Recombinant DLL3 binding proteins and their use

Abstract

The present invention relates to recombinant binding proteins comprising a designed ankyrin repeat domain with binding specificity for DLL3. In addition, the invention relates to nucleic acids encoding such binding proteins, pharmaceutical compositions comprising such binding proteins or nucleic acids, and the use of such binding proteins, nucleic acids or pharmaceutical compositions in methods of treating diseases, such as cancer, in a mammal, including a human.

Description

[0001] RECOMBINANT DLL3 BINDING PROTEINS AND THEIR USE

[0002] CROSS-REFERENCE TO RELATED APPLICATION

[0003] The present application claims the benefit of priority to US 63 / 627,705, filed on January 31, 2024; US 63 / 550,951 , filed on February 7, 2024; EP 24305751 , filed on May 14, 2024; EP 24306567, filed on September 25, 2024; and EP 24306765, filed on October 21 , 2024. The disclosures of these patent applications are incorporated herein for all purposes by reference in their entirety.

[0004] FIELD OF THE DISCLOSURE

[0005] The present invention relates to recombinant binding proteins comprising a designed ankyrin repeat domain with binding specificity for DLL3. In addition, the invention relates to nucleic acids encoding such binding proteins, pharmaceutical compositions comprising such binding proteins or nucleic acids, and the use of such binding proteins, nucleic acids or pharmaceutical compositions in methods of treating or diagnosing diseases, such as cancer, in a mammal, including a human.

[0006] BACKGROUND

[0007] The Notch pathway is a highly conserved cell signaling pathway that facilitates cell to cell signaling and it is implicated in malignant transformation, cell proliferation, cycle arrest, apoptosis, epithelial to mesenchymal transition, and suppression of neuroendocrine differentiation (Leonetti et al, Cell Oncol (Dordr); 42:261-273 (2019)). Notch receptors are type-1 transmembrane proteins with an extracellular domain consisting of Epidermal Growth Factor-like repeats which play a role in ligand interaction, and a negative regulatory region, including three LIN12 / Notch repeats (LNR) and the juxtamembrane heterodimerization domain. The Notch signaling pathway is initiated by the binding of one of five ligands (Jagged 1 , Jagged 2, Delta-like ligand 1 (DLL1), Delta-like ligand 3 (DLL3) and Delta-like ligand 4 (DLL4)) to one of the four Notch receptors (Notch 1- 4) (Leonetti et al, Cell Oncol (Dordr); 42:261-273 (2019); Crabtree JS et al, Front Oncol; 6:94.(2016). The DLL (Delta-like ligand) family of ligand proteins, which are transmembrane proteins consisting of a Delta / Serrate / LAG-2 (DSL) domain and EGF repeats, interact with EGF repeats of the Notch receptors on cell membranes, triggering Notch signaling (von Arx C et al, J Clin Med; 8 (2019). In canonical Notch signaling, ligand binding results in the intracellular cleavage of the receptor by metalloproteases, and the Notch intracellular domain then translocates into the nucleus and modulates transcription of Notch-responsive genes. Notch signaling can be oncogenic or tumor suppressive depending on the cellular context. DLL3 is a non- canonical inhibitory ligand of the Notch receptor involved in tumorigenesis (Leonetti et al, Cell Oncol (Dordr); 42:261-273 (2019). In normal cells, DLL3 regulates Notch signaling intracellularly, while in cancer cells, DLL3 is expressed on the cell surface. It regulates Notch signaling by reducing the localization of Notch receptors at the cell surface and by redirecting them to the endosomes for degradation (Chapman G et al, Hum Mol Genet, ’.20:905-916 (2011). Although DLL3 has low to undetectable expression levels in normal tissues, it is highly expressed on the cell surface of tumor cells, and has become a target for the treatment of cancer, such as melanoma (Ding X et al, Life Scf, 2019;226:149-55), bladder cancer (Koshkin VS et al. Clin Cancer Res; 2019; 25:210-21), endometrial cancer (Wang J et al, Medicine; 2018; 97:e13442), ovarian cancer (Jia D et al, Oncol Lett, 2019;17:4914-20), pancreatic cancer (Mullendore ME et al, Clin Cancer Res 2009; 15:2291-301), lung cancer (Liu ZY et al, Medicine; 2016;95:e3715) and more particularly neuroendocrine tumors (Xiu MX et al, Onco Targets Ther, 13:3881-3901 (2020)).

[0008] Different types of DLL3 specific therapeutics have been developed and explored in clinical trials for cancer treatment, including anti-DLL3 bispecific T-cell engagers, CAR T cells and antibody-drug conjugates (Xiu MX et al, Onco Targets Ther, 13:3881-3901(2020)). However, many of the clinical programs testing DLL3 binding compounds were discontinued, mainly due to adverse effects such as increased gastrointestinal and cardiovascular toxicity, or due to lack of efficacy (Blackhall F et al, Journal of Thoracic Oncology, 16(9): 1547- 1558 (2021); Yao J et al, The Oncologist, 27, 940-951; (2022)).

[0009] Moreover, DLL3 has been considered an important marker with diagnostic potential for several types of malignancies since it is a molecular target highly expressed in several tumors (Liverani et al; Endocr Pathol. 2021 Jun;32(2):309-317. doi: 10.1007 / s12022-020-09657-8; Wang et al; Medicine (Baltimore). 2018 Dec; 97(51): e13442)

[0010] Taken together, there remains a need for new DLL3-specific binding proteins and for new therapeutic approaches and / or diagnostic agents benefiting from such DLL3-specific binding proteins.

[0011] SUMMARY

[0012] The present invention provides recombinant binding proteins comprising a designed ankyrin repeat domain with binding specificity for DLL3. Further provided are such binding proteins linked to one or more binding agents, preferably ankyrin repeat domains, with binding specificity fora protein expressed on the surface of an immune cell, such as a T-cell, and / or for human serum albumin, and / or for a further Tumor Associated Antigen (TAA). Moreover, the present invention provides engineered DARPins with binding specificity for DLL3 which have a reduced number of basic amino acids (positive charges) and / or a reduced isoelectric point (pl) compared to conventional DARPins. Such engineered DARPins have been surprisingly found to reduce renal accumulation of a linked drug moiety (such as, e.g., a radionuclide) following in vivo administration of drug moiety-linked DARPins. In addition, the invention provides nucleic acids encoding such binding proteins and pharmaceutical compositions comprising such binding proteins or nucleic acids. The invention also provides the use of such binding proteins, nucleic acids or pharmaceutical compositions in methods of treating diseases, such as cancer, in a mammal, including a human.

[0013] Applicant identified, designed and generated DLL3-specific binding domains suitable to be used as building blocks in diagnostic or therapeutic agents, such as, e.g., multi-specific binding proteins, immune cell-engaging drugs, radiolabeled binding proteins or cytotoxic drug conjugated binding proteins. As the result of a complex screening and selection process and / or rational design and / or affinity maturation, DLL3-specific ankyrin repeat proteins were generated, which have beneficial properties. These recombinant binding proteins comprise a designed ankyrin repeat domain with binding specificity for DLL3. Examples of such ankyrin repeat domains or proteins with binding specificity for DLL3 are provided by SEQ ID NOs: 1-20, 127-169 and 249-256. These recombinant binding proteins are suitable to be linked to one or more TAA-specific binding agent(s) and / or a CD3 specific binding agent in order to form functional T cell engager (TCE) molecules, including multi-specific molecules. Such binding proteins in TCE format are capable of engaging the immune system, and more specifically T cells, in a localized and targeted fashion dependent on the presence of DLL3 and / or another targeted TAA on disease-associated cells, such as tumor cells. Similarly, the DLL3-specific ankyrin repeat proteins of the invention can also be linked to other immune cell-associated antigen (ICA)-specific binding agents to form other types of functional immune cell engager (ICE) molecules. Moreover, DLL3-specific binding proteins of the invention may be linked to a drug moiety, including a therapeutic moiety and / or a diagnostic moiety, to form a DARPin-drug moiety conjugate. Thus, DLL3-specific binding proteins of the invention may be linked, e.g., to therapeutic payloads, for example a radionuclide or a cytotoxic agent, in order to form DLL3- specific DARPin-drug conjugates.

[0014] Based on the disclosure provided herein, those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following embodiments (E).

[0015] Specifically, the present disclosure provides the following aspects, advantageous features and specific embodiments, respectively alone or in combination:

[0016] E1 . A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for human DLL3.

[0017] E2. The recombinant binding protein of E1 , wherein said ankyrin repeat domain comprises an ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 21 to 51 are substituted by other amino acids.

[0018] E3. The recombinant binding protein of E1 or E2, wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module.

[0019] E4. The recombinant binding protein of E3, wherein said first ankyrin repeat module and said second ankyrin repeat module each independently comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 21 to 51 are substituted by other amino acids. E5. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 21 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 22 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 22 are substituted by other amino acids.

[0020] E6. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 27 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 27 are substituted by other amino acids.

[0021] E7. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 28 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 29 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 29 are substituted by other amino acids.

[0022] E8. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 31 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 31 are substituted by other amino acids.

[0023] E9. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 33 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 33 are substituted by other amino acids.

[0024] E10. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 35 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 35 are substituted by other amino acids.

[0025] E11. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 37 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 37 are substituted by other amino acids.

[0026] E12. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 39 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 39 are substituted by other amino acids

[0027] E13. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 41 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 41 are substituted by other amino acids.

[0028] E14. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 43 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 43 are substituted by other amino acids.

[0029] E15. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 45 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 45 are substituted by other amino acids. E16. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 47 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 47 are substituted by other amino acids.

[0030] E17. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 49 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 49 are substituted by other amino acids.

[0031] E18. The recombinant binding protein of any one of E3 to E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 51 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 51 are substituted by other amino acids.

[0032] E19. The recombinant binding protein of any of E4 to E18, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0033] E20. The recombinant binding protein of E1 or E2, wherein said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module.

[0034] E21. The recombinant binding protein of E20, wherein said first ankyrin repeat module, said second ankyrin repeat module and said third ankyrin repeat module each independently comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids.

[0035] E22. The recombinant binding protein of any one of E20 to E21, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:23 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 23 are substituted by other amino acids, wherein said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and wherein said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 25 are substituted by other amino acids.

[0036] E23. The recombinant binding protein of any one of E21 to E22 said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module and said second ankyrin repeat module is located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain.

[0037] E24a. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20.

[0038] E24b. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 127 to 146.

[0039] E24c. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 147 to 169.

[0040] E24d. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 249 to 256.

[0041] E24e. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20 and 147 to 169.

[0042] E24f. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20 and 127 to 169.

[0043] E24g. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169, and 249 to 256.

[0044] E24h. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 127 to 169, and 249 to 256.

[0045] E25. The recombinant binding protein of any one of E24a to E24h, wherein A at the second last position of said SEQ ID NOs is optionally substituted by L, and / or A at the last position of said SEQ ID NOs is optionally substituted by N.

[0046] E26. The recombinant binding protein of any one of E24a to E25, wherein said binding domain with binding specificity for DLL3 binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10- 7M.

[0047] E27. The recombinant binding protein of any of E1 to E26, wherein said binding protein further comprises a binding agent with binding specificity for a tumor-associated antigen.

[0048] E28. The recombinant binding protein of E27, wherein said binding agent is an ankyrin repeat domain with binding specificity for a tumor-associated antigen.

[0049] E29. The recombinant binding protein of any one of E1 to E28, wherein said binding protein further comprises a binding agent with binding specificity for a protein expressed on the surface of an immune cell, optionally a T cell.

[0050] E30. The recombinant binding protein of E29, wherein said binding agent with binding specificity for a protein expressed on the surface of an immune cell has binding specificity for CD3.

[0051] E31. The recombinant binding protein of E30, wherein said binding agent with binding specificity for CD3 is a designed ankyrin repeat protein.

[0052] E32. The recombinant binding protein of any one of E30 to E31 , wherein said binding agent with binding specificity for CD3 comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 173 to 176.

[0053] E33. The recombinant binding protein of any one of E27 to E32, wherein said binding agent with binding specificity for a tumor-associated antigen and / or said binding agent with binding specificity for a protein expressed on the surface of an immune cell is covalently linked to said ankyrin repeat domain with binding specificity for DLL3 with a peptide linker.

[0054] E34. The recombinant binding protein of E33, wherein said peptide linker is a proline-threonine rich peptide linker or glycine-serine rich peptide linker.

[0055] E35. The recombinant binding protein of E33 to E34, wherein the amino acid sequence of said peptide linker has a length from 1 to 50 amino acids, suitably from 6 to 38 amino acids.

[0056] E36. The recombinant binding protein of any of E1 to E35, wherein said binding protein further comprises a half-life extending moiety.

[0057] E37. The recombinant binding protein of E36, wherein said half-life extending moiety comprises a binding agent with binding specificity for human serum albumin.

[0058] E38a. The recombinant binding protein of E37, wherein said binding agent with binding specificity for human serum albumin is an ankyrin repeat domain.

[0059] E38b. The recombinant binding protein of E38a, wherein said ankyrin repeat domain with binding specificity for human serum albumin comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 177 to 179, suitably SEQ ID NO: 178.

[0060] E39. The recombinant binding protein of any one of E36 to E38b, wherein said half-life extending moiety is located N-terminally of said ankyrin repeat domain with binding specificity for DLL3 within said binding protein.

[0061] E39a. The recombinant binding protein of any one of E36 to E39, wherein said binding protein comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 257 to 260, suitably SEQ ID NO: 257.

[0062] E39b. The recombinant binding protein of any one of E36 to E39, wherein said binding protein comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 261 to 264, suitably SEQ ID NO: 261.

[0063] E39c. The recombinant binding protein of any one of E36 to E39, wherein said binding protein comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 257 to 264, suitably SEQ ID NO: 257 or SEQ ID NO: 261.

[0064] E40a. The recombinant binding protein of any one of E1 to E39c, wherein said ankyrin repeat domain with binding specificity for DLL3 is a charge-modified ankyrin repeat domain, suitably charge-modified according to the methods described in U.S. Patent Application No. 18 / 362,079 and / or according to Table 3c.

[0065] E40b. The recombinant binding protein of any one of E1 to E40a, wherein said ankyrin repeat domain with binding specificity for DLL3 is a surface-engineered ankyrin repeat domain.

[0066] E40c. The recombinant binding protein of any one of E1 to E40b, wherein said ankyrin repeat domain with binding specificity for DLL3 was engineered, wherein said engineering was done on an ankyrin repeat domain with binding specificity for DLL3 selected from a DARPin library as described in Example 1 , and wherein said engineering resulted in (1) a reduction of the isoelectric point (pl) of said ankyrin repeat domain, (2) a reduction of the number of basic amino acid residues among all amino acid residues comprised in said ankyrin repeat domain, (3) a reduction of the number of Arg and Lys among all amino acid residues comprised in said ankyrin repeat domain, (4) a reduction of the number of basic amino acid residues among the framework residues comprised in said ankyrin repeat domain, (5) a reduction of the number of Arg and Lys among the framework residues comprised in said ankyrin repeat domain, (6) a reduction of the KR / DE ratio among all amino acid residues comprised in said ankyrin repeat domain, (7) a reduction of the KR / DE ratio among the framework residues comprised in said ankyrin repeat domain, and / or (8) a reduction of the KR / DE ratio among all amino acid residues comprised in the N-terminal capping module of said ankyrin repeat domain.

[0067] E40d. The recombinant binding protein of any one of E40a to E40b, wherein said ankyrin repeat domain with binding specificity for DLL3 has (1 ) a lower isoelectric point (pl), (2) a lower number of basic amino acid residues among all amino acid residues comprised in said ankyrin repeat domain, (3) a lower number of Arg and Lys among all amino acid residues comprised in said ankyrin repeat domain, (4) a lower number of basic amino acid residues among the framework residues comprised in said ankyrin repeat domain, (5) a lower number of Arg and Lys among the framework residues comprised in said ankyrin repeat domain, (6) a lower KR / DE ratio among all amino acid residues comprised in said ankyrin repeat domain, (7) a lower KR / DE ratio among the framework residues comprised in said ankyrin repeat domain, and / or (8) a lower KR / DE ratio among all amino acid residues comprised in the N-terminal capping module of said ankyrin repeat domain, in each case as compared to the ankyrin repeat domain prior to the charge-modification or surface-engineering.

[0068] E40e. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 129 to 132, 134 to 138, 142 to 144, 146, wherein said ankyrin repeat domain comprises an N-terminal capping module, at least one internal repeat module and a C-terminal capping module, and wherein said repeat domain has at least one characteristic selected from the following list of characteristics:

[0069] (a) an isoelectric point (pl) equal to or lower than pH 4.07;

[0070] (b) among all amino acid residues comprised in said repeat domain, a percentage of basic amino acid residues equal to or lower than 7.0%; and

[0071] (c) among the framework residues comprised in said repeat domain, a percentage of basic amino acid residues equal to or lower than 6.1%.

[0072] E41. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 127 to 146, wherein said ankyrin repeat domain comprises an N-terminal capping module, at least one internal repeat module and a C- terminal capping module, wherein said repeat domain is linked to a drug moiety, and wherein said repeat domain has at least one characteristic selected from the following list of characteristics:

[0073] (a) an isoelectric point (pl) equal to or lower than pH 4.6;

[0074] (b) among all amino acid residues comprised in said repeat domain, a percentage of basic amino acid residues equal to or lower than 12.0%;

[0075] (c) among all amino acid residues comprised in said repeat domain, a percentage of Arg and Lys residues equal to or lower than 8.0%;

[0076] (d) among the framework residues comprised in said repeat domain, a percentage of basic amino acid residues equal to or lower than 9.6%; and

[0077] (e) among the framework residues comprised in said repeat domain, a percentage of Arg and Lys residues equal to or lower than 6.7%.

[0078] E42. The recombinant binding protein of any one of E24b and E40a to E41, wherein said ankyrin repeat domain has a KR / DE ratio equal to or lower than 0.44, and / or wherein said ankyrin repeat domain has a KR / DE ratio among the framework residues equal to or lower than 0.36, and / or wherein said ankyrin repeat domain has a KR / DE ratio among all residues of the N-terminal capping module equal to or lower than 0.66.

[0079] E43. The recombinant binding protein of any one of E1 to E42, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10-7M, of or below 10-8M, of or below 10- 9M, or of or below 10-10M. E44. A nucleic acid encoding the recombinant binding protein of any one of E1 to E43.

[0080] E45. A cloning or expression vector comprising the nucleic acid of E44, wherein said vector is suitable for the recombinant production of a binding protein as defined in any one of E1 to E43.

[0081] E46. The vector of E45, wherein said vector is a DNA vector, an RNA vector, a plasmid, a cosmid, or a viral vector.

[0082] E47. A host cell comprising the nucleic acid of E44 or the vector of any one of E45 to E46.

[0083] E48. A pharmaceutical composition comprising the recombinant binding protein of any one of E1 to E43, the nucleic acid of E44, the vector of any one of E45 to E46 or the host cell of E47, and optionally a pharmaceutically acceptable carrier and / or diluent.

[0084] E49. The recombinant binding protein of any one of E1 to E43, the nucleic acid of E44, the vector of any one of E45 to E46, the host cell of E47 or the pharmaceutical composition of E48 for use in a method of treating a medical condition.

[0085] E50. The embodiment E49, wherein the medical condition is a cancer.

[0086] E51. A method of treating a medical condition, the method comprising the step of administering to a subject in need thereof a therapeutically effective amount of the recombinant binding protein of any one of E1 to E43, the nucleic acid of E44, the vector of any one of E45 to E46, the host cell of E47, or the pharmaceutical composition of E48.

[0087] E52. The method of E51, wherein said medical condition is a cancer.

[0088] E53. The recombinant binding protein of any one of E1 to E43, the nucleic acid of E44, the vector of any one of E45 to E46, the host cell of E47 or the pharmaceutical composition of E48 for use in a method of treating a mammal in need thereof, preferably a human, wherein said mammal has a medical condition.

[0089] E54. Use of the recombinant binding protein of any one of E1 to E43 or the nucleic acid of E44 or the vector of any one of E45 to E46 or the host cell of E47 or the pharmaceutical composition of E48 for the manufacture of a medicament for the treatment of a medical condition.

[0090] E55. The embodiment E53 or E54, wherein said medical condition is a cancer.

[0091] E56. A method of diagnosing a medical condition in a mammal, preferably a human, the method comprising the steps of:

[0092] (i) contacting a cell or tissue sample obtained from said mammal with the DLL3-specific recombinant binding protein of any one of E1 to E43; and

[0093] (ii) detecting specific binding of said binding protein to said cell or tissue sample. E57. A method of producing a recombinant binding protein, the method comprising culturing the host cell of E47 and collecting the recombinant binding protein from the cell and / or the culture medium.

[0094] BRIEF DESCRIPTION OF THE FIGURES

[0095] FIGURE 1 : SDS-PAGE of single-domain DARPin molecules purified using an AKTAxpress™ system. The proteins were prepared in NuPAGE® LDS sample buffer (Invitrogen) and heated for 10 min at 95°C. 5 pg of the samples were loaded on a NuPAGE 4-12% Bis-Tris gel (Invitrogen). PageRuler™ Prestained Protein Ladder, 10 to 180 kDa (Thermo Fisher Scientific) was used as MW marker. The separation was performed in MES buffer and the gels were stained afterwards with Coomassie Blue overnight.

[0096] FIGURE 2: Binding affinities of selected DARPin molecules with binding specificity for DLL2 measured by single trace and multi trace Surface Plasmon Resonance. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. (RU, Resonance Units; s, time in seconds).

[0097] FIGURE 3: Multi trace SPR sensograms for two selected DARPin molecules. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. (RU, Resonance Units; s, time in seconds).

[0098] FIGURE 4 (A-B) : Fig. 4A and Fig. 4B show cell binding curves of titrated, selected DLL3- binding DARPin proteins to human DLL3 expressed on HEK293T-huDLL3 cells. Two different clones were used, with high (Fig. 4A) and low (Fig. 4B) level of DLL3 expression. Median fluorescence intensities obtained are shown.

[0099] FIGURE 5 (A-B) : Fig. 5A. Binding affinities of selected DARPin molecules with binding specificity for DLL3 measured by multi trace Surface Plasmon Resonance. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. Fig. 5B. Multi trace SPR sensograms for four selected DARPin molecules. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. (RU, Resonance Units; s, time in seconds).

[0100] FIGURE 6: Cell binding EC50s of selected His-tagged ankyrin repeat proteins were determined by Flow Cytometry. Serial dilutions of DARPin proteins were incubated with HEK 239T-huDLL3 and binding was detected with rabbit anti-DARPin antibody clone 1.4.8 followed by a fluorescently labelled detection antibody (goat-anti rabbit-AF647). MFI, mean fluorescence intensity.

[0101] FIGURE 7 (A-B): Fig. 7A. Binding affinities of selected DARPin molecules with binding specificity for DLL3 measured by single traceSurface Plasmon Resonance. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. Fig. 7B. Single trace SPR sensograms for two selected DARPin molecules. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. (RU, Resonance Units; s, time in seconds).

[0102] FIGURE 8 (A-B): Fig. 8A. Binding affinities of selected DARPin molecules with binding specificity for DLL3 measured by multi trace Surface Plasmon Resonance. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. Fig. 8B. Multi trace SPR sensograms for two selected, His-tag free and Cys-terminal containing DARPin molecules respectively. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. (RU, Resonance Units; s, time in seconds).

[0103] FIGURE 9(A-B): Cell binding curves of selected DLL3- binding DARPin proteins to human DLL3 expressed on NCI-H82 and HEK293T-huDLL3 cells respectively. Fig. 9A Binding to NCI-H82 cells ; Fig. 9B. Binding to HEK293T-huDLL3 cells.

[0104] FIGURE 10 (A-B): Fig. 10A. Binding affinities of selected DARPin molecules with binding specificity for DLL3 measured by single and multi trace Surface Plasmon Resonance. Dissociation constants (KD) were calculated from the estimated on- and off-rates using standard procedures. Fig. 10B. SPR sensograms for three selected, DARPin molecules respectively. Dissociation constants (KD) were calculated from the estimated on- and off- rates using standard procedures. (RU, Resonance Units; s, time in seconds).

[0105] FIGURE 11 (A-C): Cell binding curves of selected DLL3- binding DARPin proteins, at a single concentration of 100 nM, to human DLL3 expressed on NCI-H82, HEK293T-huDLL3 and HEK293-T-WT cells respectively. Fig. 11A Binding to NCI-H82 cells; Fig.11B. Binding to HEK293T-huDLL3 cells; Fig. 11C. Binding to HEK293T- WT cells.

[0106] FIGURE 12: In vivo biodistribution of radio-labeled DARPin molecules, injected i.v. at 1mg / kg into athymic nude mice (1 MBq / mouse). Kidneys were collected 4 h post injection and radioactivity of each sample was measured using a y-counter instrument (Wizard22470, Perkin Elmer).

[0107] FIGURE 13: In vivo biodistribution of radio-labeled DARPin molecules, injected i.v. at 0.01 mg / kg into CD1 mice (10 pCi). Kidneys were collected 4 h post injection and radioactivity of each sample was measured using a y-counter instrument.

[0108] FIGURE 14 (A-B): Cell binding EC50 values of selected DLL3-specific DARPins were determined by Flow Cytometry. Serial dilutions of DARPin proteins were incubated with MC38-hDLL3 cells and binding was detected with rabbit anti-DARPin antibody clone 1.4.8 followed by a fluorescently labelled detection antibody (goat-anti rabbit-AF647). Rova (MPEXT268) was detected by anti-human AF647 antibody. Fig. 14A: DLL3- specific DARPins; Fig. 14B: Rova and non-binding DARPin controls. MFI, median fluorescence intensity.

[0109] FIGURE 15 (A-B): Analysis of ankyrin repeat protein binding to different regions of DLL3 by ELISA. Fig. 15A: The binding of DARPins to human DLL3-ECD was analyzed by ELISA in the absence (none) or presence of other DARPins as competitors, as indicated. Fig. 15B: Binding ELISA assay in which various concentrations of different constructs of human DLL3, including the entire ECD (ECD), only the NTD (NTD) or the NTD-DSL- EGF1 region (NTD-EGF1), were applied to immobilized DARPins, as indicated. The analysis was performed using GraphPad Prism 10.2.3 software. The X-axis was transformed to logarithmic values and a three parameters non-linear fit was performed. FIGURE 16 (A-F): Internalization of DLL3-specific DARPin hD01_93H09 in different cell lines, in comparison to a positive antibody control (Rova). Molecules were labelled with AF488 and the internalized signal was assessed by an anti-AF488-quencher that quenches the external fluorescence. The signal was normalized to a non-binder control. Fig. 16A: DARPin on SHP-77 cells; Fig. 16B: DARPin on NCI-H82 cells; Fig. 16C: DARPin on 293T-hDLL3 cells; Fig. 16D: Rova control on SHP-77 cells; Fig. 16E: Rova control on NCI-H82 cells; Fig. 16F: Rova control on MC38-hDLL3 cells.

[0110] FIGURES 17A to 17D: Binding of different concentrations of selected single domain (1D) and two domain (2D) DARPins to HEK293T-hDLL3 cells expressing human DLL3, in absence and presence of 10 pM human serum albumin. Figure 17A: 2D DARPins, without HSA; Figure 17B: 2D DARPins, with HSA; Figure 17C: 1D DARPins, without HSA; Figure 17D: 1D DARPins, with HSA.

[0111] FIGURES 18A and 18B: Binding of different concentrations of selected two domain (2D) DARPins to NCI-H82 cells expressing human DLL3, in absence and presence of 10 pM human serum albumin. A non-binding DARPin was used as a negative control. Figure 18A: MAM279, MAM283, and control DARPin, with and without HSA; Figure 18B: MAM282 and control DARPin, with and without HSA.

[0112] FIGURE 19: Pharmacokinetic analysis of metal-labelled DARPin (MAM279, MAM283, MAM160, MAM282) conjugates in mice. DARPin conjugates were injected i.v. at 1 mg / kg into WT BALBc mice. Serum was collected 2 min, 10 min, 30 min, 1 h, 4 h, 24 h, 48 h, 72 h post-injection. DARPin was detected and measured by ELISA. LLOQ: Lower Limit of Quantification.

[0113] FIGURE 20: Simultaneous binding of a 2D DARPin (MAM279) to DLL3 and serum albumin. Binding of a 2D DARPin (MAM279), conjugated to a chelator, to human DLL3 and human serum albumin (HSA) was determined by SPR multi-trace analysis. SPR sensograms show a first injection of MAM279 (injection 1) to immobilized hDLL3-ECD, followed by -300 sec lag time and a second injection of HSA (injection 2) with a dissociation time of 900 sec. The respective controls, where only the DARPin (thick interrupted line), only HSA (thin continuous line) or only PBST (thin interrupted line) were injected, are overlayed to the trace with all reagents used (thick continuous line). RU, Resonance Units; s, time in seconds.

[0114] FIGURES 21A to 21 F: Internalization of half-life extended DLL3-specific ankyrin repeat protein in cells expressing DLL3 on their surface. Internalization of 2D DARPin MAM279 in different cell lines was investigated and compared to the antibody Rova. Molecules were labelled with AF488 and the internalized signals were assessed using an anti-AF488-quencherthat quenches the external fluorescence. The signals were normalized to non-binding controls. Fig. 21A: MAM279 on SHP-77 cells; Fig. 21 B: MAM279 on NCI-H82 cells; Fig. 21C: MAM279 on MC38-hDLL3 cells; Fig. 21 D: Rova on SHP-77 cells; Fig. 21 E: Rova on NCI-H82 cells; Fig. 21 F: Rova on MC38-hDLL3 cells. FIGURES 22Ato 22D: Tumor inhibition by a radio-labelled DLL3-specific DARPin (MAM279) conjugate. Radio- labelled molecules (MAM279 conjugate or negative DARPin control conjugate) were injected i.v. four times weekly at 10pCi into R2G2 mice xenografted subcutaneously with NCI-H82 cells. The vertical dotted lines indicate the four weekly injections, at days 14, 21, 28 and 35 post-tumor cell xenograft. Animals were under observation daily and 3x per week tumors were measured by caliper. Animals were sacrificed when tumors reached 1500 to 2000 mm3or if termination criteria were met. In Figure 22A, tumor growth curves for all conditions and animals are shown, with the data expressed as average + / - SEM of tumor volume in mm3. In Figures 22B to 22D, tumor growth curves for individual animals are shown, injected with buffer only (Fig. 22B), radio-labelled MAM279 conjugate (Fig. 22C), or radio-labelled control DARPin conjugate (Fig. 22D). The data were expressed as tumor volume in mm3. SEM: standard error of the mean.

[0115] DETAILED DESCRIPTION OF THE INVENTION

[0116] As disclosed and exemplified herein, the disclosure provides ankyrin repeat proteins that specifically target DLL3. Designed ankyrin repeat protein libraries (W02002 / 020565; Binz et al., Nat. Biotechnol. 22, 575-582, 2004; Stumpp et al., Drug Discov. Today 13, 695-701, 2008) can be used for the selection of target-specific designed ankyrin repeat domains that bind to their target with high affinity. Such target-specific designed ankyrin repeat domains in turn can be used as valuable components of recombinant binding proteins for the treatment of diseases. Designed ankyrin repeat proteins are a class of binding molecules which have the potential to overcome limitations of monoclonal antibodies, hence allowing novel therapeutic approaches. Such ankyrin repeat proteins may comprise a single designed ankyrin repeat domain or may comprise a combination of two or more designed ankyrin repeat domains with the same or different target specificities (Stumpp et al., Drug Discov. Today 13, 695-701, 2008; U.S. Patent No. 9,458,211). Ankyrin repeat proteins comprising only a single designed ankyrin repeat domain are small proteins (14 kDa) which can be selected to bind a given target protein with high affinity and specificity. These characteristics, and the possibility of combining two, three, four or more designed ankyrin repeat domains in one protein, resulting in binding proteins with two, three, four or more different specificities, make designed ankyrin repeat proteins ideal agonistic, antagonistic and / or inhibitory drug candidates and allow for novel drug designs, including, e.g., novel designs of T cell engager drug molecules. Furthermore, such ankyrin repeat proteins can be engineered to carry various effector functions, e.g. cytotoxic agents or half-life extending agents, enabling completely new drug formats. For example, the present invention provides engineered DARPins with binding specificity for DLL3 which have a reduced number of basic amino acids (positive charges) and / or a reduced isoelectric point (pl) compared to conventional DARPins. Such engineered DARPins have been surprisingly found to reduce renal accumulation of a linked drug moiety (such as, e.g., a radionuclide) following in vivo administration of drug moiety-linked DARPins. Ankyrin repeat proteins showing reduced renal accumulation are disclosed in patent applications EP22188160, EP23151023, EP23168056, PCT / EP2023 / 071188 and US18 / 362,079 (incorporated herein by reference in their entirety). Pharmacological approaches to lower the uptake of peptide- and protein-based radiopharmaceuticals in the kidneys may help to circumvent the efforts required in modulating the structural properties of radiolabeled compounds. However, administration of such mitigation compounds acting on various parts of the reabsorption system in the kidney has shown not to be effective for all radiopharmaceuticals. A study on the prevention of renal uptake of99mTc-labeled designed ankyrin repeat proteins (DARPins) showed that common clinical strategies were not effective for reducing kidney uptake of these radiolabeled DARPins in mice. More specifically, co-injection of lysine or Gelofusine did not reduce renal uptake. Pre-administration of high doses of maleate or fructose, which inhibit ATP-mediated endocytosis, resulted in a reduction of kidney uptake of these protein scaffolds, but at a required dose not suitable for a clinical application. No other compounds were effective. As such, according to the authors, the study suggests that the renal uptake of99mTc-labeled DARPins proceeds through a mechanism independent of DARPin structure and binding site composition. (Altai, M. et al., EJNMMI research 10.1 (2020): 1-8). Thus, despite attempts to reduce renal uptake and mitigate nephrotoxicity with pharmacological and / or physicochemical approaches, this could not consistently be achieved and nephrotoxicity remains a hurdle for the application of radiopharmaceuticals in radiopharmaceutical therapy or diagnostics. Similar considerations apply to pharmaceuticals in which a small format target-specific binder is linked to a cytotoxic agent instead of a radionuclide, such as, for example, in protein conjugates using antibody mimetics or small binding moieties (Richards, D. A. Drug Discovery Today: Technologies 30 (2018): 35-46).

[0117] Taken together, designed ankyrin repeat proteins are an example of the next generation of protein therapeutics with the potential to surpass existing antibody or CAR-T drugs. In the instant application, novel binding proteins comprising an ankyrin repeat domain with binding specificity for DLL3 are disclosed. These binding proteins have beneficial and unexpected properties.

[0118] In one aspect, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain, wherein said ankyrin repeat domain has binding specificity for DLL3, and wherein said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 1 to 20, 147 to 169 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in any of SEQ ID NOs: 1 to 20, 147 to 169 are substituted by other amino acids. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NOs: 1 to 20, 147 to 169 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 1 to 20, 147 to 169 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 1 to 20, 147 to 169 and (2) sequences in which up to 3 amino acids in any of SEQ ID NOs:1 to 20, 147 to 169 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs:1 to 20, 147 to 169 and (2) sequences in which up to 2 amino acids in any of SEQ ID NOs: 1 to 20, 147 to 169 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 1 to 20, 147 to 169 and (2) sequences in which up to 1 amino acid in any of SEQ ID NOs: 1 to 20, 147 to 169 is substituted by another amino acid. In one embodiment, all of said 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitutions occur in framework positions of said ankyrin repeat domain(s). In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 20, 147 to 169.

[0119] In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 1 or a sequence in which one or two amino acids in SEQ ID NO: 1 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 2 or a sequence in which one or two amino acids in SEQ ID NO: 2 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:3 or a sequence in which one or two amino acids in SEQ ID NO: 3 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 4 or a sequence in which one or two amino acids in SEQ ID NO: 4 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 5 or a sequence in which one or two amino acids in SEQ ID NO: 5 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 6 or a sequence in which one or two amino acids in SEQ ID NO: 6 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 7 or a sequence in which one or two amino acids in SEQ ID NO: 7 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 8 or a sequence in which one or two amino acids in SEQ ID NO: 8 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 9 or a sequence in which one or two amino acids in SEQ ID NO: 9 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 10 or a sequence in which one or two amino acids in SEQ ID NO: 10 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 11 ora sequence in which one or two amino acids in SEQ ID NO: 11 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 12 or a sequence in which one or two amino acids in SEQ ID NO: 12 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 13 or a sequence in which one or two amino acids in SEQ ID NO: 13 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 14 or a sequence in which one or two amino acids in SEQ ID NO: 14 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 15 or a sequence in which one or two amino acids in SEQ ID NO: 15 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 16 or a sequence in which one or two amino acids in SEQ ID NO: 16 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 17 ora sequence in which one or two amino acids in SEQ ID NO: 17 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 18 or a sequence in which one or two amino acids in SEQ ID NO: 18 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 19 or a sequence in which one or two amino acids in SEQ ID NO: 19 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 20 ora sequence in which one or two amino acids in SEQ ID NO: 20 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 147 or a sequence in which one or two amino acids in SEQ ID NO: 147 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 148 or a sequence in which one or two amino acids in SEQ ID NO: 148 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 149 or a sequence in which one or two amino acids in SEQ ID NO: 149 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 150 or a sequence in which one or two amino acids in SEQ ID NO: 150 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 151 or a sequence in which one or two amino acids in SEQ ID NO: 151 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 152 ora sequence in which one or two amino acids in SEQ ID NO: 152 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 153 or a sequence in which one or two amino acids in SEQ ID NO: 153 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 154 or a sequence in which one or two amino acids in SEQ ID NO: 154 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 155 or a sequence in which one or two amino acids in SEQ ID NO: 155 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 156 or a sequence in which one or two amino acids in SEQ ID NO: 156 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 157 or a sequence in which one or two amino acids in SEQ ID NO: 157 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 158 or a sequence in which one or two amino acids in SEQ ID NO: 158 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 159 or a sequence in which one or two amino acids in SEQ ID NO: 159 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 160 or a sequence in which one or two amino acids in SEQ ID NO: 160 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 161 or a sequence in which one or two amino acids in SEQ ID NO: 161 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 162 or a sequence in which one or two amino acids in SEQ ID NO: 162 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 163 or a sequence in which one or two amino acids in SEQ ID NO: 163 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 164 or a sequence in which one or two amino acids in SEQ ID NO: 164 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 165 or a sequence in which one or two amino acids in SEQ ID NO: 165 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 166 or a sequence in which one or two amino acids in SEQ ID NO: 166 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 167 or a sequence in which one or two amino acids in SEQ ID NO: 167 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 168 or a sequence in which one or two amino acids in SEQ ID NO: 168 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 169 or a sequence in which one or two amino acids in SEQ ID NO: 169 are substituted by other amino acids.

[0120] In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 1. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 2. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:3. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 4. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:5. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:6. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:7. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:8. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:9. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NQ:10. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:11. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:12. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:13. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:14. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:15. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:16. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:17. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:18. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:19. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NQ:20. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:147. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:148. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:149. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NQ:150. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:151. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:152. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:153. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:154. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:155. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:156. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:157. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:158. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:159. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NQ:160. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:161. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:162. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:163. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:164. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:165. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:166. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:167. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:168. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:169.

[0121] In one aspect, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain, wherein said ankyrin repeat domain has binding specificity for DLL3, and wherein said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 249 to 256 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in any of SEQ ID NOs: 249 to 256 are substituted by other amino acids. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 249 to 256 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 249 to 256 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 249 to 256 and (2) sequences in which up to 3 amino acids in any of SEQ ID NOs:249 to 256 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs:249 to 256 and (2) sequences in which up to 2 amino acids in any of SEQ ID NOs: 249 to 256 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 249 to 256 and (2) sequences in which up to 1 amino acid in any of SEQ ID NOs: 249 to 256 is substituted by another amino acid. In one embodiment, all of said 9, 8, 7, 6, 5, 4, 3, 2, or 1 amino acid substitutions occur in framework positions of said ankyrin repeat domain(s). In one embodiment, said ankyrin repeat domain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 249 to 256.

[0122] In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 249 or a sequence in which one or two amino acids in SEQ ID NO: 249 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 250 or a sequence in which one or two amino acids in SEQ ID NO: 250 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 251 or a sequence in which one or two amino acids in SEQ ID NO: 251 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 252 or a sequence in which one or two amino acids in SEQ ID NO: 252 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 253 or a sequence in which one or two amino acids in SEQ ID NO: 253 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 254 or a sequence in which one or two amino acids in SEQ ID NO: 254 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 255 or a sequence in which one or two amino acids in SEQ ID NO: 255 are substituted by other amino acids. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 256 or a sequence in which one or two amino acids in SEQ ID NO: 256 are substituted by other amino acids.

[0123] In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 249. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 250. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 251. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 252. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 253. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 254. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 255. In one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 256.

[0124] In one embodiment, said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module. In a preferred embodiment, said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. In one embodiment, said first and said second ankyrin repeat module each comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids. Thus, in one embodiment, said ankyrin repeat domain comprises a first ankyrin repeat module having an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids and further comprises a second ankyrin repeat module having an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids.

[0125] In one particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 21 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO:21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:22 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO:22 are substituted by other amino acids.

[0126] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 21 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 22 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 22 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:21 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO:22 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 22 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 21 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:22 and (2) sequences in which up to 5 amino acids of SEQ ID NO:22 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 21 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 22 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 22 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO:21 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 22 and (2) sequences in which up to 3 amino acids of SEQ ID NO:22 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 21and (2) sequences in which up to 2 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 22 and (2) sequences in which up to 2 amino acids of SEQ ID NO:22 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:21 and (2) sequences in which 1 amino acid in SEQ ID NO: 21 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 22 and (2) sequences in which 1 amino acid of SEQ ID NO: 22 is substituted by another amino acid. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 21 , and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 22.

[0127] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 21 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 21 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 22 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 22 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 21 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 22, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0128] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:27 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 27 are substituted by other amino acids.

[0129] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 27 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 27 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 27 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 27 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 26 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 27 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 27 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 27 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 27 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 27 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 27 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 27 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 27 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 26 and (2) sequences in which 1 amino acid in SEQ ID NO: 26 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 27 and (2) sequences in which 1 amino acid of SEQ ID NO:27 is substituted by another amino acid. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 26 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 27.

[0130] In one preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO:26 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 26 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 27and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 27 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 26 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:27 , wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0131] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO:28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 29 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 29 are substituted by other amino acids.

[0132] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 9 amino acids in SEQ ID NO:28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 29 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 29 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 29 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 29 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 29 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 29 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 29 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 29 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 29 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 29 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 29 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 29 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 28 and (2) sequences in which 1 amino acid in SEQ ID NO: 28 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 29 and (2) sequences in which 1 amino acid of SEQ ID NO: 29 is substituted by another amino acid. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 28, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 29.

[0133] In one preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO:28 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 28 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 29 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 29 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:28 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 29, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0134] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 31 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 31 are substituted by other amino acids.

[0135] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:30 and (2) sequences in which up to 9 amino acids in SEQ ID NO:30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 31 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 31 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 31 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 31 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 31 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 31 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 31 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 31 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 31 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 31 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 31 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 31 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which 1 amino acid in SEQ ID NO: 30 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 31 and (2) sequences in which 1 amino acid of SEQ ID NO: 31 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 30, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 31.

[0136] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 30 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 30 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 31 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 31 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NQ:30 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 31 , wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0137] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 33 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 33 are substituted by other amino acids. Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:32 and (2) sequences in which up to 9 amino acids in SEQ ID NO:32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 33 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 33 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 33 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 33 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 33 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 33 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 33 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 33 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 33 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 33 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 33 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 33 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which 1 amino acid in SEQ ID NO: 32 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 33 and (2) sequences in which 1 amino acid of SEQ ID NO: 33 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 32, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 33. In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 32 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 32 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 33 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 33 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:32 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 33, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0138] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 35 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 35 are substituted by other amino acids.

[0139] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:34 and (2) sequences in which up to 9 amino acids in SEQ ID NO:34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 35 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 35 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 35 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 35 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 35 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 35 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 35 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 35 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 35 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 35 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 35 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 35 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which 1 amino acid in SEQ ID NO: 34 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 35 and (2) sequences in which 1 amino acid of SEQ ID NO: 35 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 34, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 35.

[0140] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 34 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 34 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 35 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 35 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:34 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 35, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0141] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 37 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 37 are substituted by other amino acids.

[0142] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:36 and (2) sequences in which up to 9 amino acids in SEQ ID NO:36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 37 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 37 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 37 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 37 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 37 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 37 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 37 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 37 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 37 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 37 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 37 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 37 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which 1 amino acid in SEQ ID NO: 36 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 37 and (2) sequences in which 1 amino acid of SEQ ID NO: 37 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 36, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 37.

[0143] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 36 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 37 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 37 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:36 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 37, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0144] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 39 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 39 are substituted by other amino acids.

[0145] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:38 and (2) sequences in which up to 9 amino acids in SEQ ID NO:38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 39 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 39 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 39 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 39 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 39 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 39 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 39 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 39 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 39 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 39 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 39 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 39 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which 1 amino acid in SEQ ID NO: 38 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 39 and (2) sequences in which 1 amino acid of SEQ ID NO: 39 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 38, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 39.

[0146] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 38 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 38 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 39 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 39 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:38 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 39, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0147] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 41 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 41 are substituted by other amino acids.

[0148] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:40 and (2) sequences in which up to 9 amino acids in SEQ ID NO:40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 41 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 41 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 41 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 41 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 41 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 41 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 41 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 41 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 41 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 41 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 41 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 41 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which 1 amino acid in SEQ ID NO: 40 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 41 and (2) sequences in which 1 amino acid of SEQ ID NO: 41 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 40, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 41.

[0149] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 40 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 41 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 41 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NQ:40 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 41 , wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0150] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 43 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 43 are substituted by other amino acids.

[0151] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:42 and (2) sequences in which up to 9 amino acids in SEQ ID NO:42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 43 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 43 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 43 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 43 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 43 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 43 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 43 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 43 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 43 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 43 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 43 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 43 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which 1 amino acid in SEQ ID NO: 42 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 43 and (2) sequences in which 1 amino acid of SEQ ID NO: 43 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 42, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 43.

[0152] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 42 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 42 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 43 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 43 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:42 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 43, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0153] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 45 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 45 are substituted by other amino acids.

[0154] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:44 and (2) sequences in which up to 9 amino acids in SEQ ID NO:44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 45 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 45 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 45 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 45 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 45 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 45 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 45 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 45 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 45 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 45 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 45 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 45 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which 1 amino acid in SEQ ID NO: 44 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 45 and (2) sequences in which 1 amino acid of SEQ ID NO: 45 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 44, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 45.

[0155] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 44 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 44 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 45 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 45 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:44 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 45, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0156] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 47 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 47 are substituted by other amino acids.

[0157] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:46 and (2) sequences in which up to 9 amino acids in SEQ ID NO:46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 47 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 47 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 47 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 47 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 47 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 47 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 47 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 47 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 47 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 47 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 31 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 47 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which 1 amino acid in SEQ ID NO: 46 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 47 and (2) sequences in which 1 amino acid of SEQ ID NO: 47 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 46, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 47.

[0158] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 46 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 46 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 47 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 47 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:46 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 47, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0159] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 49 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO:49 are substituted by other amino acids.

[0160] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:48 and (2) sequences in which up to 9 amino acids in SEQ ID NO:48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 49 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 49 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 49 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 49 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 49 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 49 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 49 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 49 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 49 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 49 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 49 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 49 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which 1 amino acid in SEQ ID NO: 48 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 49 and (2) sequences in which 1 amino acid of SEQ ID NO: 49 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 48, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 49.

[0161] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 48 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 48 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 49 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 49 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:48 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 49, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0162] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 51 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 51 are substituted by other amino acids.

[0163] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO:50 and (2) sequences in which up to 9 amino acids in SEQ ID NQ:50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 51 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 51 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 51 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 51 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 51 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 51 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 51 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 51 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 51 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 51 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 51 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 51 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which 1 amino acid in SEQ ID NO: 50 is substituted by another amino acid, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 51 and (2) sequences in which 1 amino acid of SEQ ID NO: 51 is substituted by another amino acid In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 50, and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 51.

[0164] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 50 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 50 are substituted by other amino acids, and said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 51 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 51 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO:50 and said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 51 , wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0165] In a further embodiment said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module. In a preferred embodiment, said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module and said second ankyrin repeat module is located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain.

[0166] In one embodiment, said first, said second and said third ankyrin repeat module each independently comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids. Thus, in one embodiment, said ankyrin repeat domain comprises a first ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids, a second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids and further comprises a third ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NOs: 21 to 51 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 21 to 51 are substituted by other amino acids.

[0167] In another particular embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 9, or up to 8, or up to 7, or up to 6, or up to 5, or up to 4, or up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 25 are substituted by other amino acids.

[0168] Thus, in one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1 ) SEQ ID NO: 24 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 25 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which up to 6 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 6 amino acids of SEQ ID NO: 25 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which up to 5 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 5 amino acids of SEQ ID NO: 25 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which up to 4 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 4 amino acids of SEQ ID NO: 25 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 3 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 3 amino acids of SEQ ID NO: 25 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which up to 2 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 2 amino acids of SEQ ID NO: 25 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which 1 amino acid in SEQ ID NO: 23 is substituted by another amino acid, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which 1 amino acid of SEQ ID NO: 24 is substituted by another amino acid, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 1 amino acid of SEQ ID NO: 25 are substituted by other amino acids. In one embodiment, in such an ankyrin repeat domain said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 23, said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 24, and said third repeat module comprises the amino acid sequence of SEQ ID NO: 25.

[0169] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 23 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 23 are substituted by other amino acids, said second ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 24 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 24 are substituted by other amino acids, and said third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 25 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 25 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module and wherein said second ankyrin repeat module is N-terminally located of said third ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 23, said second ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 24, and said third ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 25, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module and said second ankyrin repeat module is N- terminally located of said third ankyrin repeat module within said ankyrin repeat domain.

[0170] In one preferred embodiment, all of said amino acid substitutions of said ankyrin repeat module(s) as described and referred to herein occur in framework positions of said ankyrin repeat module(s), wherein typically the overall structure of the module(s) is not affected by the substitutions. Such an embodiment of substitution in framework positions shall apply to all embodiments irrespective of whether such substitution is explicitly described. In one preferred embodiment, all of said amino acid substitutions of said ankyrin repeat module(s) as described and referred to herein occur in framework positions and in positions other than positions 3, 4, 6, 14 and 15, preferably other than positions 2, 3, 4, 5, 6, 14 and 15, of said ankyrin repeat module(s) of SEQ ID NOs: 21 to 51 , wherein typically the overall structure of the module(s) is not affected by the substitutions.

[0171] In another aspect, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain, wherein said ankyrin repeat domain has binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169. in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 147 to 169. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with any one of SEQ ID NOs: 147 to 169. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with any one of SEQ ID NOs: 147 to 169; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with any one of SEQ ID NOs: 147 to 169. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with any one of SEQ ID NOs: 147 to 169; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of any one of SEQ ID NOs: 147 to 169.

[0172] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 147. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 147. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 147. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 147; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 147. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 147; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 147. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 147.

[0173] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 148. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0174] 148. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 148. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 148; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 148. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 148; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 148. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0175] 148.

[0176] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 149. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0177] 149. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 149. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 149; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 149. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 149; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 149. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0178] 149.

[0179] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 150. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0180] 150. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 150. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 150; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 150. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 150; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 150. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0181] 150.

[0182] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 151. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0183] 151. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 151. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 151 ; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 151. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 151; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 151. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0184] 151.

[0185] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 152. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0186] 152. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 152. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 152; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 152. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 152; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 152. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0187] 152.

[0188] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 153. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0189] 153. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 153. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 153; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 153. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 153; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 153. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0190] 153.

[0191] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 154. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0192] 154. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 154. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 154; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 154. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 154; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 154. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0193] 154.

[0194] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 155. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0195] 155. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 155. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 155; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 155. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 155; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 155. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 155. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 156. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0196] 156. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 156. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 156; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 156. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 156; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 156. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0197] 156.

[0198] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 157. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0199] 157. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 157. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 157; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 157. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 157; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 157. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0200] 157.

[0201] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 158. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0202] 158. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 158. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 158; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 158. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 158; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 158. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0203] 158.

[0204] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 159. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0205] 159. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 159. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 159; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 159. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 159; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 159. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0206] 159.

[0207] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 160. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0208] 160. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 160. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 160; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 160. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 160; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 160. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 160.

[0209] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 161. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0210] 161. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 161. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 161 ; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 161. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 161; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 161. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0211] 161.

[0212] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 162. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0213] 162. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 162. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 162; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 162. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 162; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 162. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0214] 162.

[0215] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 163. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0216] 163. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 163. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 163; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 163. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 163; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 163. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0217] 163.

[0218] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 164. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0219] 164. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 164. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 164; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 164. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 164; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 164. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0220] 164.

[0221] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 165. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0222] 165. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 165. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 165; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 165. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 165; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 165. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0223] 165.

[0224] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 166. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0225] 166. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 166. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 166; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 166. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 166; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 166. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0226] 166.

[0227] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 167. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0228] 167. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 167. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 167; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 167. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 167; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 167. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:

[0229] 167.

[0230] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 168. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:

[0231] 168. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 168. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 168; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 168. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 168; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 168. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 168. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 169. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 169. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 169. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 169; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 169. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 169; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 169. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 169.

[0232] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain, wherein said ankyrin repeat domain has binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20 , and wherein A at the second last position of SEQ ID NOs: 1 to 20 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 20 is optionally substituted by N.

[0233] Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 20. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence selected from SEQ ID NOs: 1 to 20, and wherein A at the second last position of SEQ ID NOs: 1 to 20 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 20 is optionally substituted by N.

[0234] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 1 , and wherein A at the second last position of SEQ ID NO: 1 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 1 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 1. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 1. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 1; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 1. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 1 ; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 1. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 1 .

[0235] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 2, and wherein A at the second last position of SEQ ID NO: 2 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 2 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 2. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 2. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 2; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 2. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 2; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 2. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 2.

[0236] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 3, and wherein A at the second last position of SEQ ID NO: 3 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 3 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 3. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 3. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 3; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 3. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 3; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 3. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 3.

[0237] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 4, and wherein A at the second last position of SEQ ID NO: 4 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 4 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 4. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 4. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 4; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 4. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 4; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 4. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 4.

[0238] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 5, and wherein A at the second last position of SEQ ID NO: 5 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 5 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 5. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 5. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 5; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 5. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 5; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 5. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 5. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO:6, and wherein A at the second last position of SEQ ID NO: 6 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 6 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 6. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 6. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 6; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 6. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 6; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 6. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 6.

[0239] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 7, and wherein A at the second last position of SEQ ID NO: 7 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 7 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 7. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 7. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 7; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 7. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 7; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 7. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 7.

[0240] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 8, and wherein A at the second last position of SEQ ID NO: 8 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 8 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 8. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 8. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 8; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 8. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 8; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 8. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 8.

[0241] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 9, and wherein A at the second last position of SEQ ID NO: 9 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 9 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 9. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 9. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 9; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 9. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 9; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 9. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 9.

[0242] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 10, and wherein A at the second last position of SEQ ID NO: 10 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 10 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 10. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 10. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 10; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 10. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 10; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 10. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 10.

[0243] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 11 , and wherein A at the second last position of SEQ ID NO: 11 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 11 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 11. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 11. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 11; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 11 . In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 11; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 11. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ I D NO: 11.

[0244] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 12, and wherein A at the second last position of SEQ ID NO: 12 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 12 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 12. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 12. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 12; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 12. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 12; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 12. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 12.

[0245] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 13, and wherein A at the second last position of SEQ ID NO: 13 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 13 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 13. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 13. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 13; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 13. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 13; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 13. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 13.

[0246] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 4, and wherein A at the second last position of SEQ ID NO: 14 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 14 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 14. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 14. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 14; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 14. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 14; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 14. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 14.

[0247] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 15, and wherein A at the second last position of SEQ ID NO: 15 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 15 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 15. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 15. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 15; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 15. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 15; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 15. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 15.

[0248] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 16, and wherein A at the second last position of SEQ ID NO: 16 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 16 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 16. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 16. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 16; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 16. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 16; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 16. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 16.

[0249] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 17, and wherein A at the second last position of SEQ ID NO: 17 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 17 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 17. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 17. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 17; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 17. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 17; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 17. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 17.

[0250] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 18, and wherein A at the second last position of SEQ ID NO: 18 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 18 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 18. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 18. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 18; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 18. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 18; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 18. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 18.

[0251] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 19, and wherein A at the second last position of SEQ ID NO: 19 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 19 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 19. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 19. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 19; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 19. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 19; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 19. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 19.

[0252] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 20, and wherein A at the second last position of SEQ ID NO: 20 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 20 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 20. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 20. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 20; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 20. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 20; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 20. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 20.

[0253] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein the potential interaction residues in said ankyrin repeat domain are identical to the corresponding positions in any one of the ankyrin repeat domains of SEQ ID NOs: 1 to 20 and 147 to 169.

[0254] In another aspect, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain, wherein said ankyrin repeat domain has binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 249 to 256, and wherein A at the second last position of SEQ ID NOs: 249 to 256 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 249 to 256 is optionally substituted by N.

[0255] Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 249 to 256. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with any one of SEQ ID NOs: 249 to 256. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with any one of SEQ ID NOs: 249 to 256; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with any one of SEQ ID NOs: 249 to 256. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with any one of SEQ ID NOs: 249 to 256; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of any one of SEQ ID NOs: 249 to 256. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence selected from SEQ ID NOs: 249 to 256, and wherein A at the second last position of SEQ ID NOs: 249 to 256 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 249 to 256 is optionally substituted by N.

[0256] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 249, and wherein A at the second last position of SEQ ID NO: 249 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 249 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 249. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 249. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 249; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 249. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 249; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 249. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 249.

[0257] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 250, and wherein A at the second last position of SEQ ID NO: 250 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 250 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 250. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 250. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 250; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 250. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 250; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 250. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 250.

[0258] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 251 , and wherein A at the second last position of SEQ ID NO: 251 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 251 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 251. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 251 . In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 251 ; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 251 . In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 251; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 251. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 251.

[0259] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 252, and wherein A at the second last position of SEQ ID NO: 252 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 252 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 252. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 252. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 252; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 252. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 252; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 252. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 252.

[0260] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 253, and wherein A at the second last position of SEQ ID NO: 253 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 253 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 253. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 253. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 253; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 253. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 253; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 253. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 253.

[0261] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 254, and wherein A at the second last position of SEQ ID NO: 254 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 254 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 254. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 254. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 254; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 254. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 254; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 254. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 254.

[0262] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 255, and wherein A at the second last position of SEQ ID NO: 255 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 255 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 255. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 255. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 255; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 255. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 255; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 255. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 255.

[0263] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% amino acid sequence identity with SEQ ID NO: 256, and wherein A at the second last position of SEQ ID NO: 256 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 256 is optionally substituted by N. Thus, in one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 256. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 256. In another embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 256; and in a further embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 256. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 256; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 256. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 256.

[0264] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein the potential interaction residues in said ankyrin repeat domain are identical to the corresponding positions in any one of the ankyrin repeat domains of SEQ ID NOs: 249 to 256.

[0265] In one embodiment, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds to human DLL3 in PBS with a dissociation constant (KD) of or below about 10'7M, or of or below about 10'8M, or of or below about 10'9M. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'7M. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~9M. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'1°M. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'11M.

[0266] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~7M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169. In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, wherein A at the second last position of SEQ ID NOs: 1 to 20 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 20 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 147 to 169; and in one embodiment, said binding protein binds human in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 20, 147 to 169. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 20, 147 to 169.

[0267] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 1 , and wherein A at the second last position of SEQ ID NO: 1 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 1 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 1. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 1. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 1; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10-7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 1. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 1 ; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 1. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'7M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 1 , and wherein A at the second last position of SEQ ID NO: 1 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 1 is optionally substituted by N.

[0268] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 2, and wherein A at the second last position of SEQ ID NO: 2 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 2 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 2. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 2. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 108M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 2; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant of or (KD) below 10-8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 2. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 2; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 2. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 2, and wherein A at the second last position of SEQ ID NO: 2 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 2 is optionally substituted by N.

[0269] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 4, and wherein A at the second last position of SEQ ID NO: 4 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 4 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 4. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 4. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 4; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with f SEQ ID NO: 4. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 4; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 4. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 4, and wherein A at the second last position of SEQ ID NO: 4 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 4 is optionally substituted by N.

[0270] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~1°M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 5, and wherein A at the second last position of SEQ ID NO: 5 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 5 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10 ~10M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 5. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 5. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~10M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 5; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 5. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'10M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 5; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'1°M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 5. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'10M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 5, and wherein A at the second last position of SEQ ID NO: 5 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 5 is optionally substituted by N. In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 6, and wherein A at the second last position of SEQ ID NO: 6 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 6 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 6. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 6. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 6; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10-8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 6. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 6; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 6. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 6, and wherein A at the second last position of SEQ ID NO: 6 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 6 is optionally substituted by N.

[0271] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 7, and wherein A at the second last position of SEQ ID NO: 7 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 7 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 7. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with the SEQ ID NO: 7. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 7; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10-8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with f SEQ ID NO: 7. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 7; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 7. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 7, and wherein A at the second last position of SEQ ID NO: 7 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 7 is optionally substituted by N.

[0272] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 8, and wherein A at the second last position of SEQ ID NO: 8 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 8 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 8. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 8. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 108M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 8; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 8. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 8; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 8. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 8, and wherein A at the second last position of SEQ ID NO: 8 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 8 is optionally substituted by N.

[0273] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~1°M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 9, and wherein A at the second last position of SEQ ID NO: 9 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 9 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10 ~10M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 9. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 9. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 9 and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 9. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~10M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 9; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~1°M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 9. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~10M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 9, and wherein A at the second last position of SEQ ID NO: 9 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 9 is optionally substituted by N.

[0274] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 10, and wherein A at the second last position of SEQ ID NO: 10 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 10 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 10. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below of or 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 10. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 10; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10-8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with f SEQ ID NO: 10. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 10; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 10. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 10, and wherein A at the second last position of SEQ ID NO: 10 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 10 is optionally substituted by N.

[0275] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 11 , and wherein A at the second last position of SEQ ID NO: 11 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 11 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 11. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 11. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 11 ; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with f SEQ ID NO: 11 . In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 11 ; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 11. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 11 , and wherein A at the second last position of SEQ ID NO: 11 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 11 is optionally substituted by N.

[0276] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 12, and wherein A at the second last position of SEQ ID NO: 12 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 12 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 12. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 12. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 107M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 12; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 12. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 12; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'7M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 12. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 12, and wherein A at the second last position of SEQ ID NO: 12 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 12 is optionally substituted by N.

[0277] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 13, and wherein A at the second last position of SEQ ID NO:13 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 13 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 13. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 13. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 13; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 13. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 13; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 13. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 13, and wherein A at the second last position of SEQ ID NO: 13 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 13 is optionally substituted by N.

[0278] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~1°M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 14, and wherein A at the second last position of SEQ ID NO: 14 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 14 is optionally substituted by N. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10 ~10M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 14. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 14. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 14; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10'1°M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 14. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~10M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 14; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below 10~1°M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 14. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~10M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 14, and wherein A at the second last position of SEQ ID NO: 14 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 14 is optionally substituted by N.

[0279] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 147. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 147. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 147. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 147; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 147. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 147; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 147. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 147.

[0280] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 148. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 148. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 148. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 148; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with f SEQ ID NO: 148. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 148; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 148. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:148.

[0281] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~9M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 149. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'9M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 149. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~9M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 149. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~9M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 149; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~9M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with f SEQ ID NO: 149. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: ; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~9M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 149. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~9M wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 149.

[0282] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO:150. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 150. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NQ:150. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NQ:150 ; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with f SEQ ID NO: 150. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 150; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 150. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:150.

[0283] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO:151. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 151. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 151. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 151 ; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 151. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 151; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 151 . Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 151.

[0284] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO:152. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 152. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 152. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'7152M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: ; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 152. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 157; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 152. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:152.

[0285] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 153. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 153. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 153. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 153; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 153. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 153; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 153. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:153.

[0286] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 154. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO:154. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO:154. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 154; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 154. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 154; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 107M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 154. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:154.

[0287] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 155. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 155. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 155. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 155; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 155. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO:155; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 155. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:155.

[0288] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 156. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 156. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 156. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: ; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 156. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 156; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10'8M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 156. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:156.

[0289] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 157. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 157. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 90% amino acid sequence identity with SEQ ID NO: 157. In another embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 93% amino acid sequence identity with SEQ ID NO: 157; and in a further embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises an amino acid sequence with at least 95% amino acid sequence identity with SEQ ID NO: 157. In one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 98% amino acid sequence identity with SEQ ID NO: 157; and in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) below 10~7M, and said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO: 157. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~7M, and wherein said ankyrin repeat domain comprises the amino acid sequence of SEQ ID NO:157.

[0290] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for DLL3, wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10~8M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100% amino acid sequence identity with SEQ ID NO: 158. Thus, in one embodiment, said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10'8M, and said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 158. In one embodiment, said binding...

Claims

CLAIMS1. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for DLL3, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 1 to 20, 127 to 169 and 249 to 256.

2. The binding protein of claim 1 , wherein said binding protein binds human DLL3 in PBS with a dissociation constant (KD) of or below about 10-7M.

3. The binding protein of any one of the preceding claims, wherein said binding protein further comprises a binding agent with binding specificity for a tumor-associated antigen.

4. The binding protein of claim 3, wherein said binding agent with binding specificity for a tumor-associated antigen is an ankyrin repeat domain.

5. The binding protein of any one of the preceding claims, wherein said binding protein further comprises a binding agent with binding specificity for a protein expressed on the surface of an immune cell, optionally a T cell.

6. The binding protein of claim 5, wherein said protein expressed on the surface of an immune cell is CD3.

7. The binding protein of any one of claims 5 to 6, wherein said binding agent with binding specificity for a protein expressed on the surface of an immune cell is an ankyrin repeat domain.

8. The binding protein of any one of claims 5 to 7, wherein said binding agent with binding specificity for a protein expressed on the surface of an immune cell comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 173 to 176.

9. The binding protein of any one of the preceding claims, wherein said binding protein further comprises a half-life extending moiety.

10. The binding protein of claim 9, wherein said half-life extending moiety comprises a binding agent with binding specificity for human serum albumin.

11. The binding protein of claim 10, wherein said binding agent with binding specificity for human serum albumin is an ankyrin repeat domain.

12. The binding protein of any one of claims 10 to 11 , wherein said binding agent with binding specificity for human serum albumin comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 177 to 179.

13. The binding protein of any one of the preceding claims, wherein said binding protein comprises an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 257 to 264.

14. A nucleic acid encoding the binding protein of any of the preceding claims.

15. A pharmaceutical composition comprising the binding protein of any one of claims 1 to 13 or the nucleic acid of claim 14, and optionally a pharmaceutically acceptable carrier and / or diluent.

16. The binding protein of any of claims 1 to 13, the nucleic acid of claim 14 or the pharmaceutical composition of claim 15 for use in imaging, diagnosing and / or treating a medical condition, wherein said medical condition is cancer.