv) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68; or

[0603] (xvi) a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO: 21; or

[0604] (xvii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21; or

[0605] (xviii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74; or (xix) a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 22; or

[0606] (xx) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22; or

[0607] (xxi) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80; or

[0608] (xxii) a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising a sequence set forth in SEQ ID NO: 23; or

[0609] (xxiii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23; or

[0610] (xxiv) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 81, a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86; or

[0611] (xxv) a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO: 24; or

[0612] (xxvi) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24; or

[0613] (xxvii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92; or

[0614] (xxviii) a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising a sequence set forth in SEQ ID NO: 25; or (xxix) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25; or

[0615] (xxx) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

[0616] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising a sequence set forth in SEQ ID NO: 16.

[0617] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16.

[0618] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising a sequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44.

[0619] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising a sequence set forth in SEQ ID NO: 17.

[0620] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17.

[0621] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 50.

[0622] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 18.

[0623] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18.

[0624] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56.

[0625] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 19.

[0626] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19.

[0627] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62.

[0628] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO: 20.

[0629] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20.

[0630] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68.

[0631] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO: 21

[0632] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21.

[0633] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74.

[0634] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 22.

[0635] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22. In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80.

[0636] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising a sequence set forth in SEQ ID NO: 23

[0637] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23.

[0638] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 81, a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86.

[0639] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO: 24.

[0640] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24.

[0641] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92.

[0642] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising a sequence set forth in SEQ ID NO: 25.

[0643] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25.

[0644] In one example, the nucleic acid encodes the WAS binding protein comprising the antibody variable region, wherein the antibody variable region comprises a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

[0645] The present disclosure provides a composition comprising:

[0646] (i) a first expression construct comprising a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 1 or 2 or 6 to 15; and

[0647] (ii) a second expression construct comprising a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 3 to 5 or 16 to 25; wherein the first and second polypeptides associate to form a protein comprising an antibody variable region.

[0648] The present disclosure provides a composition comprising

[0649] (i) a first expression construct comprising a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6 to 15; and

[0650] (ii) a second expression construct comprising a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 16 to 25; wherein the first and second polypeptides associate to form a protein comprising an antibody variable region.

[0651] The present disclosure also provides an expression construct comprising:

[0652] (i) a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 1 or 2 or 6 to 15; and / or

[0653] (ii) a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 3 to 5 or 16 to 25.

[0654] The present disclosure further provides an expression construct comprising:

[0655] (i) a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6 to 15; and / or

[0656] (ii) a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 16 to 25.

[0657] The present disclosure provides a cell comprising the expression construct of the present disclosure.

[0658] The present disclosure provides a cell comprising:

[0659] (i) a first expression construct comprising a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 1 or 2 or 6 to 15; and

[0660] (ii) a second expression construct comprising a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 3 to 5 or 16 to 25.

[0661] The present disclosure also provides a cell comprising:

[0662] (i) a first expression construct comprising a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6 to 15; and (ii) a second expression construct comprising a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 16 to 25.

[0663] In one example:

[0664] (i) the VH comprises a sequence set forth in SEQ ID NO: 6 and the VL comprises a sequence set forth in SEQ ID NO: 16; or

[0665] (ii)the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16; or

[0666] (iii)the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising a sequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44; or

[0667] (iv)the VH comprises a sequence set forth in SEQ ID NO: 7 and the VL comprises a sequence set forth in SEQ ID NO: 17; or

[0668] (v) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17; or

[0669] (vi)the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 50; or

[0670] (vii) the VH comprises a sequence set forth in SEQ ID NO: 8 and the VL comprises a sequence set forth in SEQ ID NO: 18; or

[0671] (viii) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18; or

[0672] (ix)the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56; or

[0673] (x) the VH comprises a sequence set forth in SEQ ID NO: 9 and the VL comprises a sequence set forth in SEQ ID NO: 19; or

[0674] (xi)the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19; or

[0675] (xii) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62; or

[0676] (xiii) the VH comprises a sequence set forth in SEQ ID NO: 10 and the VL comprises a sequence set forth in SEQ ID NO: 20; or

[0677] (xiv) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20; or

[0678] (xv) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68; or

[0679] (xvi) the VH comprises a sequence set forth in SEQ ID NO: 11 and the VL comprises a sequence set forth in SEQ ID NO: 21; or

[0680] (xvii) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21; or

[0681] (xviii) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71 ; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74; or (xix) the VH comprises a sequence set forth in SEQ ID NO: 12 and the VL comprises a sequence set forth in SEQ ID NO: 22; or

[0682] (xx) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22; or

[0683] (xxi) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80; or

[0684] (xxii) the VH comprises a sequence set forth in SEQ ID NO: 13 and the VL comprises a sequence set forth in SEQ ID NO: 23; or

[0685] (xxiii) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23; or

[0686] (xxiv) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 81, a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86; or

[0687] (xxv) the VH comprises a sequence set forth in SEQ ID NO: 14 and the VL comprises a sequence set forth in SEQ ID NO: 24; or

[0688] (xxvi) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24; or

[0689] (xxvii) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92; or

[0690] (xxviii) the VH comprises a sequence set forth in SEQ ID NO: 15 and the VL comprises a sequence set forth in SEQ ID NO: 25; or (xxix) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25; or

[0691] (xxx) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

[0692] The present disclosure provides a method of producing a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, the method comprising expressing the WAS binding protein encoded by the nucleic acid of the present disclosure in an isolated or recombinant cell.

[0693] In one example, the method further comprises isolating the WAS binding protein.

[0694] The present disclosure also provides a method of detecting Wiskott-Aldrich Syndrome (WAS) protein expression in a cell transduced with a lentiviral vector construct encoding a Wiskott-Aldrich Syndrome (WAS) protein, the method comprising detecting WAS protein in the cell with a WAS -binding protein according to the present disclosure.

[0695] In one example, the method comprises performing an enzyme-linked immunosorbent assay (ELISA), an immunohistochemical assay, flow cytometry or a western blot. For example, the method comprises performing an enzyme-linked immunosorbent assay (ELISA). In another example, the method comprises performing an immunohistochemical assay. In a further example, the method comprises performing flow cytometry. In one example, the method comprises performing a western blot.

[0696] In one example, the method further comprises determining the level of WAS protein expression from the cell.

[0697] In one example, the method further comprises selecting a population of cells for therapy if the level of WAS protein expression is sufficient to achieve a near physiological level of WAS protein in a subject and / or sufficient to achieve a platelet count of at least 100,000 platelets per microliter of blood in the subject. In one example, the method comprises selecting a population of cells for therapy if the level of WAS protein expression is sufficient to achieve a near physiological level of WAS protein in a subject. In another example, the method comprises selecting a population of cells for therapy if the level of WAS protein expression is sufficient to achieve a platelet count of at least 100,000 platelets per microliter of blood in the subject. For example, is sufficient to achieve a platelet count of 150,000 to 200,000 platelets per microliter of blood in the subject.

[0698] The present disclosure provides a method of selecting a population of cells transduced with a lentiviral vector construct encoding a Wiskott-Aldrich Syndrome (WAS) protein for therapy, the method comprising:

[0699] (i) detecting WAS protein expression in the cells using a method according to any one of claims 34 to 36; and

[0700] (ii) selecting cells for therapy if WAS protein is expressed in an amount sufficient to achieve a near physiological level of WAS protein in a subject and / or sufficient to achieve a platelet count of at least 100,000 platelets per microliter of blood in the subject..

[0701] In one example, the method further comprises formulating the selected cells into a pharmaceutical composition for administration to a subject.

[0702] The present disclosure provides a method of treating Wiskott-Aldrich Syndrome and / or a condition associated with Wiskott-Aldrich Syndrome in a subject, wherein the method comprises administering to the subject a composition comprising a population of cells transduced with a lentiviral vector construct encoding a Wiskott-Aldrich Syndrome (WAS) protein, wherein the cells have been selected according to a method of the present disclosure.

[0703] The present disclosure provides a method of monitoring engraftment of a cell transduced with a lentiviral vector construct encoding a Wiskott-Aldrich Syndrome (WAS) protein in a subject, the method comprising determining a level of WAS protein in the cell at one or more time points using a method according to the present disclosure, wherein an elevated level of the WAS protein compared to a reference level indicates engraftment of the cell in the subject.

[0704] In one example, the reference level is a predetermined level of WAS protein and / or a predetermined score.

[0705] In one example, an elevated level of WAS protein in the cell compared to the reference level is indicative of engraftment of a cell transduced with a lentiviral construct encoding a WAS protein.

[0706] In one example, a reduced level WAS protein in the cell compared to the reference level is indicative of reduced engraftment of a cell transduced with a lentiviral construct encoding a WAS protein.

[0707] In one example, the method is performed on at least one biological sample obtained from the subject. In one example, the level of WAS protein is determined in at least one biological sample obtained from the subject prior to treatment, during treatment and / or after treatment. For example, the method comprises determining the level of WAS protein in the subject before, during and / or after treatment with a cell transduced with a lentiviral vector construct encoding a WAS protein. In one example, the level of WAS protein is determined at one or more time points prior to treatment. In another example, the level of WAS protein is determined at one or more time points during treatment. In a further example, the level of WAS protein is determined at one or more time points after treatment. In another example, the level of WAS protein is determined prior to and during treatment. In a further example, the level of WAS protein is determined prior to and after treatment. In another example, the level of WAS protein is determined during and after treatment. In a further example, the level of WAS protein is determined prior to, during and after treatment.

[0708] The present disclosure provides a method of detecting Wiskott-Aldrich Syndrome (WAS) protein expression in a population of cells in a sample, the method comprising detecting WAS protein in the cells with a WAS-binding protein according to the present disclosure.

[0709] In one example, the WAS-binding protein is detectably labelled. In one example, the WAS-binding protein is biotinylated. In one example, the WAS-binding protein is fluorescently labelled.

[0710] The present disclosure provides a method of detecting Wiskott-Aldrich Syndrome (WAS) protein expression in a population of cells in a sample, the method comprising detecting WAS protein in the cells with a detectably labelled WAS-binding protein according to the present disclosure.

[0711] In one example, the sample is obtained from a subject.

[0712] In one example, the sample has been pre-treated. For example, the sample is pretreated to fix and / or permeabilise the cells. For example, the sample is pre-treated with formaldehyde and / or a non-ionic surfactant. In one example, the sample is pre-treated with formaldehyde. In one example, the sample is pre-treated with formaldehyde and a non-ionic surfactant. In another example, the sample is pre-treated with a non-ionic surfactant. Suitable non-ionic surfactants suitable for use in the present disclosure will be apparent to the skilled person and include for example, surfactants with a hydrophilic polyethylene oxide chain and an aromatic hydrocarbon lipophilic or hydrophilic group. Exemplary non-ionic surfactants include Triton® X-100.

[0713] In one example, the formaldehyde is at a concentration of about 1%. In one example, the sample is pre-treated with the formaldehyde and / or non-ionic surfactant for a period of about 5 minutes.

[0714] In one example, the sample is pre-treated at room temperature.

[0715] In one example, following the pre-treatment, the sample is diluted in a solution comprising bovine serum albumin (BSA). For example, the sample is diluted in a solution comprising HEPES-Tyrode’s (HT)-BSA.

[0716] In one example, the method comprises contacting the sample with a WAS -binding protein according to the present disclosure, such that the WAS -binding protein binds to WAS expressed on the cells in the sample.

[0717] In one example, the sample is contacted with the WAS -binding protein at a concentration of between about 1 and 25 pg / mL. For example, the WAS-binding protein contacts the sample at a concentration of about 1 pg / mL, or about 5 pg / mL, or about 7.5 pg / mL, or about 10 pg / mL, or about 12.5 pg / mL, or about 15 pg / mL, or about 17.5 pg / mL, or about 20 pg / mL. In one example, the sample is contacted with the WAS- binding protein at a concentration of about 5 pg / mL.

[0718] In one example, the method further comprises contacting the sample with fluorescently-labelled streptavidin. In one example, the method further comprises contacting the sample with streptavidin-PE. In one example, the sample is contacted with the streptavidin-PE at a concentration of between about 0.1 and 10 pg / mL. For example, about 0.1 pg / mL, or about 0.5 pg / mL, or about 1.0 pg / mL, or about 1.5 pg / mL, or about 2.0 pg / mL, or about 4 pg / mL, or about 6 pg / mL, or about 8 pg / mL, or about 10 pg / mL.

[0719] In one example, the method comprises detecting WAS protein expression using flow cytometry. For example, WAS protein expression is detected in the population of cells in the sample. In one example, the sample is a whole blood sample. In one example, the sample is a plasma sample. In one example, the population of cells includes platelets, monocytes, neutrophils and lymphocytes.

[0720] In one example, the method comprises:

[0721] (i) contacting a sample comprising a population of cells with a biotinylated WAS- binding protein according to the present disclosure;

[0722] (ii) contacting the sample with fluorescently-labelled streptavidin;

[0723] (iii)detecting the fluorescence, wherein the sample has been pre-treated with formaldehyde and / or a non-ionic surfactant.

[0724] It will be apparent to the skilled person from the disclosure herein that the expression of the fluorescent label (e.g. PE (Phycoerythrin)) is indicative of the level of WAS protein expression in the population of cells in the sample. In one example, the method comprises:

[0725] (iv) contacting a sample comprising a population of cells with a biotinylated WAS- binding protein according to the present disclosure;

[0726] (v) contacting the sample with streptavidin-PE;

[0727] (vi) detecting the PE fluorescence, wherein the sample has been pre-treated with formaldehyde and / or a non-ionic surfactant.

[0728] In one example, the samples have been further contacted with one or more cell surface markers. It will be apparent to the skilled person that the use of one or more cell surface markers is to aid in the identification of different cell populations within the sample. For example, the cell surface markers are used to determine the WAS protein expression levels in different cell populations in the sample. In one example, the populations of cells includes platelets, lymphocytes, neutrophils and monocytes.

[0729] In one example, the samples have been further contacted with one or more cell surface markers to determine platelet function. It will be apparent to the skilled person that the use of one or more cell surface markers is to aid in the identification of activated platelets and not resting platelets within the sample. For example, the cell surface markers are used to determine the platelet function levels in cell populations in the sample.

[0730] In one example, the method comprises:

[0731] (i) contacting a population of cells in a sample with one or more cell surface markers;

[0732] (ii) contacting the sample with a biotinylated WAS-binding protein according to the present disclosure;

[0733] (iii)contacting the sample with streptavidin-PE;

[0734] (iv) detecting the PE fluorescence, wherein the sample has been pre-treated with formaldehyde and / or a non-ionic surfactant.

[0735] In one example, the cell population is a population of platelets. In one example, the cell surface markers used to identify the platelets include CD61 and CD42a.

[0736] In one example, the cell population is a population of monocytes. For example, the cell surface markers used to identify the monocytes includes TLR2.

[0737] In one example, the cell population is a population of neutrophils. For example, the cell surface markers used to identify the monocytes includes CD 16.

[0738] In one example, the cell population is a population of lymphocytes. For example, the cell surface markers used to identify the monocytes includes CD45. The skilled person would be aware of other cell surface markers that could be used to differentiate cell populations within the sample.

[0739] In one example, the method further comprises determining platelet function levels in the population of cells in the sample. In one example, the method further comprises incubating the sample with one or more platelet agonists. Examples of platelet agonists include adenosine diphosphate (ADP), thrombin receptor agonist peptide (TRAP), and collagen related peptide (CRP).

[0740] In one example, the cell surface marker used to identify platelet function is GPIIb- Illa. In one example, the cell surface marker used to identify platelet function is CD62P. In one example, the cell surface marker used to identify platelet function is CD40L.

[0741] It will be apparent to the skilled person from the disclosure that reference to a first and subsequent time point is not reference to a defined or specific time point and is for the purposes of comparison only. The first, second (and any subsequent) time points may be separated by any period of time during which it is wished to monitor the engraftment of a cell transduced with a lentiviral vector construct encoding a WAS protein in the subject.

[0742] As will be apparent to the skilled person, the ability to monitor the level of WAS protein over the course of the disease and / or treatment will assist in monitoring disease progression and / or treatment responsiveness (i.e., cell engraftment).

[0743] It will be apparent to the skilled person, that methods of monitoring disease progression and treatment responsiveness (i.e., cell engraftment) in a subject will be useful for determining regression and / or recurrence in a subject.

[0744] In one example, the method comprises determining:

[0745] (i) if the level of WAS protein in the cell at a subsequent time point is reduced as compared to the level of WAS protein in the cell at a first time point; or

[0746] (ii)if the level of WAS protein in the cell at the subsequent time point is elevated as compared to the level of WAS protein in the cell at the first time point.

[0747] In one example, the method is performed on at least one biological sample obtained from the subject. Suitable biological samples for use in the present disclosure will be apparent to the skilled person and / or are described herein. In one example, the biological sample is a fluid sample. For example, the fluid sample is blood, for example, a whole blood sample, a plasma sample, a serum sample. In one example, the fluid sample is urine. In one example, the biological sample is whole blood. In another example, the biological sample is plasma. In a further example, the biological sample is serum.

[0748] In one example, the method additionally comprises providing the sample. In one example, the cell is a hematopoietic cell, such as hematopoietic progenitor / stem cell, a monocyte, a macrophage, a peripheral blood mononuclear cell, a CD4+ T lymphocyte, a CD8+ T lymphocyte, or a dendritic cell. In one example, the cell is a hemaopoietic stem cell (HSC). For example, the HSC is allogeneic or autologous. In one example, the HSC is allogeneic. In another example, the HSC is autologous.

[0749] In one example, the condition associated with WAS is selected from the group consisting of microthrombocytopenia, eczema, an autoimmune disease, a recurrent infection and combinations thereof.

[0750] In one example:

[0751] (i) the recurrent infection is selected from the group consisting of otitis media, skin abscess, pneumonia, enterocolitis, meningitis, sepsis, urinary tract infection and combinations thereof; and / or

[0752] (ii) the eczema is treatment-resistant eczema; and / or

[0753] (iii) the autoimmune disease is selected from the group consisting of hemolytic anemia, vasculitis, arthritis, neutropenia, inflammatory bowel disease, and IgA nephropathy, Henoch-Schonlein-like purpura, dermatomyositis, recurrent angioedema, uveitis and combinations thereof.

[0754] The present disclosure also provides a Wiskott-Aldrich Syndrome (WAS) protein variant comprising in order from N- to C- terminal:

[0755] (i) a GTPase-binding domain;

[0756] (ii) a cofilin-homology sequence; and

[0757] (iii) a C -terminal acid domain, wherein the WAS protein variant lacks a pleckstrin homology domain, a WASp homology 1 (WH1) domain, a proline-rich region, a WH2 domain and / or a verprolin homology domain.

[0758] In one example, the WAS protein variant lacks a pleckstrin homology domain. In another example, the WAS protein variant lacks a WH1 domain. In a further example, the WAS protein variant lacks a proline-rich region. In one example, the WAS protein variant lacks a WH2 domain. In another example, the WAS protein variant lacks a verprolin homology domain. In a further example, the WAS protein variant lacks a pleckstrin homology domain, a WASp homology 1 (WH1) domain, a proline-rich region, a WH2 domain and a verprolin homology domain.

[0759] In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal:

[0760] (i) a GTPase-binding domain; and

[0761] (ii) a cofilin-homology sequence. In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal:

[0762] (i) a GTPase-binding domain;

[0763] (ii) a cofilin-homology sequence; and

[0764] (iii)a C -terminal acid domain.

[0765] In one example, the WAS protein variant comprises in order from N- to C- terminal:

[0766] (i) a GTPase-binding domain;

[0767] (ii) a cofilin-homology sequence; and

[0768] (iii)a C -terminal acid domain.

[0769] In one example, the WAS protein variant consists of in order from N- to C- terminal:

[0770] (i) a GTPase-binding domain;

[0771] (ii) a cofilin-homology sequence; and

[0772] (iii)a C -terminal acid domain.

[0773] In one example, the WAS protein variant comprises in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; and amino acid residues 461 to 502 of SEQ ID NO: 129.

[0774] The present disclosure further provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that comprises, or consists of, in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; and amino acid residues 461 to 502 of SEQ ID NO: 129.

[0775] In one example, the GTPase-binding domain, the cofilin-homology sequence and / or the C-terminal acid domain are directly or indirectly linked to each other. For example, each of the GTPase-binding domain, the cofilin-homology sequence and the C- terminal acid domain are directly linked to each other (e.g., without an intervening linker). In another example, each of the GTPase-binding domain, the cofilin-homology sequence and the C-terminal acid domain are indirectly linked to each other. In a further example, the GTPase-binding and the cofilin-homology sequence are indirectly linked to each other and the cofilin-homology sequence and the C-terminal acid domain are directly linked to each other.

[0776] In one example, the GTPase-binding domain, the cofilin-homology sequence and / or the C-terminal acid domain are indirectly linked to each other via a linker.

[0777] In one example, the GTPase-binding and the cofilin-homology sequence are indirectly linked to each other via a linker. In one example, the linker is a peptide or a polypeptide. For example, the linker is a peptide linker comprising at least 2 amino acids in length. In one example, the linker comprises between 2 and 70 amino acids.

[0778] In one example, the linker is a rigid or a flexible linker.

[0779] In one example, the linker is selected from the group consisting of a (GS)nlinker, wherein n=l, 2, 3, 4, 5 or 6, a GSGGS linker, a GGSSG linker, a GGGGS linker, a GSGSG linker, a (Gly)s linker, a (Gly)e linker, a (GGGS)nlinker, wherein n=l, 2, 3 or 4, a (EAAAK)n linker, wherein n=l, 2 or 3, a A(EAAAK)4ALEA(EAAAK4)A linker, a AEAAAKEAAAKA linker, a (Ala-Pro)nlinker, wherein n=10-34, and a PAPAP linker.

[0780] In one example, the linker is a flexible linker. In one example, the linker comprises glycine or glycine and serine. In one example, the flexible linker is selected from the group consisting of a (GS)nlinker, wherein n=l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15, a GSGGS linker, a GGSSG linker, a GGGGS linker, a GSGSG linker, a (Gly)s linker, a (Gly)e linker, a (GGGS)nlinker, wherein n=l, 2, 3 or 4. For example, the linker is a GS6 linker as set forth in SEQ ID NO: 136 (GGSGGS). In another example, the linker is a GS13 linker.

[0781] In one example, the linker is a rigid linker. In one example, the rigid linker is selected from the group consisting of a (EAAAK)nlinker, wherein n=l, 2 or 3, a A(EAAAK)4ALEA(EAAAK4)A linker, a AEAAAKEAAAKA linker, a (Ala-Pro)nlinker, wherein n= 10-34, and a PAPAP linker.

[0782] In one example, the WAS protein variant further comprises a purification tag located at the C-terminus of the protein variant. For example, the purification tag is directly or indirectly linked to the C-terminus of the protein variant. In one example, the purification tag is directly linked to the C-terminus of the protein variant. In another example, the purification tag is indirectly linked to the C-terminus of the protein variant. Suitable linkers for linking the purification tag to the C-terminus of the protein variant will be apparent to the skilled person and / or described herein (e.g., in the above four paragraphs).

[0783] In one example, the purification tag is selected from the group consisting of a hexahistidine tag, a FLAG-tag, a calmodulin binding peptide (CBP) tag, a poly-glutamate tag, a polycysteine (Cys) tag, a polyhistidine (His) tag, a Myc-tag, a streptavidin-binding peptide (SBP) tag, a streptavidin (Strep) tag, an avidin tag, a bacteriophage V5 epitope (V5) tag, an isopeptag, a SpyTag, a biotin-carboxyl carrier protein (BCCP) tag, a Halotag, a thioredoxin (Trx) tag, a small ubiquitin-like molecule (SUMO) tag, and a maltose binding protein (MBP) tag.

[0784] In one example, the purification tag comprises a hexahistidine tag. In one example, the purification tag comprises a FLAG-tag.

[0785] In one example, the purification tag comprises a calmodulin binding peptide (CBP) tag.

[0786] In one example, the purification tag comprises a poly-glutamate tag.

[0787] In one example, the purification tag comprises a polycysteine (Cys) tag.

[0788] In one example, the purification tag comprises a polyhistidine (His) tag. For example, the purification tag is a His8 tag as set forth in SEQ ID NO: 137 (HHHHHHHH).

[0789] In one example, the purification tag comprises a Myc-tag.

[0790] In one example, the purification tag comprises a streptavidin-binding peptide (SBP) tag.

[0791] In one example, the purification tag comprises a streptavidin (Strep) tag.

[0792] In one example, the purification tag comprises an avidin tag.

[0793] In one example, the purification tag comprises a bacteriophage V5 epitope (V5) tag.

[0794] In one example, the purification tag comprises an isopeptag. For example, a peptide which binds covalently to pilin-C protein.

[0795] In one example, the purification tag comprises a SpyTag. For example, a peptide which binds covalently to SpyCatcher protein.

[0796] In one example, the purification tag comprises a biotin-carboxyl carrier protein (BCCP) tag.

[0797] In one example, the purification tag comprises a Halo-tag. For example, the purification tag comprises a modified haloalkane dehalogenase which covalently binds to synthetic ligands comprising a chloroalkane linker.

[0798] In one example, the purification tag comprises a thioredoxin (Trx) tag.

[0799] In one example, the purification tag comprises a small ubiquitin-like molecule (SUMO) tag.

[0800] In one example, the purification tag comprises a maltose binding protein (MBP) tag.

[0801] In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal:

[0802] (i) a GTPase-binding domain;

[0803] (ii) a (GS)6 linker;

[0804] (iii)a cofilin-homology sequence;

[0805] (iv)a C-terminal acid domain; and

[0806] (v) a His8 tag. In one example, the WAS protein variant comprises, in order form N- to C- terminal:

[0807] (i) a GTPase-binding domain;

[0808] (ii) a (GS)6 linker;

[0809] (iii)a cofilin-homology sequence;

[0810] (iv)a C-terminal acid domain; and

[0811] (v) a His8 tag.

[0812] In one example, the WAS protein variant consists of, in order form N- to C- terminal:

[0813] (i) a GTPase-binding domain;

[0814] (ii) a (GS)6 linker;

[0815] (iii)a cofilin-homology sequence;

[0816] (iv)a C-terminal acid domain; and

[0817] (v) a His8 tag.

[0818] In one example, the WAS protein variant comprises, or consists of, in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137).

[0819] The present disclosure provides a WAS protein variant comprising, or consisting of, in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137).

[0820] In one example, the WAS protein variant comprises in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137).

[0821] In one example, the WAS protein variant consists of in order from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137).

[0822] In one example:

[0823] (i) the GTPase-binding domain comprises a sequence set forth in SEQ ID NO: 131; and / or

[0824] (ii)the cofilin-homology sequence comprises a sequence set forth in SEQ ID NO: 132; and / or

[0825] (iii)the C-terminal acid domain comprises a sequence set forth in SEQ ID NO: 133. In one example, the GTPase-binding domain comprises a sequence set forth in SEQ ID NO: 131.

[0826] In one example, the cofilin-homology sequence comprises a sequence set forth in SEQ ID NO: 132.

[0827] In one example, the C-terminal acid domain comprises a sequence set forth in SEQ ID NO: 133.

[0828] The skilled person will appreciate that the C-terminus of cofilin-homology sequence and the N-terminus of the C-terminal acid domain overlap. For example, the 8 C-terminal amino acids of the cofilin homology sequence (i.e., DEGEDQAG) also form part of the C-terminal acid domain. For example, the cofilin-homology sequence and C- terminal acid domain comprises amino acid residues 461 to 502 of SEQ ID NO: 129. For example, the cofilin-homology sequence and C-terminal acid domain comprises a sequence set forth in SEQ ID NO: 134.

[0829] In one example, the WAS protein variant comprises in order from N- to C- terminal a sequence set forth in SEQ ID NO: 131 and a sequence set forth in SEQ ID NO: 134.

[0830] In one example, the WAS protein variant comprises in order from N- to C- terminal a sequence set forth in SEQ ID NO: 131; a sequence set forth in SEQ ID NO: 136; a sequence set forth in SEQ ID NO: 134; and a sequence set forth in SEQ ID NO: 137.

[0831] In one example, the WAS protein variant consists of in order from N- to C- terminal a sequence set forth in SEQ ID NO: 131; a sequence set forth in SEQ ID NO: 136; a sequence set forth in SEQ ID NO: 134; and a sequence set forth in SEQ ID NO: 137.

[0832] In one example, the WAS protein variant comprises a sequence set forth in SEQ ID NO: 130. For example, the WAS protein variant comprises a sequence set forth in SEQ ID NO: 130 lacking amino acids 1 to 19 (i.e., the signal peptide).

[0833] The present disclosure provides a WAS protein variant comprising a sequence set forth in SEQ ID NO: 130. The present disclosure provides a WAS protein variant comprising a sequence set forth in SEQ ID NO: 130 lacking amino acids 1 to 19 (i.e., the signal peptide).

[0834] In one example, the WAS protein variant comprises any form of the protein encoded by a nucleic acid encoding any of the foregoing proteins.

[0835] The present disclosure provides a nucleic acid encoding or expressing the WAS protein variant of the present disclosure. The present disclosure provides a nucleic acid encoding or expressing a WAS protein variant comprising a sequence set forth in SEQ ID NO: 130.

[0836] The present disclosure provides an expression construct comprising the nucleic acid encoding or expressing the WAS protein variant of the disclosure.

[0837] The present disclosure provides a mammalian cell comprising the expression construct comprising the nucleic acid encoding or expressing the WAS protein variant of the disclosure.

[0838] The present disclosure also provides a method of producing a WAS protein variant, wherein the method comprises culturing the mammalian cell according to the present disclosure and producing the WAS protein variant therefrom.

[0839] In one example, the method further comprises isolating and purifying the WAS protein variant.

[0840] In one example, the mammalian cell is a HEK293 cell line. For example, Expi393F™ cells.

[0841] The present disclosure provides a method of producing a Wiskott-Aldrich Syndrome (WAS) binding protein, the method comprising:

[0842] (i) contacting a display library comprising proteins comprising antigen binding fragments of antibodies expressed on phage with the WAS protein variant of the present disclosure; and

[0843] (ii) selecting from the library at least one protein that binds to the WAS protein variant.

[0844] In one example, the method further comprises immobilizing the WAS protein variant onto a solid surface.

[0845] The present disclosure also provides a method of producing an anti-Wiskott- Aldrich Syndrome (WAS) antibody, the method comprising:

[0846] (i) immunizing a non-human animal with the WAS protein variant of the present disclosure; and

[0847] (ii) isolating anti-WAS antibody-producing cells from the non-human animal.

[0848] In one example, the WAS protein variant is administered intradermally or intraperitoneally to the non-human animal. For example, the WAS protein variant is administered intradermally to the non-human animal. In another example, the WAS protein variant is administered intraperitoneally to the non-human animal.

[0849] Exemplary non-human animals suitable for immunization will be apparent to the skilled person and / or described herein. For example, the non-human animal is a mouse, a rat, a goat, sheep, cattle or a horse. In one example, the non-human animal is a mouse. Mouse strains suitable for use in the present disclosure will be apparent to the skilled person and include, for example, KR, BALB / c, BDP, BA, CE, C3H, 57BL, C57BL, C57L, DBA, FL, HTH, HT1, LP, NZB, NZW, RF, R III, SJL, SWR, WB, and 129. Such mice are commercially available from distributors that will be apparent to the skilled person.

[0850] In one example, isolating the anti-WAS antibody-producing cells comprises isolating spleen cells or lymphocytes.

[0851] Methods of isolating the anti-WAS antibody -producing cells from the spleen cells or lymphocytes will be apparent to the skilled person and / or described herein.

[0852] In one example, the method further comprises fusing the anti-WAS antibodyproducing cells with a myeloma cell to produce an anti-WAS antibody producing hybridoma.

[0853] Myeloma cells suitable for use in the present disclosure will be apparent to the skilled person and / or described herein. In one example, the myeloma cells are from a HGPRT (hypoxanthine-guanine phosphoribosyl transferase) deficient strain. Exemplary HGPRT-deficient cell lines include X63-Ag8(X63), NS1-ANS / 1(NS1), P3X63- Ag8.Ul(P3Ul), X63-Ag8.653(X63.653), SP2 / 0-Agl4(SP2 / 0), MPC11-

[0854] 45.6TG1.7(45.6TG), F0, S149 / 5XXO, and BU.l derived from mice; 210.RSY3.Ag.1.2.3 (Y3) derived from rats; and U266AR(SKG-007), GM1500.GTG-A12(GM1500), UC729-6, LICR-LOW-HMy2(HMy2) and 8226AR / NIP4-1 (NP41) derived from humans.

[0855] Methods of fusing the anti-WAS antibody producing cells with the myeloma cells to generate anti-WAS antibody producing hybridomas will be apparent to the skilled person and / or described herein.

[0856] In one example, the method further comprises selecting one or more anti-WAS antibody producing hybridomas. For example, if a HGPRT deficient myeloma cell line is used, the method comprises culturing cells in the presence of an HAT (hypoxanthine, aminopterin, thymidine) selection medium. In one example, unfused cells and hybridomas are cultured in vitro in a HAT medium. For example, only hybridomas resistant to aminopterin are selectively allowed to survive and proliferate.

[0857] In one example, one or more anti-WAS antibody producing hybridomas are individually cloned. For example, one or more anti-WAS antibody producing hybridomas are subjected to single cell cloning. Methods of single cell cloning will be apparent to the skilled person and / or described herein.

[0858] In one example, the method comprises determining the antibody titer of the anti- WAS antibody producing hybridoma. Methods of determining the antibody titer will be apparent to the skilled person and / or described herein. For example, the antibody titer can be determined by ELISA.

[0859] In one example, the method further comprises selecting an anti-WAS antibody producing hybridoma having a stable antibody titer.

[0860] In one example, the method comprises expanding the anti-WAS antibody producing hybridoma in vitro or in vivo.

[0861] In one example, the method comprises expanding the anti-WAS antibody producing hybridoma in vitro. For example, the method comprises expanding the anti- WAS antibody producing hybridoma in a cell culture in vitro.

[0862] In one example, the method comprises expanding the anti-WAS antibody producing hybridoma in vivo. For example, the method comprises expanding the anti- WAS antibody producing hybridoma in vivo in the abdominal cavity of a mouse of the same strain as the hybridoma to produce ascites containing the anti-WAS antibody.

[0863] In one example, the method further comprises isolating the anti-WAS antibody secreted from the hybridoma in vitro or in vivo.

[0864] In one example, the method further comprises isolating the anti-WAS antibody secreted from the hybridoma in vitro. For example, the method comprises isolating the anti-WAS antibody from the cell culture supernatant.

[0865] In one example, the method further comprises isolating the anti-WAS antibody secreted from the hybridoma in vivo. For example, the method comprises isolating the anti-WAS antibody from the ascites.

[0866] Methods of purifying an antibody secreted in vitro or in vivo will be apparent to the skilled person and / or described herein.

[0867] The present disclosure provides an anti- Wiskott-Aldrich Syndrome (WAS) antibody produced by the method of the present disclosure.

[0868] Exemplary antibodies are described herein and shall be taken to apply equally to the foregoing examples of the disclosure.

[0869] In one example, the subject is a mammal, for example a primate, such as a human.

[0870] BRIEF DESCRIPTION OF THE DRAWINGS

[0871] Figure 1 is a graphical representation showing the Wiskott-Aldrich Syndrome (WAS) protein structure.

[0872] Figure 2 is a graphical representation showing key domain boundaries based and predicted secondary structures.

[0873] Figure 3 is a graphical representation showing the recombinant WASp construct designs. Figure 4 is a graphical representation showing (A) binding of exemplary anti- WASp antibodies to WASp (2-502) at Ipg / mL; and (B) single point ELISA of anti- WASp antibodies at 10 pg / mL binding to WASp (2-502) and neuronal WASp (N- WASp) at 1 pg / mL; 401C and AB75830 controls.

[0874] Figure 5 is a graphical representation showing the percentage of WASP+cells in a titration assay with U937 WT and WASp / _cells at ratios of 1: 1, 1:2 and 1:3 stained with either the (A) 2A10-AF555 or the (B) 2A10-AF647 antibody.

[0875] Figure 6 is a graphical representation showing competitive titration of (A-B) mAb A10 (C-D) mAb A7 (E-F) mAb 5A5 in WT and KO U937 cells at varying ratios and concentrations as indicated; and competitive titration of (G-H) mAb A 10 (I- J) mAb A7 (K-L) mAb 5A5 in WT and KO Linnegcells at varying ratios and concentrations as indicated.

[0876] Figure 7 is a graphical representation showing optimization of WASp-AlO-biotin and SA-PE staining. (A) Whole blood, fixed with 1% formaldehyde and treated + / - Triton X-100 was stained with 5, 10 or 20 pg / mL anti-WASp-biotin followed by 0.5, 1, or 2 pg / mL SA-PE. (B) Fixed whole blood + / - Triton X-100 was stained with 5 pg / mL anti-WASp-biotin followed by 2, 4, or 8 pg / mL (No Wash), or washed prior to addition of anti-WASp-biotin (Pre-SA-PE Wash) or washed after staining with anti-WASp-biotin (Post-SA-PE Wash). Results shown are for platelets only.

[0877] KEY TO SEQUENCE LISTING

[0878] SEQ ID NO: 1 Consensus sequence of 2A6, 2A9, 2A11 VH amino acid sequence

[0879] SEQ ID NO: 2 Consensus sequence of 2A2, 2 A3, 2A7 VH amino acid sequence

[0880] SEQ ID NO: 3 Consensus sequence of 2A5, 2A6, 2A9 VL amino acid sequence

[0881] SEQ ID NO: 4 Consensus sequence of 2A4, 2A8 VL amino acid sequence

[0882] SEQ ID NO: 5 Consensus sequence of 2A2, 2 A3, 2A11 VL amino acid sequence

[0883] SEQ ID NO: 6 2A2 VH amino acid sequence

[0884] SEQ ID NO: 7 2 A3 VH amino acid sequence

[0885] SEQ ID NO: 8 2A4 VH amino acid sequence

[0886] SEQ ID NO: 9 2A5 VH amino acid sequence

[0887] SEQ ID NO: 10 2A6 VH amino acid sequence

[0888] SEQ ID NO: 11 2A7 VH amino acid sequence

[0889] SEQ ID NO: 12 2A8 VH amino acid sequence

[0890] SEQ ID NO: 13 2A9 VH amino acid sequence

[0891] SEQ ID NO: 14 2A10 VH amino acid sequence

[0892] SEQ ID NO: 15 2A11 VH amino acid sequence SEQ ID NO: 16 2A2 VL amino acid sequence

[0893] SEQ ID NO: 17 2A3 VL amino acid sequence

[0894] SEQ ID NO: 18 2A4 VL amino acid sequence

[0895] SEQ ID NO: 19 2A5 VL amino acid sequence

[0896] SEQ ID NO: 20 2A6 VL amino acid sequence

[0897] SEQ ID NO: 21 2A7 VL amino acid sequence

[0898] SEQ ID NO: 22 2A8 VL amino acid sequence

[0899] SEQ ID NO: 23 2A9 VL amino acid sequence

[0900] SEQ ID NO: 24 2A10 VL amino acid sequence

[0901] SEQ ID NO: 25 2A11 VL amino acid sequence

[0902] SEQ ID NO: 26 2A2 light chain amino acid sequence

[0903] SEQ ID NO: 27 2A3 light chain amino acid sequence

[0904] SEQ ID NO: 28 2A4 light chain amino acid sequence

[0905] SEQ ID NO: 29 2A5 light chain amino acid sequence

[0906] SEQ ID NO: 30 2A6 light chain amino acid sequence

[0907] SEQ ID NO: 31 2A7 light chain amino acid sequence

[0908] SEQ ID NO: 32 2A8 light chain amino acid sequence

[0909] SEQ ID NO: 33 2A9 light chain amino acid sequence

[0910] SEQ ID NO: 34 2A10 light chain amino acid sequence

[0911] SEQ ID NO: 35 2A11 light chain amino acid sequence

[0912] SEQ ID NO: 36 light chain constant domain amino acid sequence (2A4, 2A5, 2A6,

[0913] 2A7, 2A8, 2A9, 2A10)

[0914] SEQ ID NO: 37 light chain constant domain amino acid sequence (2A2, 2A3)

[0915] SEQ ID NO: 38 light chain constant domain amino acid sequence (2A11)

[0916] SEQ ID NO: 39 2A2 VH CDR1 amino acid sequence

[0917] SEQ ID NO: 40 2A2 VH CDR2 amino acid sequence

[0918] SEQ ID NO: 41 2A2 VH CDR3 amino acid sequence

[0919] SEQ ID NO: 42 2A2 VL CDR1 amino acid sequence

[0920] SEQ ID NO: 43 2A2 VL CDR2 amino acid sequence

[0921] SEQ ID NO: 44 2A2 VL CDR3 amino acid sequence

[0922] SEQ ID NO: 45 2 A3 VH CDR1 amino acid sequence

[0923] SEQ ID NO: 46 2 A3 VH CDR2 amino acid sequence

[0924] SEQ ID NO: 47 2 A3 VH CDR3 amino acid sequence

[0925] SEQ ID NO: 48 2 A3 VL CDR1 amino acid sequence

[0926] SEQ ID NO: 49 2A3 VL CDR2 amino acid sequence

[0927] SEQ ID NO: 50 2A3 VL CDR3 amino acid sequence SEQ ID NO: 51 2A4 VH CDR1 amino acid sequence

[0928] SEQ ID NO: 52 2A4 VH CDR2 amino acid sequence SEQ ID NO: 53 2A4 VH CDR3 amino acid sequence SEQ ID NO: 54 2A4 VL CDR1 amino acid sequence SEQ ID NO: 55 2A4 VL CDR2 amino acid sequence SEQ ID NO: 56 2A4 VL CDR3 amino acid sequence

[0929] SEQ ID NO: 57 2A5 VH CDR1 amino acid sequence SEQ ID NO: 58 2A5 VH CDR2 amino acid sequence SEQ ID NO: 59 2A5 VH CDR3 amino acid sequence SEQ ID NO: 60 2A5 VL CDR1 amino acid sequence SEQ ID NO: 61 2A5 VL CDR2 amino acid sequence

[0930] SEQ ID NO: 62 2A5 VL CDR3 amino acid sequence SEQ ID NO: 63 2A6 VH CDR1 amino acid sequence SEQ ID NO: 64 2A6 VH CDR2 amino acid sequence SEQ ID NO: 65 2A6 VH CDR3 amino acid sequence SEQ ID NO: 66 2A6 VL CDR1 amino acid sequence

[0931] SEQ ID NO: 67 2A6 VL CDR2 amino acid sequence SEQ ID NO: 68 2A6 VL CDR3 amino acid sequence SEQ ID NO: 69 2A7 VH CDR1 amino acid sequence SEQ ID NO: 70 2A7 VH CDR2 amino acid sequence SEQ ID NO: 71 2A7 VH CDR3 amino acid sequence

[0932] SEQ ID NO: 72 2A7 VL CDR1 amino acid sequence SEQ ID NO: 73 2A7 VL CDR2 amino acid sequence SEQ ID NO: 74 2A7 VL CDR3 amino acid sequence SEQ ID NO: 75 2A8 VH CDR1 amino acid sequence SEQ ID NO: 76 2A8 VH CDR2 amino acid sequence

[0933] SEQ ID NO: 77 2A8 VH CDR3 amino acid sequence SEQ ID NO: 78 2A8 VL CDR1 amino acid sequence SEQ ID NO: 79 2A8 VL CDR2 amino acid sequence SEQ ID NO: 80 2A8 VL CDR3 amino acid sequence SEQ ID NO: 81 2A9 VH CDR1 amino acid sequence

[0934] SEQ ID NO: 82 2A9 VH CDR2 amino acid sequence SEQ ID NO: 83 2A9 VH CDR3 amino acid sequence SEQ ID NO: 84 2A9 VL CDR1 amino acid sequence SEQ ID NO: 85 2A9 VL CDR2 amino acid sequence SEQ ID NO: 86 2A9 VL CDR3 amino acid sequence SEQ ID NO: 87 2A10 VH CDR1 amino acid sequence

[0935] SEQ ID NO: 88 2A10 VH CDR2 amino acid sequence

[0936] SEQ ID NO: 89 2A10 VH CDR3 amino acid sequence

[0937] SEQ ID NO: 90 2A10 VL CDR1 amino acid sequence

[0938] SEQ ID NO: 91 2A10 VL CDR2 amino acid sequence

[0939] SEQ ID NO: 92 2A10 VL CDR3 amino acid sequence

[0940] SEQ ID NO: 93 2A11 VH CDR1 amino acid sequence

[0941] SEQ ID NO: 94 2A11 VH CDR2 amino acid sequence

[0942] SEQ ID NO: 95 2A11 VH CDR3 amino acid sequence

[0943] SEQ ID NO: 96 2A11 VL CDR1 amino acid sequence

[0944] SEQ ID NO: 97 2A11 VL CDR2 amino acid sequence

[0945] SEQ ID NO: 98 2A11 VL CDR3 amino acid sequence

[0946] SEQ ID NO: 99 2A10 VH nucleotide sequence

[0947] SEQ ID NO: 100 2A8 VH nucleotide sequence

[0948] SEQ ID NO: 101 2A7 VH nucleotide sequence

[0949] SEQ ID NO: 102 2A11 VH nucleotide sequence

[0950] SEQ ID NO: 103 2A3 VH nucleotide sequence

[0951] SEQ ID NO: 104 2A6 VH nucleotide sequence

[0952] SEQ ID NO: 105 2A9 VH nucleotide sequence

[0953] SEQ ID NO: 106 2A2 VH nucleotide sequence

[0954] SEQ ID NO: 107 2A5 VH nucleotide sequence

[0955] SEQ ID NO: 108 2A4 VH nucleotide sequence

[0956] SEQ ID NO: 109 2A10 VL nucleotide sequence

[0957] SEQ ID NO: 110 2A8 VL nucleotide sequence

[0958] SEQ ID NO: 111 2A7 VL nucleotide sequence

[0959] SEQ ID NO: 112 2A11 VL nucleotide sequence

[0960] SEQ ID NO: 113 2A3 VL nucleotide sequence

[0961] SEQ ID NO: 114 2A6 VL nucleotide sequence

[0962] SEQ ID NO: 115 2A9 VL nucleotide sequence

[0963] SEQ ID NO: 116 2A2 VL nucleotide sequence

[0964] SEQ ID NO: 117 2A5 VL nucleotide sequence

[0965] SEQ ID NO: 118 2A4 VL nucleotide sequence

[0966] SEQ ID NO: 119 2A10 light chain constant domain nucleotide sequence

[0967] SEQ ID NO: 120 2A8 light chain constant domain nucleotide sequence

[0968] SEQ ID NO: 121 2A5 light chain constant domain nucleotide sequence

[0969] SEQ ID NO: 122 2A2 light chain constant domain nucleotide sequence SEQ ID NO: 123 2A3 light chain constant domain nucleotide sequence

[0970] SEQ ID NO: 124 2A6 light chain constant domain nucleotide sequence

[0971] SEQ ID NO: 125 2A9 light chain constant domain nucleotide sequence

[0972] SEQ ID NO: 126 2A11 light chain constant domain nucleotide sequence

[0973] SEQ ID NO: 127 2A7 light chain constant domain nucleotide sequence

[0974] SEQ ID NO: 128 2A4 light chain constant domain nucleotide sequence

[0975] SEQ ID NO: 129 Human Wiskott-Aldrich Syndrome (WAS) protein amino acid sequence

[0976] SEQ ID NO: 130 WAS protein variant amino acid sequence

[0977] SEQ ID NO: 131 GTPase-binding domain amino acid sequence

[0978] SEQ ID NO: 132 Cofilin-homology sequence

[0979] SEQ ID NO: 133 C-terminal acid domain amino acid sequence

[0980] SEQ ID NO: 134 Cofilin-homology sequence and C-terminal acid domain amino acid sequence

[0981] SEQ ID NO: 135 Murine Wiskott-Aldrich Syndrome (WAS) protein amino acid sequence

[0982] SEQ ID NO: 136 GS6 linker

[0983] SEQ ID NO: 137 His 8 tag

[0984] DETAILED DESCRIPTION

[0985] General

[0986] Throughout this specification, unless specifically stated otherwise or the context requires otherwise, reference to a single step, composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps or groups of compositions of matter.

[0987] Those skilled in the art will appreciate that the present disclosure is susceptible to variations and modifications other than those specifically described. It is to be understood that the disclosure includes all such variations and modifications. The disclosure also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present disclosure is not to be limited in scope by the specific examples described herein, which are intended for the purpose of exemplification only. Functionally-equivalent products, compositions and methods are clearly within the scope of the present disclosure. Any example of the present disclosure herein shall be taken to apply mutatis mutandis to any other example of the disclosure unless specifically stated otherwise.

[0988] Unless specifically defined otherwise, all technical and scientific terms used herein shall be taken to have the same meaning as commonly understood by one of ordinary skill in the art (for example, in immunology, immunohistochemistry, protein chemistry, and biochemistry).

[0989] Unless otherwise indicated, the recombinant protein, cell culture, and immunological techniques utilised in the present disclosure are standard procedures, well known to those skilled in the art. Such techniques are described and explained throughout the literature in sources such as, J. Perbal, A Practical Guide to Molecular Cloning, John Wiley and Sons (1984), J. Sambrook et al. Molecular Cloning: A Laboratory Manual, Cold Spring Harbour Laboratory Press (1989), T.A. Brown (editor), Essential Molecular Biology: A Practical Approach, Volumes 1 and 2, IRL Press (1991), D.M. Glover and B.D. Hames (editors), DNA Cloning: A Practical Approach, Volumes 1-4, IRL Press (1995 and 1996), and F.M. Ausubel et al. (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present), Ed Harlow and David Lane (editors) Antibodies: A Laboratory Manual, Cold Spring Harbour Laboratory, (1988), and J.E. Coligan et al. (editors) Current Protocols in Immunology, John Wiley & Sons (including all updates until present).

[0990] The description and definitions of variable regions and parts thereof, immunoglobulins, antibodies and fragments thereof herein may be further clarified by the discussion in Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991, Bork et al., J Mol. Biol. 242, 309- 320, 1994, Chothia and Lesk J. Mol Biol. 796:901 -917, 1987, Chothia et al. Nature 342, 877-883, 1989, Al-Lazikani et al., J Mol Biol 273, 927-948, 1997 and / or Lohse et al., Cancer Research 76(2); 403-17, 2015.

[0991] Any discussion of a protein or antibody herein will be understood to include any variants of the protein or antibody produced during manufacturing and / or storage. For example, during manufacturing or storage an antibody can be deamidated (e.g., at an asparagine or a glutamine residue) and / or have misincorporated amino acid residues (e.g., a serine misincorporated in place of an asparagine residue) and / or have altered glycosylation and / or have a glutamine residue converted to pyroglutamine and / or have a N-terminal or C-terminal residue removed or “clipped” and / or have part or all of a signal sequence incompletely processed and, as a consequence, remain at the terminus of the antibody. It is understood that a composition comprising a particular amino acid sequence may be a heterogeneous mixture of the stated or encoded sequence and / or variants of that stated or encoded sequence.

[0992] The term “and / or”, e.g., “X and / or Y” shall be understood to mean either “X and Y” or “X or Y” and shall be taken to provide explicit support for both meanings or for either meaning.

[0993] Throughout this specification the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0994] All publications cited herein are hereby incorporated by reference in their entirety. Where reference is made to a URL or other such identifier or address, it is understood that such identifiers can change and particular information on the internet can come and go, but equivalent information can be found by searching the internet. Reference thereto evidences the availability and public dissemination of such information.

[0995] Any discussion of documents, acts, materials, devices, articles or the like that has been included in the present specification is solely for the purpose of providing a context for the present invention. It is not to be taken as an admission that any or all of these matters form part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application.

[0996] Selected Definitions

[0997] As used herein, the term “Wiskott-Aldrich Syndrome (WAS) protein” also known as WASp refers to a protein encoded by the WAS gene. For the purposes of nomenclature only and not limitation, an exemplary sequence of a human Wiskott-Aldrich Syndrome (WAS) protein is set out in Swiss-Prot Accession P42768 and SEQ ID NO: 129. The sequence of WAS protein from other species can be determined using sequences provided herein and / or in publicly available databases and / or determined using standard techniques (e.g., as described in Ausubel et al., (editors), Current Protocols in Molecular Biology, Greene Pub. Associates and Wiley-Interscience (1988, including all updates until present) or Sambrook et al., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press (1989). For the purposes of nomenclature only and not limitation an exemplary sequence of a murine WAS protein is set out in SEQ ID NO: 135.

[0998] The gene that encodes the WAS protein is located in the short arm of chromosome X (XP1 1.22-11.23) and is about 9 kb, including 12 exons, and encoding 502 amino acids. For the purposes of nomenclature only and not limitation an exemplary sequence of the gene that encodes WAS protein is set out in NCBI Reference Sequence NP_000368.

[0999] The term “protein” shall be taken to include a single polypeptide chain, i.e., a series of contiguous amino acids linked by peptide bonds or a series of polypeptide chains covalently or non-covalently linked to one another (i.e., a polypeptide complex). For example, the series of polypeptide chains can be covalently linked using a suitable chemical or a disulphide bond. Examples of non-covalent bonds include hydrogen bonds, ionic bonds, Van der Waals forces, and hydrophobic interactions.

[1000] The term “polypeptide” or “polypeptide chain” will be understood from the foregoing paragraph to mean a series of contiguous amino acids linked by peptide bonds.

[1001] The term "isolated protein" or "isolated polypeptide" is a protein or polypeptide that by virtue of its origin or source of derivation is not associated with naturally - associated components that accompany it in its native state; is substantially free of other proteins from the same source. A protein may be rendered substantially free of naturally associated components or substantially purified by isolation, using protein purification techniques known in the art. By “substantially purified” is meant the protein is substantially free of contaminating agents, e.g., at least about 70% or 75% or 80% or 85% or 90% or 95% or 96% or 97% or 98% or 99% free of contaminating agents.

[1002] As used herein, the term “nucleotide sequence” or “nucleic acid sequence” will be understood to mean a series of contiguous nucleotides (or bases) covalently linked to a phosphodiester backbone.

[1003] The term “recombinant” shall be understood to mean the product of artificial genetic recombination. Accordingly, in the context of a recombinant protein comprising an antibody antigen binding domain, this term does not encompass an antibody naturally- occurring within a subject’s body that is the product of natural recombination that occurs during B cell maturation. However, if such an antibody is isolated, it is to be considered an isolated protein comprising an antibody antigen binding domain. Similarly, if nucleic acid encoding the protein is isolated and expressed using recombinant means, the resulting protein is a recombinant protein comprising an antibody antigen binding domain. A recombinant protein also encompasses a protein expressed by artificial recombinant means when it is within a cell, tissue or subject, e.g., in which it is expressed.

[1004] As used herein, the term “antigen binding site” shall be taken to mean a structure formed by a protein that is capable of binding or specifically binding to an antigen. The antigen binding site need not be a series of contiguous amino acids, or even amino acids in a single polypeptide chain. For example, in a Fv produced from two different polypeptide chains the antigen binding site is made up of a series of amino acids of a VL and a VH that interact with the antigen and that are generally, however not always in the one or more of the CDRs in each variable region. In some examples, an antigen binding site is or comprises a VH or a VL or a Fv. In some examples, the antigen binding site comprises one or more CDRs of an antibody. The antigen binding site need not be in the context of an entire antibody, e.g., it can be in isolation (e.g., a domain antibody) or in another form, e.g., as described herein, such as a scFv.

[1005] The skilled artisan will be aware that an “antibody” is generally considered to be a protein that comprises a variable region made up of a plurality of polypeptide chains, e.g., a polypeptide comprising a VL and a polypeptide comprising a VH. An antibody also generally comprises constant domains, some of which can be arranged into a constant region, which includes a constant fragment or fragment crystallizable (Fc), in the case of a heavy chain. A VH and a VL interact to form a Fv comprising an antigen binding region that is capable of specifically binding to one or a few closely related antigens. Generally, a light chain from mammals is either a K light chain or a X light chain and a heavy chain from mammals is a, 5, a, y, or p. Antibodies can be of any type (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgGi, IgGi, IgGs, IgG4, IgAi and IgAi) or subclass. The term “antibody” also encompasses humanized antibodies, primatized antibodies, human antibodies and chimeric antibodies.

[1006] The terms "full-length antibody," "intact antibody" or "whole antibody" are used interchangeably to refer to an antibody in its substantially intact form, as opposed to an antigen binding fragment of an antibody. Specifically, whole antibodies include those with heavy and light chains including an Fc region. The constant domains may be wildtype sequence constant domains (e.g., human wild-type sequence constant domains) or amino acid sequence variants thereof.

[1007] As used herein, “variable region" refers to the portions of the light and / or heavy chains of an antibody as defined herein that is capable of specifically binding to an antigen and includes amino acid sequences of complementarity determining regions (CDRs); i.e., CDR1, CDR2, and CDR3, and framework regions (FRs). Exemplary variable regions comprise three or four FRs (e.g., FR1, FR2, FR3 and optionally FR4) together with three CDRs. In the case of a protein derived from an IgNAR, the protein may lack a CDR2. VH refers to the variable region of the heavy chain. VL refers to the variable region of the light chain.

[1008] As used herein, the term "complementarity determining regions” (syn. CDRs; i.e., CDR1, CDR2, and CDR3) refers to the amino acid residues of an antibody variable region the presence of which are necessary for antigen binding. Each variable region typically has three CDR regions identified as CDR1, CDR2 and CDR3. The amino acid positions assigned to CDRs and FRs can be defined according to Kabat Sequences of Proteins of Immunological Interest, National Institutes of Health, Bethesda, Md., 1987 and 1991 or other numbering systems in the performance of this disclosure, e.g., the canonical numbering system of Chothia and Lesk J. Mol Biol. 196: 901-917, 1987; Chothia et al. Nature 342, 877-883, 1989; and / or Al-Lazikani et al., J Mol Biol 273: 927-948, 1997; the IMGT numbering system of Lefranc et al., Devel. And Compar. Immunol., 27: 55- 77 , 2003; or the AHO numbering system of Honnegher and Pliikthun J. Mol. Biol., 309: 657-670, 2001. For example, according to the numbering system of Kabat, VH framework regions (FRs) and CDRs are positioned as follows: residues 1-30 (FR1 ), 31- 35 (CDR1), 36-49 (FR2), 50-65 (CDR2), 66-94 (FR3), 95-102 (CDR3) and 103- 113 (FR4). According to the numbering system of Kabat, VL FRS and CDRs are positioned as follows: residues 1-23 (FR1), 24-34 (CDR1), 35-49 (FR2), 50-56 (CDR2), 57-88 (FR3), 89-97 (CDR3) and 98-107 (FR4). The present disclosure is not limited to FRs and CDRs as defined by the Kabat numbering system, but includes all numbering systems, including those discussed above. In one example, reference herein to a CDR (or a FR) is in respect of those regions according to the Kabat numbering system.

[1009] "Framework regions" (FRs) are those variable region residues other than the CDR residues.

[1010] As used herein, the term “Fv” shall be taken to mean any protein, whether comprised of multiple polypeptides or a single polypeptide, in which a VL and a VH associate and form a complex having an antigen binding site, i.e., capable of specifically binding to an antigen. The VH and the VL which form the antigen binding site can be in a single polypeptide chain or in different polypeptide chains. Furthermore, an Fv of the disclosure (as well as any protein of the disclosure) may have multiple antigen binding sites which may or may not bind the same antigen. This term shall be understood to encompass fragments directly derived from an antibody as well as proteins corresponding to such a fragment produced using recombinant means. In some examples, the VH is not linked to a heavy chain constant domain (CH) 1 and / or the VL is not linked to a light chain constant domain (CL). Exemplary Fv containing polypeptides or proteins include a Fab fragment, a Fab’ fragment, a F(ab’) fragment, a scFv, a diabody, a triabody, a tetrabody or higher order complex, or any of the foregoing linked to a constant region or domain thereof, e.g., CH2 or CH3 domain, e.g., a minibody. A "Fab fragment" consists of a monovalent antigen-binding fragment of an immunoglobulin, and can be produced by digestion of a whole antibody with the enzyme papain, to yield a fragment consisting of an intact light chain and a portion of a heavy chain or can be produced using recombinant means. A "Fab' fragment" of an antibody can be obtained by treating a whole antibody with pepsin, followed by reduction, to yield a molecule consisting of an intact light chain and a portion of a heavy chain comprising a VH and a single constant domain. Two Fab' fragments are obtained per antibody treated in this manner. A Fab’ fragment can also be produced by recombinant means. A "F(ab')2 fragment” of an antibody consists of a dimer of two Fab' fragments held together by two disulfide bonds, and is obtained by treating a whole antibody molecule with the enzyme pepsin, without subsequent reduction. A “Fabi” fragment is a recombinant fragment comprising two Fab fragments linked using, for example a leucine zipper or a CH3 domain. A “single chain Fv” or “scFv” is a recombinant molecule containing the variable region fragment (Fv) of an antibody in which the variable region of the light chain and the variable region of the heavy chain are covalently linked by a suitable, flexible polypeptide linker.

[1011] As used herein, the term “binds” in reference to the interaction of a compound or an antigen binding site thereof with an antigen means that the interaction is dependent upon the presence of a particular structure (e.g., an antigenic determinant or epitope) on the antigen. For example, an antibody recognizes and binds to a specific protein structure rather than to proteins generally. If an antibody binds to epitope "A", the presence of a molecule containing epitope “A” (or free, unlabeled “A”), in a reaction containing labeled “A” and the protein, will reduce the amount of labeled “A” bound to the antibody.

[1012] As used herein, the term “epitope” (syn. “antigenic determinant”) shall be understood to mean a region of WAS protein to which a compound comprising an antigen binding site of an antibody binds. This term is not necessarily limited to the specific residues or structure to which the compound makes contact. For example, this term includes the region spanning amino acids contacted by the binding protein and / or 5-10 or 2-5 or 1-3 amino acids outside of this region. In some examples, the epitope comprises a series of discontinuous amino acids that are positioned close to one another when WAS protein is folded, i.e., a “conformational epitope”. The skilled artisan will also be aware that the term "epitope" is not limited to peptides or polypeptides. For example, the term “epitope” includes chemically active surface groupings of molecules such as sugar side chains, phosphoryl side chains, or sulfonyl side chains, and, in certain examples, may have specific three dimensional structural characteristics, and / or specific charge characteristics.

[1013] The term “competitively inhibits” shall be understood to mean that a compound (i.e., WAS-binding protein or antibody) of the disclosure (or an antigen binding site thereof) reduces or prevents binding of a recited antibody or protein to WAS protein or WAS protein variant of the disclosure. This may be due to the protein (or antigen binding site) and antibody binding to the same or an overlapping epitope. It will be apparent from the foregoing that the compound need not completely inhibit binding of the antibody, rather it need only reduce binding by a statistically significant amount, for example, by at least about 10% or 20% or 30% or 40% or 50% or 60% or 70% or 80% or 90% or 95%. Preferably, the compound reduces binding of the protein or antibody to WAS protein by at least about 30%, more preferably by at least about 50%, more preferably, by at least about 70%, still more preferably by at least about 75%, even more preferably, by at least about 80% or 85% and even more preferably, by at least about 90%. Methods for determining competitive inhibition of binding are known in the art and / or described herein. For example, the antibody is exposed to WAS protein either in the presence or absence of the compound. If less antibody binds in the presence of the compound than in the absence of the compound, the compound is considered to competitively inhibit binding of the antibody. In one example, the competitive inhibition is not due to steric hindrance.

[1014] “Overlapping” in the context of two epitopes shall be taken to mean that two epitopes share a sufficient number of amino acid residues to permit a compound (or protein comprising an antigen binding site thereof) that binds to one epitope to competitively inhibit the binding of a compound (or protein comprising an antigen binding site) that binds to the other epitope. For example, the “overlapping” epitopes share at least 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 9 or 20 amino acids.

[1015] As used herein, the term “cross-reacts” or “cross-reactivity” will be understood to mean that a protein raised against a specific antigen has a competing affinity to another antigen (e.g., a mutant form of the antigen or other species).

[1016] As used herein, the term “subject” shall be taken to mean any animal including humans, for example a mammal. Exemplary subjects include but are not limited to humans and non-human primates. In one example, the subject is a human.

[1017] As used herein, the term "expression construct" or “expression cassette” refers to one or more genetic sequences within a vector which can express a RNA, and, in some embodiments, subsequently a protein. The expression construct comprises at least one promoter and at least one gene of interest. In one example, the expression cassette is positionally and sequentially oriented within the vector such that the nucleic acid in the cassette can be transcribed into RNA, and when necessary, translated into a protein or a polypeptide, undergo appropriate post-translational modifications required for activity in the transformed cell (e.g. transduced stem cell), and be translocated to the appropriate compartment for biological activity by targeting to appropriate intracellular compartments or secretion into extracellular compartments. In one example, the cassette has its 3' and 5' ends adapted for ready insertion into a vector, e.g., it has restriction endonuclease sites at each end.

[1018] Wiskott-Aldrich Syndrome (WAS) Binding Proteins

[1019] The present disclosure provides a Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region.

[1020] Antibodies

[1021] The present disclosure provides a WAS binding protein as described herein according to any example, wherein the binding protein comprises an antigen binding site of an antibody. In some examples, the WAS binding protein is an antibody.

[1022] In one example, the antibody is a recombinant antibody. For example, an antibody or protein comprising a variable region thereof is produced using a standard method, e.g., as is known in the art or briefly described herein.

[1023] Monoclonal antibodies are one exemplary form of an antibody contemplated by the present disclosure. The term “monoclonal antibody" or “mAb” refers to a homogeneous antibody population capable of binding to the same antigen(s), for example, to the same epitope within the antigen. This term is not intended to be limited as regards to the source of the antibody or the manner in which it is made.

[1024] Immunization-based. Methods

[1025] Methods for generating antibodies are known in the art and / or described in Harlow et al., 1988. Generally, in such methods a protein or immunogenic fragment or epitope thereof or a cell expressing and displaying same (i.e., an immunogen), optionally formulated with any suitable or desired carrier, adjuvant, or pharmaceutically acceptable excipient, is administered to a non-human animal, for example, a mouse, chicken, rat, rabbit, guinea pig, dog, horse, cow, goat or pig. The immunogen may be administered intranasally, intramuscularly, sub-cutaneously, intravenously, intradermally, intraperitoneally, or by other known route.

[1026] The production of polyclonal antibodies may be monitored by sampling blood of the immunized animal at various points following immunization. One or more further immunizations may be given, if required to achieve a desired antibody titer. The process of boosting and titering is repeated until a suitable titer is achieved. When a desired level of immunogenicity is obtained, the immunized animal is bled and the serum isolated and stored, and / or the animal is used to generate monoclonal antibodies (mAbs). For the production of mAbs any one of a number of known techniques may be used, such as, for example, the procedure exemplified in US4196265 or Harlow et al., 1988.

[1027] For example, a suitable animal is immunized with an immunogen under conditions sufficient to stimulate antibody producing cells. Rabbits and rodents such as mice and rats are exemplary animals. Mice genetically-engineered to express human immunoglobulin proteins and, for example, do not express murine immunoglobulin proteins, can also be used to generate an antibody of the present disclosure (e.g., as described in W02002066630).

[1028] Following immunization, somatic cells with the potential for producing antibodies, e.g., B lymphocytes (B cells), are selected for use in the mAb generating protocol. These cells may be obtained from biopsies of spleens, tonsils or lymph nodes, or from a peripheral blood sample. The B cells from the immunized animal are then fused with cells of an immortal myeloma cell, generally derived from the same species as the animal that was immunized with the immunogen.

[1029] Hybrids are amplified by culture in a selective medium comprising an agent that blocks the de novo synthesis of nucleotides in the tissue culture media. Exemplary agents are aminopterin, methotrexate and azaserine.

[1030] The amplified hybridomas are subjected to a functional selection for antibody specificity and / or titer, such as, for example, by flow cytometry and / or immunohistochemstry and / or immunoassay (e.g. radioimmunoassay, enzyme immunoassay, cytotoxicity assay, plaque assay, dot immunoassay, and the like).

[1031] Alternatively, ABL-MYC technology (NeoClone, Madison WI 53713, USA) is used to produce cell lines secreting mAbs (e.g., as described in Largaespada et al., 1996).

[1032] Library-Based Methods

[1033] The present disclosure also encompasses screening of libraries of antibodies or antigen binding fragments thereof (e.g., comprising variable regions thereof).

[1034] Examples of libraries contemplated by this disclosure include naive libraries (from unchallenged subjects), immunized libraries (from subjects immunized with an antigen) or synthetic libraries. Nucleic acid encoding antibodies or regions thereof (e.g., variable regions) are cloned by conventional techniques (e.g., as disclosed in Sambrook et al., 2001) and used to encode and display proteins using a method known in the art. Other techniques for producing libraries of proteins are described in, for example in US6300064 (e.g., a HuCAL library of Morphosys AG); US5885793; US6204023; US6291158; or US6248516. The antigen binding fragments according to the disclosure may be soluble secreted proteins or may be presented as a fusion protein on the surface of a cell, or particle (e.g., a phage or other virus, a ribosome or a spore). Various display library formats are known in the art. For example, the library is an in vitro display library (e.g., a ribosome display library, a covalent display library or a mRNA display library, e.g., as described in US7270969). In yet another example, the display library is a phage display library wherein proteins comprising antigen binding fragments of antibodies are expressed on phage, e.g., as described in US6300064; US5885793; US6204023; US6291158; or US6248516. Other phage display methods are known in the art and are contemplated by the present disclosure. Similarly, methods of cell display are contemplated by the disclosure, e.g., bacterial display libraries, e.g., as described in US5516637; yeast display libraries, e.g., as described in US6423538 or a mammalian display library.

[1035] Methods for screening display libraries are known in the art. In one example, a display library of the present disclosure is screened using affinity purification, e.g., as described in Scopes, 1994. Methods of affinity purification typically involve contacting proteins comprising antigen binding fragments displayed by the library with a target antigen and, following washing, eluting those domains that remain bound to the antigen.

[1036] Any variable regions or scFvs identified by screening are readily modified into a complete antibody, if desired. Exemplary methods for modifying or reformatting variable regions or scFvs into a complete antibody are described, for example, in Jones et al., 2010; or Jostock et al., 2004; or W02012040793. Alternatively, or additionally, standard cloning methods are used, e.g., as described in Ausubel et al., 1987, and / or Sambrook et al., 2001.

[1037] Deimmunized, Chimeric, Humanized, Svnhumanized, Primatized and Human Proteins

[1038] The proteins of the present disclosure may be a humanized protein.

[1039] The term “humanized protein” shall be understood to refer to a protein comprising a human-like variable region, which includes CDRs from an antibody from a non-human species (e.g., mouse or rat or non-human primate) grafted onto or inserted into FRs from a human antibody (this type of antibody is also referred to a “CDR-grafted antibody”). Humanized proteins also include proteins in which one or more residues of the human protein are modified by one or more amino acid substitutions and / or one or more FR residues of the human protein are replaced by corresponding non-human residues. Humanized proteins may also comprise residues which are found in neither the human antibody or in the non-human antibody. Any additional regions of the protein (e.g., Fc region) are generally human. Humanization can be performed using a method known in the art, e.g., US5225539, US6054297, US7566771 or US5585089. The term “humanized protein” also encompasses a super-humanized protein, e.g., as described in US7732578.

[1040] The proteins of the present disclosure may be human proteins. The term “human protein” as used herein refers to proteins having variable and, optionally, constant antibody regions found in humans, e.g. in the human germline or somatic cells or from libraries produced using such regions. The “human” antibodies can include amino acid residues not encoded by human sequences, e.g. mutations introduced by random or site directed mutations in vitro (in particular mutations which involve conservative substitutions or mutations in a small number of residues of the protein, e.g. in 1, 2, 3, 4 or 5 of the residues of the protein). These “human antibodies” do not necessarily need to be generated as a result of an immune response of a human, rather, they can be generated using recombinant means (e.g., screening a phage display library) and / or by a transgenic animal (e.g., a mouse) comprising nucleic acid encoding human antibody constant and / or variable regions and / or using guided selection (e.g., as described in or US5565332). This term also encompasses affinity matured forms of such antibodies. For the purposes of the present disclosure, a human protein will also be considered to include a protein comprising FRs from a human antibody or FRs comprising sequences from a consensus sequence of human FRs and in which one or more of the CDRs are random or semirandom, e.g., as described in US6300064 and / or US6248516.

[1041] The proteins of the present disclosure may be synhumanized proteins. The term “synhumanized protein” refers to a protein prepared by a method described in W02007 / 019620. A synhumanized protein includes a variable region of an antibody, wherein the variable region comprises FRs from a New World primate antibody variable region and CDRs from a non-New World primate antibody variable region. For example, a synhumanized protein includes a variable region of an antibody, wherein the variable region comprises FRs from a New World primate antibody variable region and CDRs from a mouse or rat antibody.

[1042] The proteins of the present disclosure may be primatized proteins. A “primatized protein” comprises variable region(s) from an antibody generated following immunization of a non-human primate (e.g., a cynomolgus macaque). Optionally, the variable regions of the non-human primate antibody are linked to human constant regions to produce a primatized antibody. Exemplary methods for producing primatized antibodies are described in US6113898.

[1043] In one example a protein of the disclosure is a chimeric protein. The term “chimeric proteins” refers to proteins in which an antigen binding domain is from a particular species (e.g., murine, such as mouse or rat) or belonging to a particular antibody class or subclass, while the remainder of the protein is from a protein derived from another species (such as, for example, human or non-human primate) or belonging to another antibody class or subclass. In one example, a chimeric protein is a chimeric antibody comprising a VH and / or a VL from a non-human antibody (e.g., a murine antibody) and the remaining regions of the antibody are from a human antibody. The production of such chimeric proteins is known in the art, and may be achieved by standard means (as described, e.g., in US6331415; US5807715; US4816567 and US4816397).

[1044] The present disclosure also contemplates a deimmunized protein, e.g., as described in W02000 / 34317 and W02004 / 108158. De-immunized antibodies and proteins have one or more epitopes, e.g., B cell epitopes or T cell epitopes removed (i.e., mutated) to thereby reduce the likelihood that a subject will raise an immune response against the antibody or protein.

[1045] Antibodv Binding Domain Containing Proteins

[1046] Single-Domain Antibodies

[1047] In some examples, a compound of the disclosure is a protein that is or comprises a single-domain antibody (which is used interchangeably with the term “domain antibody” or “dAb”). A single-domain antibody is a single polypeptide chain comprising all or a portion of the heavy chain variable region of an antibody. In certain examples, a single-domain antibody is a human single-domain antibody (Domantis, Inc., Waltham, MA; see, e.g., US6248516).

[1048] Single Chain Fv (scFv) Fragments and dimeric-scFv (di-scFv)

[1049] The skilled artisan will be aware that scFvs comprise VH and VL regions in a single polypeptide chain. The polypeptide chain further comprises a polypeptide linker between the VH and VL which enables the scFv to form the desired structure for antigen binding (i.e., for the VH and VL of the single polypeptide chain to associate with one another to form a Fv). For example, the linker comprises in excess of 12 amino acid residues with (Gly4Ser)3 being one of the more favoured linkers for a scFv.

[1050] Alternatively, or in addition, the present disclosure provides a dimeric scFv, i.e., a protein comprising two scFv molecules linked by a non-covalent or covalent linkage, e.g., by a leucine zipper domain (e.g., derived from Fos or Jun) (see, for example, Kruif and Logtenberg, 1996). Alternatively, two scFvs are linked by a peptide linker of sufficient length to permit both scFvs to form and to bind to an antigen, e.g., as described in US20060263367.

[1051] For a review of scFv, see Pliickthun (1994).

[1052] Diabodies, Triabodies, Tetrabodies

[1053] Exemplary proteins comprising an antibody antigen binding domain are diabodies, triabodies, tetrabodies and higher order protein complexes such as those described in W098 / 044001 and W094 / 007921.

[1054] For example, a diabody is a protein comprising two associated polypeptide chains, each polypeptide chain comprising the structure VL-X-VH or VH-X-VL, wherein VL is an antibody light chain variable region, VH is an antibody heavy chain variable region, X is a linker comprising insufficient residues to permit the VH and VL in a single polypeptide chain to associate (or form an Fv) or is absent, and wherein the VH of one polypeptide chain binds to a VL of the other polypeptide chain to form an antigen binding site, i.e., to form an Fv molecule capable of specifically binding to one or more antigens. The VL and VH can be the same in each polypeptide chain or the VL and VH can be different in each polypeptide chain so as to form a bispecific diabody (i.e., comprising two Fvs having different specificity).

[1055] Constant Domain Fusions

[1056] The present disclosure encompasses proteins comprising a variable region and a constant region or a domain(s) thereof, e.g., Fc, CH2 and / or CH3 domain. The skilled artisan will be aware of the meaning of the terms constant region and constant domain based on the disclosure herein and references discussed herein.

[1057] Constant region sequences useful for producing the proteins of the present disclosure may be obtained from a number of different sources. In some examples, the constant region or portion thereof of the protein is derived from a human antibody. Moreover, the constant domain or portion thereof may be derived from any antibody class, including IgM, IgG, IgD, IgA and IgE, and any antibody isotype, including IgGi, IgGi. IgGs and IgG4.

[1058] In one example, the antibody is an IgGl or IgG4 isotype. For example, the antibody is an IgGl isotype. In another example, the antibody is an IgG4 isotype.

[1059] A variety of constant region gene sequences are available in the form of publicly accessible deposits or the sequence thereof is available from publicly available databases. Constant regions can be selected having a particular effector function (or lacking a particular effector function) or with a particular modification to reduce immunogenicity. I l l

[1060] The present disclosure also contemplates proteins comprising mutant constant regions or domains, e.g., as described in US7217797; US7217798; or US20090041770 (having increased half-life) or US2005037000 (increased ADCC).

[1061] Heavy Chain Antibodies

[1062] Heavy chain antibodies differ structurally from many other forms of antibodies, in so far as they comprise a heavy chain, but do not comprise a light chain. Accordingly, these antibodies are also referred to as “heavy chain only antibodies”. Heavy chain antibodies are found in, for example, camelids and cartilaginous fish (also called IgNAR).

[1063] A general description of heavy chain antibodies from camelids and the variable regions thereof and methods for their production and / or isolation and / or use is found inter alia in the following references WO94 / 04678, WO97 / 49805 and WO 97 / 49805.

[1064] A general description of heavy chain antibodies from cartilaginous fish and the variable regions thereof and methods for their production and / or isolation and / or use is found inter alia in W02005 / 118629.

[1065] Other Antibodies and Antibody Fragments

[1066] The present disclosure also contemplates other antibodies and antibody fragments, such as:

[1067] (i) “key and hole” bispecific proteins as described in US5,731,168;

[1068] (ii) heteroconjugate proteins, e.g., as described in US4,676,980;

[1069] (iii) heteroconjugate proteins produced using a chemical cross-linker, e.g., as described in US4,676,980; and

[1070] (iv) Fabs (e.g., as described in EP19930302894).

[1071] De-immunized Antibodies and Proteins

[1072] The present disclosure also contemplates a de-immunized antibody or protein. De-immunized antibodies and proteins have one or more epitopes, e.g., B cell epitopes or T cell epitopes removed (i.e., mutated) to thereby reduce the likelihood that a mammal will raise an immune response against the antibody or protein. Methods for producing de-immunized antibodies and proteins are known in the art and described, for example, in W02000 / 34317, W02004 / 108158 and W02004 / 064724.

[1073] Methods for introducing suitable mutations and expressing and assaying the resulting protein will be apparent to the skilled artisan based on the description herein. Mutations to WAS-Binding Proteins

[1074] The present disclosure also contemplates mutant forms of a binding protein and / or an antibody of the disclosure. For example, such a mutant antibody comprises one or more conservative amino acid substitutions compared to a sequence set forth herein. In some examples, the antibody comprises 30 or fewer or 20 or fewer or 10 or fewer, e.g., 9 or 8 or 7 or 6 or 5 or 4 or 3 or 2 conservative amino acid substitutions. A "conservative amino acid substitution" is one in which the amino acid residue is replaced with an amino acid residue having a similar side chain and / or hydropathicity and / or hydrophilicity.

[1075] In one example, a mutant protein has only, or not more than, one or two or three or four or five or six conservative amino acid changes when compared to a naturally occurring protein. Details of conservative amino acid changes are provided below. As the skilled person would be aware, e.g., from the disclosure herein, such minor changes can reasonably be predicted not to alter the activity of the protein.

[1076] Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), P-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).

[1077] The present disclosure also contemplates non-conservative amino acid changes (e.g., substitutions) in a protein of the present disclosure, e.g., in a CDR, such as CDR3. For example, the present inventors have identified several non-conservative amino acid substitutions that can be made while retaining an activity of a protein of the disclosure. In one example, the protein comprises fewer than 6 or 5 or 4 or 3 or 2 or 1 non- conservative amino acid substitutions, e.g., in a CDR3, such as in a CDR3.

[1078] In one example, the mutation(s) occur within a FR of an antigen binding domain of an antibody of the disclosure. In another example, the mutation(s) occur within a CDR of an antibody of the disclosure.

[1079] Exemplary methods for producing mutant forms of an antibody include:

[1080] • mutagenesis of DNA (Thie et al., Methods Mol. Biol. 525: 309-322, 2009) or

[1081] RNA (Kopsidas et al., Immunol. Lett. 07:163-168, 2006; Kopsidas et al. BMC Biotechnology, 7: 18, 2007; and WO1999 / 058661);

[1082] • introducing a nucleic acid encoding the polypeptide into a mutator cell, e.g., XL-

[1083] IRed, XL-mutS and XL-mutS-Kanr bacterial cells (Stratagene);

[1084] • DNA shuffling, e.g., as disclosed in Stemmer, Nature 370: 389-91, 1994; and • site directed mutagenesis, e.g., as described in Dieffenbach (ed) and Dveksler (ed) (In PCR Primer: A Laboratory Manual, Cold Spring Harbor Laboratories, NY, 1995).

[1085] The present disclosure also contemplates one or more insertions or deletions compared to a sequence set forth herein. In some examples, the protein comprises 10 or fewer, e.g., 9 or 8 or 7 or 6 or 5 or 4 or 3 or 2 insertions and / or deletions.

[1086] Constant Regions

[1087] The present disclosure encompasses proteins and / or antibodies described herein comprising a constant region of an antibody. This includes antigen binding fragments of an antibody fused to a Fc.

[1088] Sequences of constant regions useful for producing the proteins of the present disclosure may be obtained from a number of different sources. In some examples, the constant region or portion thereof of the protein is derived from a human antibody. The constant region or portion thereof may be derived from any antibody class, including IgM, IgG, IgD, IgA and IgE, and any antibody isotype, including IgGl, IgG2, IgG3 and IgG4. In one example, the constant region is human isotype IgGl or IgG4. For example, the constant region is human isotype IgGl. In one example, the constant region is human isotype IgG4 or a stabilized IgG4 constant region.

[1089] In one example, the Fc region of the constant region has a reduced ability to induce effector function, e.g., compared to a native or wild-type human IgGl or IgG3 Fc region. In one example, the effector function is antibody -dependent cell-mediated cytotoxicity (ADCC) and / or antibody-dependent cell-mediated phagocytosis (ADCP) and / or complement-dependent cytotoxicity (CDC). Methods for assessing the level of effector function of an Fc region containing protein are known in the art and / or described herein.

[1090] In one example, the Fc region is an IgG4 Fc region (i.e., from an IgG4 constant region), e.g., a human IgG4 Fc region. Sequences of suitable IgG4 Fc regions will be apparent to the skilled person and / or available in publically available databases (e.g., available from National Center for Biotechnology Information).

[1091] In one example, the constant region is a stabilized IgG4 constant region. The term “stabilized IgG4 constant region” will be understood to mean an IgG4 constant region that has been modified to reduce Fab arm exchange or the propensity to undergo Fab arm exchange or formation of a half-antibody or a propensity to form a half antibody. “Fab arm exchange" refers to a type of protein modification for human IgG4, in which an IgG4 heavy chain and attached light chain (half-molecule) is swapped for a heavy-light chain pair from another IgG4 molecule. Thus, IgG4 molecules may acquire two distinct Fab arms recognizing two distinct antigens (resulting in bispecific molecules). Fab arm exchange occurs naturally in vivo and can be induced in vitro by purified blood cells or reducing agents such as reduced glutathione. A “half antibody” forms when an IgG4 antibody dissociates to form two molecules each containing a single heavy chain and a single light chain.

[1092] In one example, a stabilized IgG4 constant region comprises a proline at position 241 of the hinge region according to the system of Kabat (Kabat et al., Sequences of Proteins of Immunological Interest Washington DC United States Department of Health and Human Services, 1987 and / or 1991). This position corresponds to position 228 of the hinge region according to the EU numbering system (Kabat et al., Sequences of Proteins of Immunological Interest Washington DC United States Department of Health and Human Services, 2001 and Edelman et al., Proc. Natl. Acad. USA, 63, 78-85, 1969). In human IgG4, this residue is generally a serine. Following substitution of the serine for proline, the IgG4 hinge region comprises a sequence CPPC. In this regard, the skilled person will be aware that the “hinge region” is a proline-rich portion of an antibody heavy chain constant region that links the Fc and Fab regions that confers mobility on the two Fab arms of an antibody. The hinge region includes cysteine residues which are involved in inter-heavy chain disulfide bonds. It is generally defined as stretching from Glu226 to Pro243 of human IgGl according to the numbering system of Kabat. Hinge regions of other IgG isotypes may be aligned with the IgGl sequence by placing the first and last cysteine residues forming inter-heavy chain disulphide (S-S) bonds in the same positions (see for example W02010 / 080538).

[1093] Additional examples of stabilized IgG4 antibodies are antibodies in which arginine at position 409 in a heavy chain constant region of human IgG4 (according to the EU numbering system) is substituted with lysine, threonine, methionine, or leucine (e.g., as described in W02006 / 033386). The Fc region of the constant region may additionally or alternatively comprise a residue selected from the group consisting of: alanine, valine, glycine, isoleucine and leucine at the position corresponding to 405 (according to the EU numbering system). Optionally, the hinge region comprises a proline at position 241 (i.e., a CPPC sequence) (as described above).

[1094] In another example, the Fc region is a region modified to have reduced effector function, i.e., a “non-immunostimulatory Fc region”. For example, the Fc region is an IgGl Fc region comprising a substitution at one or more positions selected from the group consisting of 268, 309, 330 and 331. In another example, the Fc region is an IgGl Fc region comprising one or more of the following changes E233P, L234V, L235A and deletion of G236 and / or one or more of the following changes A327G, A33OS and P33 IS (Armour et al., Eur J Immunol. 29:2613-2624, 1999; Shields et al., J Biol Chem. 276(9): 6591-604, 2001). Additional examples of non-immunostimulatory Fc regions are described, for example, in Dall'Acqua et al., J Immunol. 177 : 1129-1138 2006; and / or Hezareh J Virol ;75: 12161-12168, 2001).

[1095] In another example, the Fc region is a chimeric Fc region, e.g., comprising at least one CH2 domain from an IgG4 antibody and at least one CH3 domain from an IgGl antibody, wherein the Fc region comprises a substitution at one or more amino acid positions selected from the group consisting of 240, 262, 264, 266, 297, 299, 307, 309, 323, 399, 409 and 427 (EU numbering) (e.g., as described in W02010 / 085682). Exemplary substitutions include 240F, 262L, 264T, 266F, 297Q, 299A, 299K, 307P, 309K, 309M, 309P, 323F, 399S, and 427F.

[1096] WAS Binding Protein Conjugates

[1097] The present disclosure also provides conjugates of WAS binding proteins described herein according to any example. For example, a WAS binding protein comprising an antibody variable region is conjugated to a detectable label.

[1098] As used herein, the term “conjugate” or “conjugated” shall be understood to encompass both indirect and direct binding. For example, direct conjugation includes chemical conjugation, which can be non-covalent or covalent or genetic conjugation (also referred to as “fusion”). In one example, the conjugation is covalent, e.g., a disulphide bond.

[1099] As used herein, a “detectable label” is a molecular or atomic tag or marker that generates or can be induced to generate an optical or other signal or product that can be detected visually or by using a suitable detector. Detectable labels are well known in the art and include, for example, a radiolabel, an enzyme, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, a prosthetic group, a contrast agent and an ultrasound agent.

[1100] In one example, a protein as described herein according to any example comprises one or more detectable markers to facilitate detection and / or isolation. For example, the compound comprises a fluorescent label such as, for example, fluorescein (FITC), 5,6- carboxymethyl fluorescein, Texas red, nitrobenz-2-oxa-l,3- diazol-4-yl (NBD), coumarin, dansyl chloride, rhodamine, 4'-6-diamidino-2- phenylinodole (DAPI), and the cyanine dyes Cy3, Cy3.5, Cy5, Cy5.5 and Cy7, fluorescein (5-carboxyfluorescein-N- hydroxysuccinimide ester), rhodamine (5,6- tetramethyl rhodamine). The absorption and emission maxima, respectively, for these fluors are: FITC (490 nm; 520 nm), Cy3 (554 nm; 568 nm), Cy3.5 (581 nm; 588 nm), Cy5 (652 nm: 672 nm), Cy5.5 (682 nm; 703 nm) and Cy7 (755 nm; 778 nm). Exemplary fluorescent dyes will be apparent to the skilled person and include for example, Alexa Fluor® 647 (AF647; ThermoFisher; absorption and emission maxima 650 nm and 671 nm) and AF555 (absorption and emission maxima 555 nm and 580 nm).

[1101] Alternatively, or in addition, the protein as described herein according to any example is labeled with, for example, a fluorescent semiconductor nanocrystal (as described, for example, in US6,306,610).

[1102] Alternatively, or in addition, the protein is labeled with, for example, a magnetic or paramagnetic compound, such as, iron, steel, nickel, cobalt, rare earth materials, neodymium-iron-boron, ferrous-chromium-cobalt, nickel-ferrous, cobalt- platinum, or strontium ferrite.

[1103] In one example, a detectable label is an enzyme. The enzyme can act on an appropriate substrate to result in production of a detectable dye. Examples of enzymes useful in the disclosure include, without limitation, alkaline phosphatase and horseradish peroxidase. Alternatively or in addition, the enzyme can be, for example, luciferase. The enzyme can be linked to the protein or antibody by conventional chemical methods, or it can be expressed together with the protein or antibody as a fusion protein.

[1104] Radioisotopes useful as detectable labels in the disclosure are well known in the art and can include3H,nC,18F,35S, ^Cu,67Ga,68Ga, "mTc,i nIn,1231,1241,125I, and131I. Attachment of any gamma emitting radioactive materials, e.g., "mTc andi nIn, which can react with carboxyl, amino, or sulfhydryl groups of the protein or antibody of the discloure is suitable for use in detection methods using gamma scintigraphy. Attachment of radioactivenC,18F,64Cu,67Ga,68Ga,124I, and131I compounds which can react with carboxyl, amino, or sulfhydryl groups of the protein or antibody is suitable for use in detection methods using PET / SPECT imaging.

[1105] Methods of WAS Protein Detection

[1106] The present disclosure provides a method of detecting Wiskott-Aldrich Syndrome (WAS) protein expression in a cell transduced with a lentiviral vector construct encoding a Wiskott-Aldrich Syndrome (WAS) protein, the method comprising detecting WAS protein in the cell with a WAS -binding protein according to the present disclosure.

[1107] As used herein, the term “detect” or “detecting” refers to the identification of the presence or existence of WAS protein or nucleic acid encoding WAS protein in a cell or sample. As used herein, the terms "transduce" or "transduction" refer to the delivery of a gene(s) using a viral or retroviral vector by means of infection rather than by transfection. For example, a WAS gene carried by a lentiviral vector can be transduced into a cell through infection and provirus integration. Thus, a "transduced gene" is a gene that has been introduced into the cell via lentiviral or vector infection and provirus integration.

[1108] As used herein, the term "lentiviral vector" is used to denote any form of a nucleic acid derived from a lentivirus and used to transfer genetic material into a cell via transduction. The term encompasses lentiviral vector nucleic acids, such as DNA and RNA, encapsulated forms of these nucleic acids, and viral particles in which the viral vector nucleic acids have been packaged.

[1109] In one example, the method comprises determining the level of WAS protein expression from the cell.

[1110] As used herein, the term “level” in reference to WAS protein shall be understood to refer to a measure of the encoded protein. Various methods of assessing the quantity of protein are available to the skilled person and the skilled person will recognise that the specific level will vary depending on the method of assessment used. It will also be apparent that this term encompasses both an absolute and relative value. For example, the level may be relative to a reference or control sample. In another example, the level may be an absolute value of protein present in the sample. In a further example, the level may be relative to achieving a desired platelet count. For example, a level of WAS protein is the level required to achieve a platelet count of at least 100,000 platelets per microliter of blood in a subject. In one example, a level of WAS protein is the level required to achieve a platelet count of at least 150,000 -200,000 platelets per microliter of blood in a subject. In another example, the level may be relative to a desired physiological level. For example, a level of WAS protein is the level sufficient to achieve a near physiological level of WAS protein in the subject to achieve a platelet count of at least 100,000 platelets per microliter of blood in the subject.

[1111] In one example, methods of the present disclosure involve extracting or isolating protein fractions from the cell or a biological sample comprising a population of cells.

[1112] Methods for the extraction of protein fractions from the cell or biological samples will be apparent to the skilled person and / or are described herein and include, for example, column-based techniques. A commercial kit may be used for protein extraction including for example, isolation with the AllPrep Protein Universal Kit (Qiagen).

[1113] In one example, the quality and / or quantity of the extracted protein may also be determined by any method known to a person skilled in the art e.g. spectrophotometrically at 260, 280 and 230 nm, agarose gel electrophoreses, or Bioanalyzer analysis (Agilent). For example, quantity of protein may be assessed using the Nanodrop spectrophotometer (ThermoScientific) and Qubit Fluorometer (Life Technologies). For example, quality of protein may be assessed using Bioanalyser and TapeStation systems (Agilent).

[1114] Normalisation and controls

[1115] In one example of any method described herein, the level of WAS protein is normalized. For example, the level of WAS protein is normalized to a standard to obtain a normalized level of WAS protein.

[1116] The term “normalizing” or “normalized” as used herein refers to the level of the protein, relative to the mean level of a set or control set of reference proteins. The reference is based on their minimal variation across patients, tissues, or treatments.

[1117] In one example of any method described herein, the method comprises normalizing the level of WAS protein to a standard to obtain a normalized level of the WAS protein.

[1118] In one example, the standard is an endogenous control. For example, the endogenous control is a protein that shows minimal variation across patients, tissues, or treatments. For example, the endogenous control protein is a housekeeping protein.

[1119] Suitable proteins for use as a housekeeping protein in the present disclosure will be apparent to the skilled person and / or described herein.

[1120] In one example, the control is an exogenous control, for example an exogenous protein of known concentration is added to the biological sample before protein extraction (e.g., a spike-in control). Spike-in controls may be added to a sample before protein is recovered, the amount of the spike-in control recovered after protein is direct...

Claims

CLAIMS1. A Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant that lacks at least one of a pleckstrin homology domain, a WASp homology 1 (WH1) domain, a proline-rich region, a WH2 domain and / or a verprolin homology domain, and wherein the antibody variable region does not detectably bind to neuronal WAS protein.

2. The WAS binding protein of claim 1, wherein the WAS protein variant binds to a human WAS protein and murine WAS protein, wherein the WAS protein variant comprises, or consists of, in order from N- to C- terminal:(i) a GTPase-binding domain;(ii) a cofilin-homology sequence; and(iii) a C -terminal acid domain.

3. A Wiskott-Aldrich Syndrome (WAS) binding protein, wherein the protein comprises an antibody variable region, wherein the antibody variable region binds to a WAS protein variant, wherein the WAS protein variant comprises, or consists of, in order from N- to C- terminal:(i) a GTPase-binding domain; and(ii) a cofilin-homology sequence; and(iii) a C -terminal acid domain.

4. The WAS binding protein of claim 3, wherein the GTPase-binding and the cofilin- homology sequence are indirectly linked to each other via a linker, wherein the linker:(i) is a peptide linker comprising at least 2 amino acids in length;(ii) is selected from the group consisting of a (GS)nlinker, wherein n=l, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14 or 15, a GSGGS linker, a GGSSG linker, a GGGGS linker, a GSGSG linker, a (Gly)s linker, a (Gly)e linker, a (GGGS)nlinker, wherein n=l, 2, 3 or 4, a (EAAAK)nlinker, wherein n=l, 2 or 3, a A(EAAAK)4ALEA(EAAAK4)A linker, a AEAAAKEAAAKA linker, a (Ala- Pro)nlinker, wherein n=10-34, and a PAPAP linker; and / or(iii) is a GS6 linker.

5. The WAS binding protein of claim 2, wherein the WAS protein variant further comprises a purification tag located at the C-terminus of the protein variant, wherein the purification tag is selected from the group consisting of a hexahistidine tag, a FLAG-tag, a calmodulin binding peptide (CBP) tag, a poly-glutamate tag, a polycysteine (Cys) tag, a polyhistidine (His) tag, a Myc-tag, a streptavidin-binding peptide (SBP) tag, a streptavidin (Strep) tag, an avidin tag, a bacteriophage V5 epitope (V5) tag, an isopeptag, a SpyTag, a biotin-carboxyl carrier protein (BCCP) tag, a Halo-tag, a thioredoxin (Trx) tag, a small ubiquitin-like molecule (SUMO) tag, a maltose binding protein (MBP) tag; a His8 tag, and combinations thereof.

6. The WAS binding protein of claim 1 wherein the WAS protein variant comprises, or consists of, in order from N- to C- terminal:(i) a GTPase-binding domain;(ii) a (GS)6 linker;(iii) a cofilin-homology sequence;(iv) a C-terminal acid domain; and(v) a His8 tag.

7. The WAS binding protein of claim 1, wherein the WAS protein variant comprises:(i) from N- to C- terminal amino acid residues 242 to 310 of SEQ ID NO: 129; a GGSGGS linker (SEQ ID NO: 136); amino acid residues 461 to 502 of SEQ ID NO: 129; and a His8 tag (SEQ ID NO: 137);(ii)from N- to C- terminal a sequence set forth in SEQ ID NO: 131; a sequence set forth in SEQ ID NO: 136; a sequence set forth in SEQ ID NO: 134; and a sequence set forth in SEQ ID NO: 137;(iii)a sequence set forth in SEQ ID NO: 130 lacking amino acids 1 to 19; and / or(iv) a sequence set forth in SEQ ID NO: 129 and / or the murine WAS protein comprises a sequence set forth in SEQ ID NO: 135.

8. The WAS binding protein of claim 1, wherein the antibody variable region comprises:(i) a heavy chain variable region (VH) comprising a sequence set forth in any one of SEQ ID NOs: 14 or 1 or 2 or 6 to 13 or 15; and a light chain variable region (VL) comprising a sequence set forth in any one of SEQ ID NOs: 24 or 3 to 5 or 16 to 23 or 25; or(ii) a VH comprising three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 14 or 1 or 2 or 6 to 13 or 15; and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 24 or 3 to 5 or 16 to 23 or 25.

9. The WAS binding protein of claim 1, wherein the binding protein is selected from the group consisting of:(i) a single chain Fv fragment (scFv);(ii) a dimeric scFv (di-scFv);(iii) a diabody;(iv) a triabody;(v) a tetrabody;(vi) a Fab;(vii) a F(ab’)2;(viii) a Fv;(ix) one of (i) to (viii) linked to a constant region of an antibody, Fc or a heavy chain constant domain (CH) 2 and / or CH3; and(x) an antibody.

10. The WAS binding protein of claim 1, wherein the binding protein is an antibody and comprises:(i) a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO: 24; or(ii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24; or(iii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92; or(iv) a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25; or(v) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 1 and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 20, 23 or 25; or(vi) a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21; or(vii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 2 and a VL comprising three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 16, 17 or 21; or(viii) a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising a sequence set forth in SEQ ID NO: 3; or(ix) a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 9, 10 or 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 3; or(x) a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising a sequence set forth in SEQ ID NO: 4; or(xi) a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NO: 8 or 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 4; or(xii) a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising a sequence set forth in SEQ ID NO: 5; or(xiii) a VH comprising three CDRs of a VH comprising a sequence set forth in any one of SEQ ID NOs: 6, 7 or 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 5; or(xiv) a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising a sequence set forth in SEQ ID NO: 16; or(xv) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16; or(xvi) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising asequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44; or(xvii) a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising a sequence set forth in SEQ ID NO: 17; or(xviii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17; or(xix) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 50; or(xx) a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 18; or(xxi) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18; or(xxii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56; or(xxiii) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 19; or(xxiv) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19; or(xxv) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62; or(xxvi) a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO: 20; or(xxvii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20; or(xxviii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68; or(xxix) a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO: 21; or(xxx) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21; or(xxxi) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74; or(xxxii) a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 22; or(xxxiii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22; or(xxxiv) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80; or(xxxv) a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising a sequence set forth in SEQ ID NO: 23; or(xxxvi) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23; or(xxxvii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 81, a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86; or(xxxviii) a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising a sequence set forth in SEQ ID NO: 25; or(xxxix) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25; or(xl)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

11. The WAS binding protein of claim 1, wherein the binding protein is an antibody and further comprises a light chain constant domain comprising a sequence set forth in any one of SEQ ID NO: 36, 37 or 38.

12. The WAS binding protein of claim 1, wherein the binding protein is an antibody and comprises:(i) VH comprising a sequence set forth in SEQ ID NO: 14, a VL comprising a sequence set forth in SEQ ID NO: 24 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or(ii) a VH comprising a sequence set forth in SEQ ID NO: 14 and a light chain comprising a sequence set forth in SEQ ID NO: 34; or(iii) a VH comprising a sequence set forth in SEQ ID NO: 6, a VL comprising a sequence set forth in SEQ ID NO: 16; and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 37; or(iv) a VH comprising a sequence set forth in SEQ ID NO: 6, a light chain comprising a sequence set forth in SEQ ID NO: 26; or(v) a VH comprising a sequence set forth in SEQ ID NO: 7, a VL comprising a sequence set forth in SEQ ID NO: 17 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 37; or(vi) a VH comprising a sequence set forth in SEQ ID NO: 7 and a light chain comprising a sequence set forth in SEQ ID NO: 27; or(vii) a VH comprising a sequence set forth in SEQ ID NO: 8, a VL comprising a sequence set forth in SEQ ID NO: 18 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or(viii) a VH comprising a sequence set forth in SEQ ID NO: 8 and a light chain comprising a sequence set forth in SEQ ID NO: 28; or(ix) a VH comprising a sequence set forth in SEQ ID NO: 9, a VL comprising a sequence set forth in SEQ ID NO: 19 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or(x) a VH comprising a sequence set forth in SEQ ID NO: 9 and a light chain comprising a sequence set forth in SEQ ID NO: 29; or(xi) a VH comprising a sequence set forth in SEQ ID NO: 10, a VL comprising a sequence set forth in SEQ ID NO: 20 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or(xii) a VH comprising a sequence set forth in SEQ ID NO: 10 and a light chain comprising a sequence set forth in SEQ ID NO: 30; or(xiii) a VH comprising a sequence set forth in SEQ ID NO: 11, a VL comprising a sequence set forth in SEQ ID NO: 21 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or(xiv) a VH comprising a sequence set forth in SEQ ID NO: 11 and a light chain comprising a sequence set forth in SEQ ID NO: 31; or(xv) a VH comprising a sequence set forth in SEQ ID NO: 12, a VL comprising a sequence set forth in SEQ ID NO: 22 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or(xvi) a VH comprising a sequence set forth in SEQ ID NO: 12 and a light chain comprising a sequence set forth in SEQ ID NO: 32; or(xvii) a VH comprising a sequence set forth in SEQ ID NO: 13, a VL comprising a sequence set forth in SEQ ID NO: 23 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 36; or(xviii) a VH comprising a sequence set forth in SEQ ID NO: 13 and a light chain comprising a sequence set forth in SEQ ID NO: 33; or(xix) a VH comprising a sequence set forth in SEQ ID NO: 15, a VL comprising a sequence set forth in SEQ ID NO: 25 and a light chain constant domain comprising a sequence set forth in SEQ ID NO: 38; or(xx) a VH comprising a sequence set forth in SEQ ID NO: 15 and a light chain comprising a sequence set forth in SEQ ID NO: 35.

13. The WAS binding protein of claim 1, wherein the binding protein is an antibody and comprises:(i) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 99 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109; or(ii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 99, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 109 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 119; or(iii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 107 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117; or(iv) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 107, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 117 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 127; or(v) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 100 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110; or(vi) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 100, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 110 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 120; or(vii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 101 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111; or(viii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 101, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 111 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 121; or(ix) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 102 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112; or(x) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 102, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 112 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 122; or(xi) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 103 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113; or(xii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 103, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 113 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 123; or(xiii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 104 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114; or(xiv) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 104, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 114 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 124; or(xv) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 105 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115; or(xvi) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 105, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 115 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 125; or(xvii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 106 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116; or(xviii) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 106, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 116 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 126; or(xix) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 108 and a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118; or(xx) a VH comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 108, a VL comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 118 and a light chain constant domain comprising a sequence encoded by a nucleic acid comprising SEQ ID NO: 128.

14. The WAS binding protein of claim 1, wherein the WAS binding protein is conjugated to a detectable label, for example, wherein the detectable label is selected from the group consisting of an enzyme, a radiolabel, a fluorescent label, a luminescent label, a bioluminescent label, a magnetic label, a prosthetic group and a contrast agent.

15. A nucleic acid encoding a Wiskott-Aldrich Syndrome (WAS) binding protein comprising an antibody variable region that binds to WAS protein, wherein the antibody variable region comprises:(i) a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO: 24; or(ii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24; or(iii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92; or(iv) a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising a sequence set forth in SEQ ID NO: 16; or(v) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16; or(vi) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising a sequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44; or(vii)a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising a sequence set forth in SEQ ID NO: 17; or(viii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17; or(ix) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 50; or(x) a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising a sequence set forth in SEQ ID NO: 18; or(xi) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18; or(xii)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and a VL comprising aCDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56; or(xiii) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO: 19; or(xiv) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19; or(xv)a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62; or(xvi) a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO: 20; or(xvii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20; or(xviii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68; or(xix) a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO: 21; or(xx)a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21; or(xxi) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74; or(xxii) a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO: 22; or(xxiii) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22; or(xxiv) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80; or(xxv) a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising a sequence set forth in SEQ ID NO: 23; or(xxvi) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23; or(xxvii) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 81, a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86; or(xxviii) a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising a sequence set forth in SEQ ID NO: 25; or(xxix) a VH comprising three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and a VL comprising three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25; or(xxx) a VH comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and a VL comprising a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

16. The nucleic acid of claim 15, wherein the VH and VL are in a single polypeptide chain encoded by a single nucleic acid or wherein the VH and VL are in separate polypeptide chains, wherein each polypeptide chain is encoded by a separate nucleic acid, for example, wherein if the VH and VL are in the same polypeptide chain, the protein is:(i) a single chain Fv fragment (scFv);(ii) a dimeric scFv (di-scFv); or(iii) at least one of (i) and / or (ii) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (CH) 2 and / or CH3; or if the VH and VL are in separate polypeptide chains, the protein is:(i) a diabody;(ii) a triabody;(iii) a tetrabody;(iv) a Fab;(v) a F(ab')2;(vi) a Fv;(vii) an antibody; or(viii) one of (i) to (vi) linked to a constant region of an antibody, a Fc or a heavy chain constant domain (CH)2 and / or CH3.

17. A composition comprising:(i) a first expression construct comprising a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 14 or 1 or 2 or 6 to 13 or 15; and(ii) a second expression construct comprising a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 24 or 3 to 5 or 16 to 23 or 25; wherein the first and second polypeptides associate to form a protein comprising an antibody variable region.

18. An expression construct comprising:(i) a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 14 or 1 or 2 or 6 to 13 or 15; and / or(ii) a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 24 or 3 to 5 or 16 to 23 or 25.

19. A cell comprising:(i) a first expression construct comprising a first nucleic acid encoding a first polypeptide comprising a heavy chain variable region (VH), wherein the VH comprises three complementarity determining regions (CDRs) of a VH comprising a sequence set forth in any one of SEQ ID NOs: 14 or 1 or 2 or 6 to 13 or 15; and(ii) a second expression construct comprising a second nucleic acid encoding a second polypeptide comprising a light chain variable region (VL), wherein the VL comprises three CDRs of a VL comprising a sequence set forth in any one of SEQ ID NOs: 24 or 3 to 5 or 16 to 23 or 25.

20. The composition of claim 17, wherein:(i) the VH comprises a sequence set forth in SEQ ID NO: 14 and the VL comprises a sequence set forth in SEQ ID NO: 24; or(ii) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 14 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 24; or(iii) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 87, a CDR2 comprising a sequence set forth in SEQ ID NO: 88, and a CDR3 comprising a sequence set forth in SEQ ID NO: 89; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 90, a CDR2 comprising a sequence set forth in SEQ ID NO: 91 and a CDR3 comprising a sequence set forth in SEQ ID NO: 92; or(iv) the VH comprises a sequence set forth in SEQ ID NO: 6 and the VL comprises a sequence set forth in SEQ ID NO: 16; or(v) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 6 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 16; or(vi) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 39, a CDR2 comprising a sequence set forth in SEQ ID NO: 40, and a CDR3 comprising a sequence set forth in SEQ ID NO: 41; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 42, a CDR2 comprising a sequence set forth in SEQ ID NO: 43 and a CDR3 comprising a sequence set forth in SEQ ID NO: 44; or(vii) the VH comprises a sequence set forth in SEQ ID NO: 7 and the VL comprises a sequence set forth in SEQ ID NO: 17; or(viii) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 7 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 17; or(ix) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 45, a CDR2 comprising a sequence set forth in SEQ ID NO: 46, and a CDR3 comprising a sequence set forth in SEQ ID NO: 47; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 48, a CDR2 comprising a sequence set forth in SEQ ID NO: 49 and a CDR3 comprising a sequence set forth in SEQ ID NO: 50; or(x) the VH comprises a sequence set forth in SEQ ID NO: 8 and the VL comprises a sequence set forth in SEQ ID NO: 18; or(xi) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 8 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 18; or(xii) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 51, a CDR2 comprising a sequence set forth in SEQ ID NO: 52, and a CDR3 comprising a sequence set forth in SEQ ID NO: 53; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 54, a CDR2 comprising a sequence set forth in SEQ ID NO: 55 and a CDR3 comprising a sequence set forth in SEQ ID NO: 56; or(xiii) the VH comprises a sequence set forth in SEQ ID NO: 9 and the VL comprises a sequence set forth in SEQ ID NO: 19; or(xiv) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 9 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 19; or(xv) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 57, a CDR2 comprising a sequence set forth in SEQ ID NO: 58, and a CDR3 comprising a sequence set forth in SEQ ID NO: 59; and the VL comprisesa CDR1 comprising a sequence set forth in SEQ ID NO: 60, a CDR2 comprising a sequence set forth in SEQ ID NO: 61 and a CDR3 comprising a sequence set forth in SEQ ID NO: 62; or(xvi) the VH comprises a sequence set forth in SEQ ID NO: 10 and the VL comprises a sequence set forth in SEQ ID NO: 20; or(xvii) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 10 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 20; or(xviii) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 63, a CDR2 comprising a sequence set forth in SEQ ID NO: 64, and a CDR3 comprising a sequence set forth in SEQ ID NO: 65; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 66, a CDR2 comprising a sequence set forth in SEQ ID NO: 67 and a CDR3 comprising a sequence set forth in SEQ ID NO: 68; or(xix) the VH comprises a sequence set forth in SEQ ID NO: 11 and the VL comprises a sequence set forth in SEQ ID NO: 21; or(xx) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 11 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 21; or(xxi) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 69, a CDR2 comprising a sequence set forth in SEQ ID NO: 70, and a CDR3 comprising a sequence set forth in SEQ ID NO: 71; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 72, a CDR2 comprising a sequence set forth in SEQ ID NO: 73 and a CDR3 comprising a sequence set forth in SEQ ID NO: 74; or(xxii) the VH comprises a sequence set forth in SEQ ID NO: 12 and the VL comprises a sequence set forth in SEQ ID NO: 22; or(xxiii) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 12 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 22; or(xxiv) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 75, a CDR2 comprising a sequence set forth in SEQ ID NO: 76, and a CDR3 comprising a sequence set forth in SEQ ID NO: 77; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 78, a CDR2 comprising a sequence set forth in SEQ ID NO: 79 and a CDR3 comprising a sequence set forth in SEQ ID NO: 80; or(xxv) the VH comprises a sequence set forth in SEQ ID NO: 13 and the VL comprises a sequence set forth in SEQ ID NO: 23; or(xxvi) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 13 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 23; or(xxvii) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 81 , a CDR2 comprising a sequence set forth in SEQ ID NO: 82, and a CDR3 comprising a sequence set forth in SEQ ID NO: 83; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 84, a CDR2 comprising a sequence set forth in SEQ ID NO: 85 and a CDR3 comprising a sequence set forth in SEQ ID NO: 86; or(xxviii) the VH comprises a sequence set forth in SEQ ID NO: 15 and the VL comprises a sequence set forth in SEQ ID NO: 25; or(xxix) the VH comprises three CDRs of a VH comprising a sequence set forth in SEQ ID NO: 15 and the VL comprises three CDRs of a VL comprising a sequence set forth in SEQ ID NO: 25; or(xxx) the VH comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 93, a CDR2 comprising a sequence set forth in SEQ ID NO: 94, and a CDR3 comprising a sequence set forth in SEQ ID NO: 95; and the VL comprises a CDR1 comprising a sequence set forth in SEQ ID NO: 96, a CDR2 comprising a sequence set forth in SEQ ID NO: 97 and a CDR3 comprising a sequence set forth in SEQ ID NO: 98.

Images