Recombinant CD117 binding proteins and their use

Abstract

The present invention relates to recombinant binding proteins comprising a designed ankyrin repeat domain with binding specificity for CD117. 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 medical conditions, such as cancer, and in methods of conditioning a mammal, including a human, for a stem cell transplant, such as a hematopoietic stem cell transplant.

Description

[0001] RECOMBINANT CD117 BINDING PROTEINS AND THEIR USE

[0002] FIELD OF THE DISCLOSURE

[0003] The present invention relates to recombinant binding proteins comprising a designed ankyrin repeat domain with binding specificity for CD117. 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 medical conditions, such as cancer, and in methods of conditioning a mammal, including a human, for a stem cell transplant, such as a hematopoietic stem cell transplant.

[0004] BACKGROUND

[0005] Selective cell depletion shows great potential for treating a number of medical conditions, and is used, for example, for conditioning of patients for stem cell transplantation, treatment of autoimmune diseases, e.g. by B cell depletion therapy, and treatment of certain cancers (Lee et al. (2020) Nature Reviews Drug Discovery, volume 20, pp. 179-199).

[0006] Conditioning is a process by which a patient is prepared (i.e., “conditioned”) for receiving a transplant containing stem cells, such as, e.g., hematopoietic stem cells (HSCs). Conditioning procedures thereby promote the successful engraftment of a stem cell transplant, and they are performed prior to engraftment in order to create conducive conditions for the patient to receive the transplant.

[0007] Currently, there are a number of non-specific (i.e., non-targeting) conditioning methods used in hematopoietic stem cell transplantation (HSCT)-related indications and hemoglobinopathies, including, but not limited to, the use of irradiation (e.g., total body irradiation (TBI)) and DNA alkylating / modifying agents, both of which are highly toxic, not only to hematopoietic cells, but also to non-hematopoietic cells and many of the patient's organs. These harsh conditioning regimens typically result in the destruction of the recipient patient's immune system and niche cells and can in many cases lead to lifethreatening complications due to toxicity (Russel et al; Mol Ther Methods Clin Dev; 2021 ; 21 : 710-727; Radtke; Mol Ther Methods Clin Dev; 2023; 28: 385-386).

[0008] Accordingly, the development of more targeted conditioning regimens that selectively deplete an endogenous hematopoietic stem cell population, while avoiding the undesirable toxicity of the aforementioned non-specific conditioning methods, is needed. Depletion of stem cells, such as HSCs, may be facilitated by targeting certain molecules expressed on HSCs, including, for example, CD117.

[0009] CD117 (also referred to as c-KIT or Stem Cell Factor Receptor (SCRF); UniProt: P10721) is a 145 kDa single transmembrane, receptor tyrosine kinase that binds the ligand Stem Cell Factor (SCF; UniProt: P21583) and it is the product of the ckit gene. SCF induces homodimerization of cKIT, which activates its tyrosine kinase activity and signaling through both the PI3-AKT and MAPK pathways (Kindblom et al., Am J. Path. 1998 152(5):1259). CD117 is highly expressed on hematopoietic stem cells (HSCs) and this expression pattern makes CD117 a potential target for conditioning procedures useful for a broad range of diseases.

[0010] Despite the availability of several conditioning approaches (Arai et al; Mol Ther; 2018; 26(5): 1181- 1197), there is still a need for efficient methods and compositions targeting stem cells, which can be used for conditioning. Such methods and compositions may also be useful for treating diseases, where selective cell depletion would be therapeutic.

[0011] CD117 was initially discovered as an oncogene and has been studied in the field of oncology (see, for example, Stankov et al. (2014) Curr Pharm Des. 20(17):2849-80). CD117 reportedly plays an important oncogenic role in solid tumors including gastrointestinal stromal tumors (GISTs) and small cell lung cancer (SCLC), while CD117-positive non-small cell lung cancer (NSCLC) cells reportedly exhibit cancer stem cell (CSC) characteristics including self-renewal and chemoresistance (Levina et al; Cancer Res. 70:338-346. 2010). Previous experimental evidence suggests that the presence of CSCs may be associated with the prognosis of the patient in various types of cancers (Yang et al; Int J Biol Sci. 12:1568-1577. 2016).

[0012] CD117 is also a marker widely used in immunohistochemistry to help distinguish particular types of tumors in histological tissue sections. It is used primarily in the diagnosis of GISTs, which are positive for CD117, but negative for markers such as desmin and S-100, which are expressed, however, in smooth muscle and neural tumors (Willmore-Payne et al; Cancer; 2005; 105(3): 165-70; doi: 10.1002 / cncr.21064). CD117 as a marker can also be used in the diagnosis of mast cell tumors and in distinguishing seminomas from embryonal carcinomas (Leong et al; (2003). Manual of Diagnostic Cytology (2 ed.). Greenwich Medical Media, Ltd. Pp. 149-151).

[0013] Taken together, there remains a need for new therapeutic and diagnostic approaches and agents benefiting from CD117-specific binding.

[0014] SUMMARY

[0015] The present invention provides recombinant binding proteins comprising a designed ankyrin repeat domain with binding specificity for CD117. Further provided are such binding proteins linked to one or more binding agents, preferably ankyrin repeat domains, with binding specificity for a protein expressed on the surface of an immune cell, for human serum albumin and / or or for a Tumor Associated Antigen (TAA). 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.

[0016] Applicant identified, designed, and generated CD1 17-specific binding domains, which are suitable to be used as building blocks in diagnostic or therapeutic agents, such as, e.g., multi-specific binding proteins, and have beneficial properties. As the result of a complex screening process and rational design, multiple CD117-specific ankyrin repeat proteins were generated and produced, namely DARPin proteins comprising SEQ ID NO: 1 , SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 , SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO:

[0017] 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21 , SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO:

[0018] 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO:

[0019] 30, SEQ ID NO: 31 , and SEQ ID NO: 32. These recombinant binding proteins all comprise a designed ankyrin repeat domain with binding specificity for CD117. These recombinant binding proteins are suitable to be linked to one or more other functional moieties in one molecule. Such other functional moieties include a half-life extending moiety and / or a TAA-specific binding agent(s), which may result in avidity driven multi-specific molecules. Moreover, binding proteins of the invention may further be linked to other binding agents, such as binding agents with binding specificity for surface molecules expressed in immune cells.

[0020] 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).

[0021] Specifically, the present disclosure provides the following aspects, advantageous features and specific embodiments, respectively alone or in combination:

[0022] E1 . A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for human CD117.

[0023] 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids.

[0024] 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.

[0025] E4. The recombinant binding protein of E2 or 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids.

[0026] E5. The recombinant binding protein of E4, wherein said first 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 in SEQ ID NO: 33 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: 34 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 34 are substituted by other amino acids.

[0027] E6. The recombinant binding protein of E4, wherein said first 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 in SEQ ID NO: 35 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids.

[0028] E7. The recombinant binding protein of E4, wherein said first 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 in SEQ ID NO: 37 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: 38 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 38 are substituted by other amino acids.

[0029] E8. The recombinant binding protein of E4, wherein said first 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 in SEQ ID NO: 39 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: 40 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 40 are substituted by other amino acids.

[0030] E9. The recombinant binding protein of E4, wherein said first 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 in SEQ ID NO: 41 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: 42 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 42 are substituted by other amino acids.

[0031] E10. The recombinant binding protein of E4, wherein said first 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 in SEQ ID NO: 43 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: 44 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 44 are substituted by other amino acids.

[0032] E11 . The recombinant binding protein of E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 56 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 56 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: 57 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 57 are substituted by other amino acids.

[0033] E12. The recombinant binding protein of E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 58 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 58 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: 59 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 59 are substituted by other amino acids. E13. The recombinant binding protein of E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 60 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 60 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: 61 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 61 are substituted by other amino acids.

[0034] E14. The recombinant binding protein of E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 71 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 71 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids.

[0035] E15. The recombinant binding protein of E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 72 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 72 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids.

[0036] E16. The recombinant binding protein of E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 73 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 73 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids.

[0037] E17. The recombinant binding protein of E4, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 74 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 74 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids.

[0038] E18. The recombinant binding protein of E6, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 75 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 75 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids.

[0039] E19. The recombinant binding protein of E6, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 76 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 76 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: 42 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 42 are substituted by other amino acids.

[0040] E20. The recombinant binding protein of any of E4 to E19, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain. E21 . 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. E22. The recombinant binding protein of E2 or E21 , 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids.

[0041] E23. The recombinant binding protein of E22, wherein said first 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 in SEQ ID NO: 45 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: 46 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 46 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: 47 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 47 are substituted by other amino acids.

[0042] E24. The recombinant binding protein of E22, 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, 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, and wherein said third 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 of SEQ ID NO: 50 are substituted by other amino acids.

[0043] E25. The recombinant binding protein of E22, wherein said first 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 in SEQ ID NO: 51 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: 52 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 52 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: 53 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 53 are substituted by other amino acids.

[0044] E26. The recombinant binding protein of E22, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 54 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 54 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: 55 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 55 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: 53 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 53 are substituted by other amino acids.

[0045] E27. The recombinant binding protein of E22, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 62 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 62 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: 63 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 63 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: 64 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 64 are substituted by other amino acids.

[0046] E28. The recombinant binding protein of E22, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 65 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 65 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: 66 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 66 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: 67 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 67 are substituted by other amino acids.

[0047] E29. The recombinant binding protein of E22, wherein said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 68 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 68 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: 69 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 69 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: 70 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 70 are substituted by other amino acids.

[0048] E30. The recombinant binding protein of any of E22 to E29, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module, and wherein said second ankyrin repeat module is located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain.

[0049] E31 . A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117, 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 32, and wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N.

[0050] E32. The recombinant binding protein of E31 , wherein said recombinant binding protein competes with Stem Cell Factor (SCF) in binding to CD117, 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 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 and wherein A at the second last position of any one of SEQ ID NOs: 1 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 is optionally substituted by L, and / or A at the last position of any one of SEQ ID NOs: 1 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 is optionally substituted by N.

[0051] E33. The recombinant binding protein of E31 , wherein said recombinant binding protein does not compete with Stem Cell Factor (SCF) in binding to CD117, 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: 3, 4, 11 or 13 and wherein A at the second last position of any one of SEQ ID NOs: 3, 4, 11 or 13 is optionally substituted by L, and / or A at the last position of any one of SEQ ID NOs: 3, 4, 11 or 13 is optionally substituted by N.

[0052] E34. The recombinant binding protein of any of E1 to E33, wherein said recombinant binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, of or below about 10-9M, of or below about 10'10M, of or below about 10-11M.

[0053] E35. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 1 .

[0054] E36. The recombinant binding protein of E35, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about

[0055] E37. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 2.

[0056] E38. The recombinant binding protein of E37, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about

[0057] E39. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 3.

[0058] E40. The recombinant binding protein of E39, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M. E41 . The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 4.

[0059] E42. The recombinant binding protein of E41 , wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M or of or below about 10-9M.

[0060] E43. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 5.

[0061] E44. The recombinant binding protein of E43, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below aboutl 0-8M, or of or below about 10-9M, or of or below about 10'1°M, or of or below about 10-11M.

[0062] E45. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 6.

[0063] E46. The recombinant binding protein of E45, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 10'1°M, or of or below 10-11M.

[0064] E47. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 7.

[0065] E48. The recombinant binding protein of E47, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about

[0066] E49. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 8.

[0067] E50. The recombinant binding protein of E49, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about

[0068] E51 . The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 9.

[0069] E52. The recombinant binding protein of E51 , wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about

[0070] E53. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 10. E54. The recombinant binding protein of E53, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below aboutl

[0071] E55. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 11 .

[0072] E56. The recombinant binding protein of E55, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below aboutl 0-8M or of or below about 10-9M.

[0073] E57. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 12.

[0074] E58. The recombinant binding protein of E57, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about

[0075] E59. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 13.

[0076] E60. The recombinant binding protein of E59, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M or of or below aboutl 0-9M.

[0077] E61 . The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 14.

[0078] E62. The recombinant binding protein of E61 , wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 10'1°M.

[0079] E63. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 15.

[0080] E64. The recombinant binding protein of E63, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 10'1°M.

[0081] E65. The recombinant binding protein of any of E1 to E33, wherein said ankyrin repeat domain with binding specificity for CD117 comprises an amino acid sequence with at least 80% amino acid sequence identity with SEQ ID NO: 16.

[0082] E66. The recombinant binding protein of E65, wherein said recombinant binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below aboutl 0-8M, or of or below about 10-9M, or of or below about 10'1°M.

[0083] E67. The recombinant binding protein of any of E1 to E66, wherein said recombinant binding protein further comprises a binding agent with binding specificity for a tumor-associated antigen. E68. The recombinant binding protein of E67, wherein said binding agent is an ankyrin repeat domain with binding specificity for a tumor-associated antigen.

[0084] E69. The recombinant binding protein of any one of E1 to E68, wherein said recombinant binding protein further comprises a binding agent with binding specificity for a protein expressed on the surface of an immune cell, preferably an NK cell, a monocyte or a macrophage.

[0085] E70. The recombinant binding protein of E69, wherein said binding agent with binding specificity for a protein expressed on the surface of an immune cell, preferably an NK cell or a macrophage, has binding specificity for CD16a.

[0086] E71 . The recombinant binding protein of E70, wherein said binding agent with binding specificity for CD16a is a designed ankyrin repeat protein.

[0087] E72. The recombinant binding protein E71 , wherein said binding agent with binding specificity for CD16a 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.

[0088] E73. The recombinant binding protein of any one of E67 to E72, 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, preferably an NK cell, a monocyte or a macrophage, is covalently linked to said ankyrin repeat domain with binding specificity for CD117 with a peptide linker.

[0089] E74. The recombinant binding protein of E73, wherein said peptide linker is a proline-threonine rich peptide linker or glycine-serine rich linker.

[0090] E75. The recombinant binding protein of E73 to E74, wherein the amino acid sequence of said peptide linker has a length from 1 to 50 amino acids, preferably from 6 to 38 amino acids.

[0091] E76. The recombinant binding protein of any of E1 to E75, wherein said binding protein further comprises a half-life extending moiety.

[0092] E77. The recombinant binding protein of E76, wherein said half-life extending moiety comprises a binding agent with binding specificity for human serum albumin.

[0093] E78. The recombinant binding protein of E77, wherein said binding agent with binding specificity for human serum albumin is an ankyrin repeat domain comprising an amino acid sequence of any one of SEQ ID NOs: 148 to 150, preferably SEQ ID NO: 149.

[0094] E79. The recombinant binding protein of any one of E76 to E78, wherein said half-life extending moiety is located N-terminally of said ankyrin repeat domain with binding specificity for CD117 within said binding protein.

[0095] E80. A nucleic acid encoding the recombinant binding protein of any one of E1 to E79.

[0096] E81. A cloning or expression vector comprising the nucleic acid of E80, wherein said vector is suitable for the recombinant production of a recombinant binding protein as defined in any one of E1 to E79.

[0097] E82. The vector of E81 , wherein said vector is a DNA vector, an RNA vector, a plasmid, a cosmid, or a viral vector.

[0098] E83. A host cell comprising the nucleic acid of E80 or the vector of any one of E81 to E82. E84. A pharmaceutical composition comprising the recombinant binding protein of any one of E1 to E79 or the nucleic acid of E80, the vector of any one of E81 to E82 or the host cell of E83 and optionally a pharmaceutically acceptable carrier and / or diluent.

[0099] E85. The recombinant binding protein of any one of E1 to E79, the nucleic acid of E80, the vector of any one of E81 to E82, the host cell of E83 or the pharmaceutical composition of E84 for use in a method of treating a medical condition.

[0100] E86. The recombinant binding protein of E85, the nucleic acid of E85, the vector of E85, the host cell of E85 or the pharmaceutical composition of E85, wherein the medical condition is a cancer.

[0101] E87. A method of treating a medical condition, the method comprising the step of administering to a patient in need thereof a therapeutically effective amount of the recombinant binding protein of any one of E1 to E79, the nucleic acid of E80, the vector of any one of E81 to E82, the host cell of E83, or the pharmaceutical composition of E84.

[0102] E88. The method of E87, wherein said medical condition is a cancer.

[0103] E89. The recombinant binding protein of any one of E1 to E79, the nucleic acid of E80, the vector of any one of E81 to E82, the host cell of E83 or the pharmaceutical composition of E84 for use in a method of conditioning a mammal in need thereof, preferably a human.

[0104] E90. A method of conditioning a mammal in need thereof, preferably a human, the method comprising the step of administering to said mammal in need thereof a therapeutically effective amount of the recombinant binding protein of any one of E1 to E79, the nucleic acid of E80, the vector of any one of E81 to E82, the host cell of E83 or the pharmaceutical composition of E84.

[0105] E91 . Use of the recombinant binding protein of any one of E1 to E79 or the nucleic acid of E80 or the vector of any one of E81 to E82 or the host cell of E83 or the pharmaceutical composition of E84 for the manufacture of a medicament for the treatment of a medical condition and / or for the conditioning of a mammal in need thereof.

[0106] E92. The use of E91 , wherein said medical condition is a cancer.

[0107] E93. A method of diagnosing a medical condition in a mammal, preferably a human, the method comprising the steps of:

[0108] (i) contacting a cell or tissue sample obtained from said mammal with the CD117-specific recombinant binding protein of any one of E1 to E79; and

[0109] (ii) detecting specific binding of said binding protein to said cell or tissue sample.

[0110] E94. A process for the production of a recombinant binding protein according to any one of E1 to E79, comprising culturing a host cell according to E83, purifying and recovering said recombinant binding protein.

[0111] BRIEF DESCRIPTION OF THE FIGURES

[0112] Figure 1. Binding of 2.5 nM Flag-tagged 96 well IMAC purified proteins to 2.55 nM biotinylated human CD117-Fc in Homogeneous Time Resolved Fluorescence (HTRF). The HTRF signal over PBS is shown for selected CD117-specific designed ankyrin repeat proteins. Columns 1 to 16 show the HTRF signal of DARPin protein #1 , DARPin protein #2, DARPin protein #3, DARPin protein #4, DARPin protein #5, DARPin protein #6, DARPin protein #7, DARPin protein #8, DARPin protein #9, DARPin protein #10, DARPin protein #11 , DARPin protein #12, DARPin protein #13, DARPin protein #14, DARPin protein #15 and DARPin protein #16, respectively.

[0113] Figure 2 (A-E). Cell binding of 96-well purified designed ankyrin repeat proteins. Titrated amount of selected designed ankyrin repeat proteins (from 10nM (1 :3 dilution steps)) was added to CD117- expressing cells for 30 minutes at 4°C. Tested proteins bound to cells were detected with anti-DARPin 1.1.1 antibodies. Median fluorescence intensities obtained are shown. Fig. 2A. Cell binding of DARPin proteins #6, #7 and #2; Fig. 2B. Cell binding of DARPin proteins #8, #9 and #10; Fig. 2C. Cell binding of DARPin proteins #3, #11 and #12; Fig. 2D. Cell binding of DARPin proteins #1 , #4 and #13; Fig. 2E. Cell binding of DARPin proteins #5, #14, #15 and #16.

[0114] Figure 3 (A-E). Cell binding of 96-well purified designed ankyrin repeat proteins. Titrated amount of selected designed ankyrin repeat proteins (from 10nM (1 :3 dilution steps)) was added to CD117- expressing cells for 30 minutes at 4°C. Tested proteins bound to cells were detected with anti-DARPin 1.1.1 antibodies. Median fluorescence intensities obtained are shown. Fig. 3A. Cell binding of DARPin proteins #4 and #28; Fig. 3B. Cell binding of DARPin proteins #3, #26 and #27; Fig. 3C. Cell binding of DARPin proteins #1 , #17, #18 and #19; Fig. 3D. Cell binding of DARPin proteins #2, #20, #21 , #22, #23, #24 and #25; Fig. 3E. Cell binding of DARPin proteins #5, #29, #30, #31 and #32.

[0115] Figure 4 (A-D). SCF (1 nM) competition cell binding of 96-well purified designed ankyrin repeat proteins. Titrated amount of selected designed ankyrin repeat protein, or of a control benchmark monoclonal anti-CD117 antibody which does not compete with SCF, was added to CD117-expressing cells (Kasumi-3 cells) for 30 minutes at 4°C. Tested proteins bound to cells were detected with anti- DARPin 1.1.1 antibodies (Streptavidin AF647). Median fluorescence intensities obtained are shown. Fig. 4A. Competition cell binding of DARPin proteins #10, #7, #9, #14, #1 and benchmark anti-CD117 monoclonal antibody; Fig. 4B. Competition cell binding of DARPin proteins #5, and #12; Fig. 4C. Competition cell binding of DARPin proteins #2, #6, and #15; Fig. 4D. Competition cell binding of DARPin proteins #3, #4, #6, #11 and #13.

[0116] Figure 5. DARPin dependent cellular cytotoxicity assay (DDCC). DARPin proteins #33 to #48, with binding specificity to CD117 and CD16a, and DARPin protein #49 with binding specificity to CD16a only, were tested in a Jurkat DDCC reporter assay in the presence (Fig. 5A) or absence (Fig. 5B) of target expressing cells (Kasumi-1 cells).

[0117] Figure 6. NK cell degranulation assay in the presence of Kasumi-1 cells. DARPin proteins #33 to #48, with binding specificity for CD117 and CD16a, and DARPin protein #49 with binding specificity to CD16a only, at concentrations of 10 nM, 1 nM, 0.1 nM and 0 nM were tested for their capacity to mediate degranulation (% of CD107a) of isolated primary NK cells (gated as live CD56+).

[0118] Figure 1. DARPin dependent cellular phagocytosis assay (DDCP). DARPin proteins 33# to #48 were tested for their capacity to mediate DDCP (% of double positive CD11 b+Cell Trace+) of target cells (Kasumi-1) by MO-like macrophages. Concentrations of 10 nM, 1 nM, 0.1 nM and 0 nM were tested.

[0119] DETAILED DESCRIPTION OF THE INVENTION

[0120] As disclosed and exemplified herein, the present disclosure provides ankyrin repeat proteins that specifically bind target CD117. 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 binding 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 with increased safety profile, including, e.g., multispecific drugs comprising a CD117-specific binding agent and at least one further localizer such as a tumor associated antigen binding agent and / or a binding agent with binding specificity for a protein expressed on the surface of an immune cell, preferably an NK cell, a monocyte or a macrophage. 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. Taken together, designed ankyrin repeat proteins are an example of the next generation of protein therapeutics with the potential to surpass existing antibody drugs.

[0121] In one aspect, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117.

[0122] In one embodiment said ankyrin repeat domain comprises an ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 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 one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. Thus, in one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 8 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 7 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 6 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 5 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 4 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 3 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 2 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 1 amino acid in any one of SEQ ID NOs: 33 to 76 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 residue positions of said ankyrin repeat module(s). In one embodiment, said ankyrin repeat module comprises or consists of an amino acid sequence selected from the group consisting of SEQ ID NOs: 33 to 76.

[0123] In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 33 or a sequence in which one or two amino acids in SEQ ID NO: 33 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 34 or a sequence in which one or two amino acids in SEQ ID NO: 34 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 35 or a sequence in which one or two amino acids in SEQ ID NO: 35 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 36 or a sequence in which one or two amino acids in SEQ ID NO: 36 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 37 or a sequence in which one or two amino acids in SEQ ID NO: 37 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 38 or a sequence in which one or two amino acids in SEQ ID NO: 38 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 39 or a sequence in which one or two amino acids in SEQ ID NO: 39 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 40 or a sequence in which one or two amino acids in SEQ ID NO: 40 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 41 or a sequence in which one or two amino acids in SEQ ID NO: 41 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 42 or a sequence in which one or two amino acids in SEQ ID NO: 42 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 43 or a sequence in which one or two amino acids in SEQ ID NO: 43 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 44 or a sequence in which one or two amino acids in SEQ ID NO: 44 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 45 or a sequence in which one or two amino acids in SEQ ID NO: 45 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 46 or a sequence in which one or two amino acids in SEQ ID NO: 46 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 47 or a sequence in which one or two amino acids in SEQ ID NO: 47 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 48 or a sequence in which one or two amino acids in SEQ ID NO: 48 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 49 or a sequence in which one or two amino acids in SEQ ID NO: 49 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 50 or a sequence in which one or two amino acids in SEQ ID NO: 50 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 51 or a sequence in which one or two amino acids in SEQ ID NO: 51 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 52 or a sequence in which one or two amino acids in SEQ ID NO: 52 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 53 or a sequence in which one or two amino acids in SEQ ID NO: 53 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 54 or a sequence in which one or two amino acids in SEQ ID NO: 54 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 55 or a sequence in which one or two amino acids in SEQ ID NO: 55 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 56 or a sequence in which one or two amino acids in SEQ ID NO: 56 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 57 or a sequence in which one or two amino acids in SEQ ID NO: 57 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 58 or a sequence in which one or two amino acids in SEQ ID NO: 58 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 59 or a sequence in which one or two amino acids in SEQ ID NO: 59 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 60 or a sequence in which one or two amino acids in SEQ ID NO: 60 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 61 or a sequence in which one or two amino acids in SEQ ID NO: 61 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 62 or a sequence in which one or two amino acids in SEQ ID NO: 62 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 63 or a sequence in which one or two amino acids in SEQ ID NO: 63 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 64 or a sequence in which one or two amino acids in SEQ ID NO: 64 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 65 or a sequence in which one or two amino acids in SEQ ID NO: 65 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 66 or a sequence in which one or two amino acids in SEQ ID NO: 66 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 67 or a sequence in which one or two amino acids in SEQ ID NO: 67 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 68 or a sequence in which one or two amino acids in SEQ ID NO: 68 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 69 or a sequence in which one or two amino acids in SEQ ID NO: 69 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 70 or a sequence in which one or two amino acids in SEQ ID NO: 70 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 71 or a sequence in which one or two amino acids in SEQ ID NO: 71 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 72 or a sequence in which one or two amino acids in SEQ ID NO: 72 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 73 or a sequence in which one or two amino acids in SEQ ID NO: 73 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 74 or a sequence in which one or two amino acids in SEQ ID NO: 74 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 75 or a sequence in which one or two amino acids in SEQ ID NO: 75 are substituted by other amino acids. In one embodiment, said ankyrin repeat module comprises the amino acid sequence of SEQ ID NO: 76 or a sequence in which one or two amino acids in SEQ ID NO: 76 are substituted by other amino acids.

[0124] In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 33. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 34. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 35. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 36. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 37. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 38. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 39. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 40. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 41. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 42. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 43. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 44. In one embodiment, said ankyrin repeat module comprises consists ofthe amino acid sequence of SEQ ID NO: 45. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 46. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 47. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 48. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 49. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 50. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 51. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 52. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 53. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 54. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 55. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 56. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 57. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 58. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 59. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 60. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 61. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 62. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 63. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 64. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 65. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 66. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 67. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 68. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 69. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 70. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 71. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 72. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 73. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 74. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 75. In one embodiment, said ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 76.

[0125] 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 independently comprises an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 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 one of SEQ ID NOs: 33 to 76 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids and further comprises a second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 36 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids.

[0126] 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: 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 in SEQ ID NO: 33 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: 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 of SEQ ID NO: 34 are substituted by other amino acids.

[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: 33 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 33 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: 34 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 34 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 or consists of the amino acid sequence of SEQ ID NO: 33 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 34, 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: 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 in SEQ ID NO: 35 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: 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 of SEQ ID NO: 36 are substituted by other amino acids.

[0129] In one preferred embodiment, said first 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 in SEQ ID NO: 35 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: 36 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 36 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 or consists of the amino acid sequence of SEQ ID NO: 35 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 36, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0130] 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: 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 in SEQ ID NO: 37 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: 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 of SEQ ID NO: 38 are substituted by other amino acids.

[0131] In one preferred embodiment, said first 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 in SEQ ID NO: 37 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: 38 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 38 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 or consists of the amino acid sequence of SEQ ID NO: 37 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 38, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0132] 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: 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 in SEQ ID NO: 39 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: 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 of SEQ ID NO: 40 are substituted by other amino acids.

[0133] In a preferred embodiment, said first 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 in SEQ ID NO: 39 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: 40 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 40 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 or consists of the amino acid sequence of SEQ ID NO: 39 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 40, 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: 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 in SEQ ID NO: 41 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: 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 of SEQ ID NO: 42 are substituted by other amino acids.

[0135] In a preferred embodiment, said first 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 in SEQ ID NO: 41 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: 42 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 42 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 or consists of the amino acid sequence of SEQ ID NO: 41 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 42, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0136] 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: 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 in SEQ ID NO: 43 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: 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 of SEQ ID NO: 44 are substituted by other amino acids.

[0137] In a preferred embodiment, said first 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 in SEQ ID NO: 43 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: 44 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 44 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 or consists of the amino acid sequence of SEQ ID NO: 43 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 44, 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: 56 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: 56 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: 57 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: 57 are substituted by other amino acids.

[0139] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 56 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 56 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: 57 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 57 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 or consists of the amino acid sequence of SEQ ID NO: 56 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 57, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0140] 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: 58 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: 58 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: 59 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: 59 are substituted by other amino acids.

[0141] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 58 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 58 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: 59 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 59 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 or consists of the amino acid sequence of SEQ ID NO: 58 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 59, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0142] 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: 60 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: 60 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: 61 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: 61 are substituted by other amino acids.

[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: 60 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 60 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: 61 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 61 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 or consists of the amino acid sequence of SEQ ID NO: 60 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 61 , 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: 71 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: 71 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: 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 of SEQ ID NO: 36 are substituted by other amino acids.

[0145] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 71 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 71 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: 36 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 36 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 or consists of the amino acid sequence of SEQ ID NO: 71 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 36, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0146] 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: 72 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: 72 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: 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 of SEQ ID NO: 36 are substituted by other amino acids.

[0147] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 72 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 72 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: 36 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 36 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 or consists of the amino acid sequence of SEQ ID NO: 72 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 36, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0148] 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: 73 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: 73 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: 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 of SEQ ID NO: 36 are substituted by other amino acids.

[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: 73 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 73 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: 36 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 36 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 or consists of the amino acid sequence of SEQ ID NO: 73 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 36, 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: 74 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: 74 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: 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 of SEQ ID NO: 36 are substituted by other amino acids.

[0151] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 74 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 74 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: 36 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 36 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 or consists of the amino acid sequence of SEQ ID NO: 74 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 36, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0152] 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: 75 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: 75 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: 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 of SEQ ID NO: 36 are substituted by other amino acids.

[0153] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 75 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 75 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: 36 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 36 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 or consists of the amino acid sequence of SEQ ID NO: 75 and said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 36, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0154] 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: 76 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: 76 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: 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 of SEQ ID NO: 42 are substituted by other amino acids.

[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: 76 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 76 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: 42 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 42 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 or consists of the amino acid sequence of SEQ ID NO: 76 and said second ankyrin repeat module comprises or consists the amino acid sequence of SEQ ID NO: 42, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

[0156] 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.

[0157] 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) any one of SEQ ID NOs: 33 to 76 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 one of SEQ ID NOs: 33 to 76 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids, a second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids. 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: 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 in SEQ ID NO: 45 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: 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 of SEQ ID NO: 46 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: 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.

[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: 45 and (2) sequences in which up to 3, or up to

[0159] 2, or up to 1 amino acids in SEQ ID NO: 45 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: 46 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 46 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: 47 and (2) sequences in which up to

[0160] 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 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 or consists of the amino acid sequence of SEQ ID NO: 45, said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 46, and said third ankyrin repeat module comprises or consists of 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 and said second ankyrin repeat module is N- terminally located of said third ankyrin repeat module within said ankyrin repeat domain.

[0161] 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, 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, and said third 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 of SEQ ID NO: 50 are substituted by other amino acids. 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

[0162] 2, or up to 1 amino acids in SEQ ID NO: 48 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: 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, and said third 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

[0163] 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 50 are substituted by other amino acids, wherein said first ankyrin repeat module is located N-terminally of said second or said 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 or consists of the amino acid sequence of SEQ ID NO: 48, said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 49, and said third ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 50, 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.

[0164] 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: 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 SEQ ID NO: 51 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: 52 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: 52 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: 53 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: 53 are substituted by other amino acids.

[0165] In a preferred embodiment, said first 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

[0166] 2, or up to 1 amino acids in SEQ ID NO: 51 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: 52 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 52 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: 53 and (2) sequences in which up to

[0167] 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 53 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 or consists of the amino acid sequence of SEQ ID NO: 51 , said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 52, and said third ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 53, wherein 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.

[0168] 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: 54 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: 54 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: 55 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: 55 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: 53 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: 53 are substituted by other amino acids.

[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: 54 and (2) sequences in which up to 3, or up to

[0170] 2, or up to 1 amino acids in SEQ ID NO: 54 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: 55 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 55 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: 53 and (2) sequences in which up to

[0171] 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 53 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 located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 54, said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 55, and said third ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 53, 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.

[0172] 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: 62 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: 62 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: 63 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: 63 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: 64 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: 64 are substituted by other amino acids.

[0173] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 62 and (2) sequences in which up to 3, or up to

[0174] 2, or up to 1 amino acids in SEQ ID NO: 62 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: 63 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 63 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: 64 and (2) sequences in which up to

[0175] 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 64 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 located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 62, said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 63, and said third ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 64, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module and wherein said second ankyrin repeat module is located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain.

[0176] 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: 65 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: 65 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: 65 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: 66 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: 67 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: 67 are substituted by other amino acids.

[0177] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 65 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids in SEQ ID NO: 65 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: 66 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 66 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: 67 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 67 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 located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 65, said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 66, and said third ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 67, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module and wherein said second ankyrin repeat module is located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain.

[0178] 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: 68 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: 68 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: 69 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: 69 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: 70 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: 70 are substituted by other amino acids.

[0179] In a preferred embodiment, said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 68 and (2) sequences in which up to 3, or up to

[0180] 2, or up to 1 amino acids in SEQ ID NO: 68 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: 69 and (2) sequences in which up to 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 69 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: 70 and (2) sequences in which up to

[0181] 3, or up to 2, or up to 1 amino acids of SEQ ID NO: 70 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 located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain. Further, in a more preferred embodiment, said first ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 68, said second ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 69, and said third ankyrin repeat module comprises or consists of the amino acid sequence of SEQ ID NO: 70, wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module and wherein said second ankyrin repeat module is located N-terminally of said third ankyrin repeat module within said ankyrin repeat domain.

[0182] 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 residue 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 residue positions shall apply to all embodiments irrespective of whether such substitution is explicitly described.

[0183] In one preferred embodiment, all of said amino acid substitutions of said ankyrin repeat module(s) as described and referred to herein occur in positions other than positions 3, 4, 6, 14 and 15 of said ankyrin repeat module(s) of SEQ ID NOs: 33 to 76, wherein typically the overall structure of the module(s) is not affected by the substitutions.

[0184] 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 CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 32, and wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N.

[0185] 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 32. 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 32. 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 32; 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 32. 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 32; and in one embodiment, said ankyrin repeat domain comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 32. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of an amino acid sequence selected from SEQ ID NOs: 1 to 32, and wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N.

[0186] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 1.

[0187] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 2.

[0188] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 3.

[0189] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 4.

[0190] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 5.

[0191] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 6.

[0192] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 7.

[0193] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 8.

[0194] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 9. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 10.

[0195] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 11.

[0196] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 8, 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 12.

[0197] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 13.

[0198] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 14.

[0199] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 15.

[0200] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 16.

[0201] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 17.

[0202] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 18.

[0203] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 19.

[0204] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 20.

[0205] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 21 , and wherein A at the second last position of SEQ ID NO: 21 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 21 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 21.

[0206] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 22, and wherein A at the second last position of SEQ ID NO: 22 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 22 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 22. In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 23, and wherein A at the second last position of SEQ ID NO: 23 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 23 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 23.

[0207] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 24, and wherein A at the second last position of SEQ ID NO: 24 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 24 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 24.

[0208] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 25, and wherein A at the second last position of SEQ ID NO: 25 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 25 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 25.

[0209] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 26, and wherein A at the second last position of SEQ ID NO: 26 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 26 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 26.

[0210] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 27, and wherein A at the second last position of SEQ ID NO: 27 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 27 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 27.

[0211] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 28, and wherein A at the second last position of SEQ ID NO: 28 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 28 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 28.

[0212] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 29, and wherein A at the second last position of SEQ ID NO: 29 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 29 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 29.

[0213] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 30, and wherein A at the second last position of SEQ ID NO: 30 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 30 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 30.

[0214] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 31 , and wherein A at the second last position of SEQ ID NO: 31 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 31 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 31.

[0215] In one embodiment, said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 32, and wherein A at the second last position of SEQ ID NO: 32 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 32 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 32.

[0216] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein the potential interaction residues in said ankyrin repeat domain are identical or substantially identical to the corresponding positions in any one of the ankyrin repeat domains of SEQ ID NOs: 1 to 32.

[0217] In one embodiment, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds to human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 10"1°M, or of or below about 10-11M. Thus, in one embodiment, said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 10'10M, or of or below about 10-11M. In another embodiment, said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M. In another embodiment, said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-9M. In another embodiment, said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'10M. In another embodiment, said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about10-11M.

[0218] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 10'1°M, or of or below about 10-11M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 32, wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N. In another embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9or of or below about 10'1°M, or of or below about 10'11and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 32, wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, and wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 1 to 32, wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N.

[0219] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0220] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with 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. Thus, in one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0221] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 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%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, and wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of 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.

[0222] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0223] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below of or below about 10'8M, or of or below about 10'9M or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0224] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0225] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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. In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M , and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0226] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of SEQ ID NO: 9, 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: 9 is optionally substituted by N.

[0227] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'10M , and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0228] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, and wherein said ankyrin repeat domain comprises or consists of 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.

[0229] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 1 O'10M , and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0230] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, and wherein said ankyrin repeat domain comprises or consists of 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.

[0231] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M , and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of 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.

[0232] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 1 O'10M , and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of 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: 14 is optionally substituted by N.

[0233] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M, or of or below about 10-9M, or of or below about 1 O'10M , and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 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 recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10'8M, or of or below about 10'9M, or of or below about 10'1°M and wherein said ankyrin repeat domain comprises or consists of the amino acid sequence of 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.

[0234] A typical and preferred determination of dissociation constants (KD) of the inventive recombinant binding proteins with binding specificity for CD117 by Surface Plasmon Resonance (SPR) analysis is described in Example 3. Thus, in one embodiment said binding specificity for CD117 of the recombinant binding proteins comprising an ankyrin repeat domain is determined in PBS containing 0.005% Tween 20 by Surface Plasmon Resonance (SPR). In one embodiment said binding specificity for CD117 of the recombinant binding proteins comprising an ankyrin repeat domain is determined in PBS by Surface Plasmon Resonance (SPR) as described in Example 3.

[0235] In one aspect, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 1 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 and wherein A at the second last position of any one of SEQ ID NOs: 1 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 is optionally substituted by L, and / or A at the last position of any one of SEQ ID NOs: 1 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 is optionally substituted by N.

[0236] In one aspect, said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein does not compete with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 3, 4, 11 or 13 and wherein A at the second last position of any one of SEQ ID NOs: 3, 4, 11 or 13 is optionally substituted by L, and / or A at the last position of any one of SEQ ID NOs: 3, 4, 11 or 13 is optionally substituted by N.

[0237] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 33 are substituted by other amino acids, and said second ankyrin repeat module comprising 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 of SEQ ID NO: 34 are substituted by other amino acids.

[0238] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 35 are substituted by other amino acids, and said second ankyrin repeat module comprising 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 of SEQ ID NO: 36 are substituted by other amino acids.

[0239] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein does not compete with Stem Cell Factor in binding to CD1 17, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 37 are substituted by other amino acids, and said second ankyrin repeat module comprising 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 of SEQ ID NO: 38 are substituted by other amino acids.

[0240] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein does not compete with Stem Cell Factor in binding to CD1 17, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 39 are substituted by other amino acids, and said second ankyrin repeat module comprising 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 of SEQ ID NO: 40 are substituted by other amino acids.

[0241] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 41 are substituted by other amino acids, and said second ankyrin repeat module comprising 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 of SEQ ID NO: 42 are substituted by other amino acids.

[0242] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 43 are substituted by other amino acids, and wherein said second ankyrin repeat module comprising 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 of SEQ ID NO: 44 are substituted by other amino acids.

[0243] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein does not compete with Stem Cell Factor in binding to CD1 17, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 56 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 56 are substituted by other amino acids, and said second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 57 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 57 are substituted by other amino acids.

[0244] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 58 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 58 are substituted by other amino acids, and said second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 59 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 59 are substituted by other amino acids.

[0245] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein does not compete with Stem Cell Factor in binding to CD1 17, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, said first ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 60 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 60 are substituted by other amino acids, and said second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 61 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 61 are substituted by other amino acids. In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 45 are substituted by other amino acids, said second ankyrin repeat module comprising 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 of SEQ ID NO: 46 are substituted by other amino acids, and said third ankyrin repeat module comprising 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.

[0246] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module, said first ankyrin repeat module comprising 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 in SEQ ID NO: 51 are substituted by other amino acids, said second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 52 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 52 are substituted by other amino acids, and said third ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 53 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 53 are substituted by other amino acids.

[0247] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module, said first ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 54 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 54 are substituted by other amino acids, said second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 55 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 55 are substituted by other amino acids, and said third ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 53 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 53 are substituted by other amino acids.

[0248] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module, said first ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 62 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 62 are substituted by other amino acids, said second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 63 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 63 are substituted by other amino acids, and said third ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 64 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 64 are substituted by other amino acids.

[0249] In one embodiment said recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117, wherein said binding protein competes with Stem Cell Factor in binding to CD117, and wherein said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module, said first ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 65 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 65 are substituted by other amino acids, said second ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 66 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 66 are substituted by other amino acids, and said third ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 67 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 67 are substituted by other amino acids.

[0250] A typical and preferred determination of competitive binding of the inventive recombinant binding proteins with binding specificity for CD117 against Stem Cell Factor to CD117 is described in Example 4.

[0251] In one embodiment, the invention relates to a recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C, higher than 68°C, higher than 70°C, higher than 72°C, higher than 75°C, higher than 78°C, higher than 80°C, of about 75°C, of about 80°C, of about 82°C, of about 85°C, of between 65°C and 95°C, of between 70°C and 90°C, or of between 72°C and 88°C. Thus, in one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 95°C. In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 72°C and 88°C. In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or100% amino acid sequence identity with any one of SEQ ID NOs: 1 to 32, wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higherthan 68°C. In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C.

[0252] In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 72°C.

[0253] In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C.

[0254] In another embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C.

[0255] In a further embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In an even further embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 85°C.

[0256] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 1 , 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 80°C.

[0257] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 2, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 68°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 70°C.

[0258] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 3, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 80°C.

[0259] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 4, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 72°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 75°C.

[0260] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 5, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 95°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 90°C.

[0261] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 6, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 65°C.

[0262] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 7, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 90°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 85°C.

[0263] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 8, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 95°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 90°C.

[0264] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 9, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 90°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 85°C.

[0265] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 10, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 95°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 90°C.

[0266] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 12, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 72°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 75°C.

[0267] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 13, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 90°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 85°C.

[0268] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 15, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 95°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 90°C.

[0269] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 16, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 95°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 90°C.

[0270] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 17, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 80°C.

[0271] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 18, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 80°C.

[0272] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 19, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 80°C.

[0273] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 20, 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; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 68°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 70°C.

[0274] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 21 , wherein A at the second last position of SEQ ID NO: 21 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 21 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 65°C.

[0275] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 22, wherein A at the second last position of SEQ ID NO: 22 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 22 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 65° C.

[0276] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 23, wherein A at the second last position of SEQ ID NO: 23 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 23 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 72°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 75°C.

[0277] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 24, wherein A at the second last position of SEQ ID NO: 24 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 24 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 65°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 68°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 70°C.

[0278] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 25, wherein A at the second last position of SEQ ID NO: 25 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 25 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 72°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 75°C.

[0279] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 26, wherein A at the second last position of SEQ ID NO: 26 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 26 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 80° C.

[0280] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 27, wherein A at the second last position of SEQ ID NO: 27 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 27 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 78°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 75°C and 80°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 80° C.

[0281] In one embodiment, said recombinant binding protein comprises an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 28, wherein A at the second last position of SEQ ID NO: 28 is optionally substituted by L, and / or A at the last position of SEQ ID NO: 28 is optionally substituted by N; and wherein said ankyrin repeat domain has a melting temperature (Tm) higher than 70°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 72°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) higher than 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of between 65°C and 75°C. In one embodiment, said ankyrin repeat domain has a melting temperature (Tm) of about 75°C. A typical and preferred determination of the melting temperature (Tm) of the recombinant binding proteins comprising ankyrin repeat domain with binding specificity for CD117 by Circular Dichroism (CD) spectroscopy is described in Example 2. Thus, in one embodiment, said melting temperature (Tm) of the recombinant binding proteins comprising an ankyrin repeat domain is determined in TBS pH 8.0 (50 mM Tris, 500 mM NaCI) by Circular Dichroism (CD) spectroscopy. In one embodiment, said melting temperature (Tm) of the recombinant binding proteins comprising an ankyrin repeat domains is determined in TBS pH 8.0 (50 mM Tris, 500 mM NaCI) by Circular Dichroism (CD) spectroscopy as described in Example 2.

[0282] The repeat domains, preferably ankyrin repeat domains, of the recombinant binding protein disclosed herein preferably comprise a N-terminal and / or a C-terminal capping module (thereafter also referred to as capping repeats or capping units). Capping modules are located at the N-and / or C-terminal end of an ankyrin repeat domain, typically forming tight tertiary interactions (i.e. tertiary structure interactions) with the ankyrin repeat module(s) in between, thereby providing a cap that shields the hydrophobic core of the ankyrin repeat domain at the side from exposure to the solvent. The N-and / or C-terminal capping modules may be derived from a capping unit or other structural unit found in a naturally occurring repeat protein adjacent to a repeat unit. Examples of capping sequences are described in International Patent Publication Nos. WO 2002 / 020565 and WO 2012 / 069655, in U.S. Patent Publication No. US20130296221 , and by Interlandi et al., J Mol Biol. 2008 Jan 18;375(3):837- 54. Examples of N-terminal capping modules (i.e. N-terminal capping repeats) are SEQ ID NOs: 77 to 98 and examples of C-terminal capping modules (i.e. C-terminal capping repeats) are SEQ ID NOs: 100 to 144.

[0283] In an exemplary embodiment, the N-terminal capping module comprises the amino acid sequence of any one of SEQ ID NOs: 77 to 98, optionally wherein up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 amino acid(s) of any one of SEQ ID NOs: 77 to 98 are exchanged by any amino acids.

[0284] In an exemplary embodiment, the C-terminal capping module comprises the amino acid sequence of any one of SEQ ID NO: 100 to 144, optionally wherein up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 amino acid(s) of any one of SEQ ID NOs: 100 to 144 are exchanged by any amino acids.

[0285] Advantageously, in some embodiments, certain amino acid residues in the N-terminal capping module and / or the C-terminal capping module of the designed ankyrin repeat domain herein provided are altered, resulting in improved pharmacokinetic properties, including a prolonged terminal half-life, of the designed ankyrin repeat domain and of the recombinant binding proteins comprising the designed ankyrin repeat domain. The altered amino acid residues may be surface exposed residues.

[0286] In one preferred embodiment, said ankyrin repeat domain with binding specificity for CD117 comprises from N-terminus to C-terminus: an N-terminal capping module; at least one, at least two, at least three or more ankyrin repeat module(s) specifically binding to CD117 as described more specifically in any one of the embodiments herein; and a C-terminal capping module. In some aspects, amino acid substitution(s) made to the binding agents do not change the KD value by more than about 1000-fold, more than about 100-fold, or more than about 10-fold, compared to the KD value of the unsubstituted binding agents. For example, in some aspects, the amino acid substitution(s) do not change the KD value by more than about 1000-fold, more than about 300-fold, more than about 100-fold, more than about 50-fold, more than about 25-fold, more than about 10-fold, or more than about 5-fold, compared to the KD value of the binding agent comprising any of the sequences of SEQ ID NOs: 1 to 32.

[0287] In certain embodiments, the substitution is a conservative substitution according to Table 1. In certain embodiments, the substitution is made outside the structural core residues of the ankyrin repeat domain, e.g., in the beta loops that connect the alpha-helices.

[0288] Table 1 : Amino acid substitutions

[0289] Furthermore, the CD117-binding domain of the invention may optionally further comprise a “G,” an “S,” or a “GS” sequence at its N-terminus. Accordingly, in some embodiments, the CD117-binding domain provided herein (i) comprises an amino acid sequence that is at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 1 to 32, and (ii) further comprises at its N-terminus a G, an S, or a GS. In an exemplary embodiment, the CD117-binding domain comprises an amino acid sequence that is at least 90% identical to any one of SEQ ID NOs: 1 to 32, and further comprises at its N-terminus a G, an S, or a GS. In an exemplary embodiment, the CD117-binding domain comprises an amino acid sequence that is at least 95% identical to any one of SEQ ID NOs: 1 to 32, and further comprises at its N-terminus a G, an S, or a GS. In an exemplary embodiment, the CD117-binding domain comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 32, and further comprises at its N-terminus a G, an S, or a GS.

[0290] In another aspect of the invention, the recombinant binding protein with binding specificity for CD117 further comprises a binding agent with binding specificity for a protein expressed on the surface of an immune cell, preferably a natural killer (NK) cell, a monocyte or a macrophage. As an example, in one particular embodiment, a recombinant binding protein of the invention further comprises a binding agent with binding specificity for a protein expressed on the surface of a NK cell, said protein being CD16a. In one embodiment said binding agent with binding specificity for CD16a is a designed ankyrin repeat domain. In one embodiment said designed ankyrin repeat domain comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 156.

[0291] In the context of the present invention, a binding agent may be an antibody, an antibody mimetic, including a scaffold protein or a repeat protein, a designed repeat domain, preferably a designed ankyrin repeat domain, or any other suitable binding molecules known in the art. In one embodiment, said binding agent is an antibody. In another embodiment, said binding agent is a designed repeat domain, preferably a designed ankyrin repeat domain.

[0292] In one embodiment, said binding agent is linked, conjugated, fused or otherwise physically attached to said CD117-specific ankyrin repeat domain. In one embodiment, said binding agent is covalently linked to said CD117-specific ankyrin repeat domain. In one embodiment, said binding agent is covalently linked to said CD117-specific ankyrin repeat domain with a peptide linker. In one embodiment, said peptide linker is a proline-threonine rich peptide linker. In one embodiment, said peptide linker is the proline-threonine rich peptide linker of SEQ ID NO: 151. In one embodiment, said binding agent is covalently linked to said CD117-specific ankyrin repeat domain with the proline-threonine rich peptide linker of SEQ ID NO: 151. In another embodiment, said peptide linker is a glycine-serine rich peptide linker. In one embodiment, said peptide linker is the glycine-serine rich peptide linker of SEQ ID NO: 152. In one embodiment, said binding agent is covalently linked to said CD117-specific ankyrin repeat domain with the glycine-serine rich peptide linker of SEQ ID NO: 152.

[0293] In another aspect of the invention, the recombinant binding protein of the invention further comprises a binding agent with binding specificity for a tumor-associated antigen. Thus, in a particular embodiment, the recombinant binding protein of the invention comprises an ankyrin repeat domain with binding specificity for CD117 as described more specifically in any of the aspects or embodiments herein and further comprises an additional binding agent with binding specificity for a tumor-associated antigen.

[0294] In one embodiment, said binding agent with binding specificity for a tumor-associated antigen is linked, conjugated, fused or otherwise physically attached to said ankyrin repeat domain with binding specificity for CD117. In one embodiment, said binding agent with binding specificity for a tumor-associated antigen is covalently linked to said ankyrin repeat domain with binding specificity for CD117. In one embodiment, said binding agent with binding specificity for a tumor-associated antigen is covalently linked to said ankyrin repeat domain with binding specificity for CD117 with a peptide linker. In one embodiment, the amino acid sequence of said peptide linker has a length from 1 to 50 amino acids, preferably from 6 to 38 amino acids. In one embodiment, said peptide linker is a proline-threonine rich peptide linker or glycine-serine rich linker. In one embodiment, said peptide linker is the prolinethreonine rich peptide linker of SEQ ID NO:151 or the glycine-serine rich linker of SEQ ID NO:152. In one embodiment, said binding agent with binding specificity for a tumor-associated antigen is covalently linked to said ankyrin repeat domain with binding specificity for CD117 with the proline-threonine rich peptide linker of SEQ ID NO: 151 or the glycine-serine rich linker of SEQ ID NO:152. In one preferred embodiment, said binding agent with binding specificity for a tumor-associated antigen is a designed ankyrin repeat domain with binding specificity for a disease-associated antigen.

[0295] In one embodiment, the recombinant binding protein of the invention comprises an ankyrin repeat domain with binding specificity for CD117 as described more specifically in any of the aspects or embodiments herein and further comprises two or more ankyrin repeat domains with binding specificity for a tumor-associated antigen.

[0296] In one aspect of the invention, the recombinant binding protein further comprises a half-life extending moiety.

[0297] Thus, in a particular embodiment, the recombinant binding protein of the invention comprises an ankyrin repeat domain with binding specificity for CD117 as described more specifically in any of the aspects or embodiments herein and further comprises a half-life extending moiety. In a particular embodiment the recombinant binding protein of the invention comprises an ankyrin repeat domain with binding specificity for CD117, an ankyrin repeat domain with binding specificity for one or more tumor associated antigen(s) and / or a binding agent with binding specificity for a protein expressed on the surface of an immune cell, preferably an NK cell or a macrophage, and further comprises a half-life extending moiety. In one embodiment said binding agent with binding specificity for said TAA and / or said protein expressed on the surface of an immune cell, preferably an NK cell or a macrophage, more preferably said protein being CD16a is an ankyrin repeat domain. In one embodiment said designed ankyrin repeat domain with binding specificity for CD16a comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 156.

[0298] In one embodiment, said half-life extending moiety comprises a binding agent with binding specificity for human serum albumin.

[0299] In one embodiment, said half-life extending moiety is a designed ankyrin binding domain with binding specificity for human serum albumin. In one embodiment, said designed ankyrin binding domain with binding specificity for human serum albumin comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with any one of SEQ ID NOs: 148 to 150. Thus, in one embodiment, the recombinant binding protein of the invention comprises an ankyrin repeat domain with binding specificity for CD117 as described more specifically in any of the aspects or embodiments herein and further comprises an ankyrin binding domain with binding specificity for human serum albumin comprising an amino acid sequence with at least 80% amino acid sequence identity with any one of SEQ ID NOs: 148 to 150. In one embodiment, said ankyrin repeat domain with binding specificity for human serum albumin comprises an amino acid sequence with at least 90% amino acid sequence identity with any one of SEQ ID NOs: 148 to 150. In another embodiment, said ankyrin repeat domain with binding specificity for human serum albumin comprises an amino acid sequence with at least 93% amino acid sequence identity with any one of SEQ ID NOs: 148 to 150; and in a further embodiment, said ankyrin repeat domain with binding specificity for human serum albumin comprises an amino acid sequence with at least 95% amino acid sequence identity with any one of SEQ ID NOs: 148 to 150. In one embodiment, said ankyrin repeat domain with binding specificity for human serum albumin comprises an amino acid sequence with at least 98% amino acid sequence identity with any one of SEQ ID NOs: 148 to 150; and in a further embodiment, said ankyrin repeat domain with binding specificity for human serum albumin comprises or consists of the amino acid sequence of any one of SEQ ID NOs: 148 to 150.

[0300] Thus, in one embodiment, the recombinant binding protein of the invention comprises an ankyrin repeat domain with binding specificity for CD117 and further comprises an ankyrin repeat domain with binding specificity for human serum albumin, and wherein said ankyrin repeat domain with binding specificity for CD117 comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 32 and wherein said ankyrin repeat domain with binding specificity for human serum albumin comprises the amino acid sequence of any one of SEQ ID NOs: 148 to 150, preferably the amino acid sequence of SEQ ID NO: 149. In a preferred embodiment, said ankyrin repeat domain with binding specificity for human serum albumin is located N-terminally of said ankyrin repeat domain with binding specificity for CD117 within said binding protein.

[0301] In a preferred embodiment, said designed ankyrin binding domain with binding specificity for human serum albumin comprises an amino acid sequence with at least 80%, at least 81 %, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91 %, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% amino acid sequence identity with SEQ ID NO: 149. Thus, in one embodiment, the recombinant binding protein of the invention comprises an ankyrin repeat domain with binding specificity for CD117 and further comprises an ankyrin repeat domain with binding specificity for human serum albumin, and wherein ankyrin repeat domain with binding specificity for CD117 comprises the amino acid sequence of any one of SEQ ID NOs: 1 to 32, and wherein said ankyrin repeat domain with binding specificity for human serum albumin comprises the amino acid sequences of SEQ ID NO: 149. In a preferred embodiment, said ankyrin repeat domain with binding specificity for human serum albumin is located N-terminally of said ankyrin repeat domain with binding specificity for CD117.

[0302] In one embodiment, a recombinant binding protein of the present invention comprising an ankyrin repeat domain with binding specificity for CD117 and further comprising an ankyrin repeat domain with binding specificity for human serum albumin exhibits an increased terminal half-life, preferably an increased terminal half-life of at least 5%, preferably 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, or 250%, compared to a corresponding recombinant binding protein comprising said ankyrin repeat domain with binding specificity for CD117 but not comprising said ankyrin repeat domain with binding specificity for human serum albumin.

[0303] In one embodiment, the recombinant binding protein of the invention comprises an ankyrin repeat domain having binding specificity for CD117 as described more specifically in any of the aspects or embodiments herein and further comprises two ankyrin repeat domains with binding specificity for human serum albumin as described more specifically in any of the aspects or embodiments herein.

[0304] In some embodiments, the half-life extending moiety comprises an immunoglobulin domain. In some embodiments, the immunoglobulin domain comprises an Fc domain. In some embodiments, the Fc domain is derived from any one of the known heavy chain isotypes: IgG (y), IgM (p), IgD (6), IgE (s), or IgA (a). In some embodiments, the Fc domain is derived from any one of the known heavy chain isotypes or subtypes: IgGi (y1), lgG2 (y2), lgG3 (y3), lgG4 (y4), IgAi (a1), lgA2 (a2). In some embodiments, the Fc domain is the Fc domain of human IgGi.

[0305] In some embodiments, the Fc domain comprises an uninterrupted native sequence (i.e., wild type sequence) of an Fc domain. In some embodiments, the immunoglobulin Fc domain comprises a variant Fc domain resulting in altered biological activity. For example, at least one point mutation or deletion may be introduced into the Fc domain so as to reduce or eliminate the effector activity (e.g., International Patent Publication No. WO 2005 / 063815), and / or to increase the homogeneity during the production of the recombinant binding protein. In some embodiments, the Fc domain is the Fc domain of human IgGi and comprises one or more of the following effector-null substitutions: L234A, L235A, and G237A (Eu numbering). In some embodiments, the Fc domain does not comprise the lysine located at the C- terminal position of human lgG1 (i.e., K447 by Eu numbering). The absence of the lysine may increase homogeneity during the production of the recombinant binding protein. In some embodiments, the Fc domain comprises the lysine located at the C-terminal position (K447, Eu numbering). In one embodiment, the recombinant binding protein of the invention further comprises a polypeptide tag. A polypeptide tag is an amino acid sequence attached to a polypeptide / protein, wherein said amino acid sequence is useful forthe purification, detection, ortargeting of said polypeptide / protein, orwherein said amino acid sequence improves the physicochemical behavior of the polypeptide / protein, or wherein said amino acid sequence possesses an effector function. The individual polypeptide tags of a binding protein may be connected to other parts of the binding protein directly or via a peptide linker. Polypeptide tags are all known in the art. Examples of polypeptide tags are small polypeptide sequences, for example, His, HA, myc, FLAG, or Strep-tags, or polypeptides such as enzymes (for example alkaline phosphatase), which allow the detection of said polypeptide / protein, or polypeptides which can be used for targeting (such as immunoglobulins or fragments thereof) and / or as effector molecules.

[0306] In another aspect, the invention relates to a nucleic acid encoding the amino acid sequence of an ankyrin repeat domain or a recombinant binding protein of the present invention. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of a recombinant binding protein of the present invention. In one embodiment, the invention relates to a nucleic acid encoding an amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 32. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 1. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 2. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 3. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 4. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 5. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 6. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 7. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 8. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 9. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO:10. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 11. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO:12. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 13. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 14. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 15. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 16. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 17. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 18. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 19. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 20. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 21. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 22. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 23. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 24. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 25. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 26. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 27. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 28. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 29. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 30. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 31. In one embodiment, the invention relates to a nucleic acid encoding the amino acid sequence of SEQ ID NO: 32.

[0307] Furthermore, the invention relates to vectors comprising any nucleic acid of the invention. Nucleic acids are well known to the skilled person in the art. In the examples, nucleic acids were used to produce designed ankyrin repeat domains or recombinant binding proteins of the invention in E. coli. Example nucleic acids of the invention are provided by SEQ ID NOs: 174 to 205 which encode the amino acid sequences of SEQ ID NOs: 1 to 32, respectively.

[0308] In one aspect, the invention relates to a pharmaceutical composition comprising a recombinant binding protein and / or a designed ankyrin repeat domain of the present invention, and / or a nucleic acid encoding a recombinant binding protein and / or a designed ankyrin repeat domain of the present invention, and optionally a pharmaceutically acceptable carrier and / or diluent.

[0309] In one embodiment, the invention relates to a pharmaceutical composition comprising a recombinant binding protein or a nucleic acid encoding a recombinant binding protein of the present invention, and optionally a pharmaceutically acceptable carrier and / or diluent.

[0310] Pharmaceutically acceptable carriers and / or diluents are known to the person skilled in the art and are explained in more detail below.

[0311] A pharmaceutical composition comprises a recombinant binding protein, and / or a designed ankyrin repeat domain, and / or a nucleic acid, preferably a recombinant binding protein and / or a nucleic acid, as described herein and a pharmaceutically acceptable carrier, excipient or stabilizer, for example as described in Remington's Pharmaceutical Sciences 16thedition, Osol, A. Ed., 1980.

[0312] Suitable carriers, excipients or stabilizers known to one of skill in the art include, for example, saline, Ringer's solution, dextrose solution, Hank's solution, fixed oils, ethyl oleate, 5% dextrose in saline, substances that enhance isotonicity and chemical stability, buffers and preservatives. Other suitable carriers include any carrier that does not itself induce the production of antibodies harmful to the individual receiving the composition such as proteins, polysaccharides, polylactic acids, polyglycolic acids, polymeric amino acids and amino acid copolymers. A pharmaceutical composition may also be a combination formulation, comprising an additional active agent, such as an anti-cancer agent or an anti-angiogenic agent, or an additional bioactive compound. The formulations to be used for in vivo administration must be aseptic or sterile. This is readily accomplished by filtration through sterile filtration membranes.

[0313] One embodiment of the present invention relates to the use of a recombinant binding protein of the present invention comprising an ankyrin repeat domain with binding specificity for CD117 and further comprising an ankyrin repeat domain with binding specificity for human serum albumin for manufacturing a pharmaceutical composition, wherein said recombinant binding protein exhibits an increased terminal half-life, preferably an increased terminal half-life of at least 5%, preferably 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, or 250%, compared to a corresponding recombinant binding protein comprising said ankyrin repeat domain with binding specificity for CD117 but not comprising said ankyrin repeat domain with binding specificity for serum albumin. In one embodiment of the invention, a recombinant binding protein comprises an ankyrin repeat domain having binding specificity for CD117 and further comprises two ankyrin repeat domains with binding specificity for serum albumin.

[0314] In one embodiment, a pharmaceutical composition comprises at least one recombinant binding protein as described herein and a detergent such as nonionic detergent, a buffer such as phosphate buffer, and a sugar such as sucrose. In one embodiment, such a composition comprises recombinant binding proteins as described above and PBS.

[0315] In one embodiment, the invention relates to a pharmaceutical composition, a recombinant binding protein, or a nucleic acid according to the present invention for use in the treatment of a disease. For that purpose, the pharmaceutical composition, the nucleic acid or the recombinant binding protein according to the present invention is administered to a patient in need thereof in a therapeutically effective amount. Administration may include topical administration, oral administration, and parenteral administration. The typical route of administration is parenteral administration. In parental administration, the pharmaceutical composition of this invention will be formulated in a unit dosage injectable form such as a solution, suspension or emulsion, in association with the pharmaceutically acceptable excipients as defined above. The dosage and mode of administration will depend on the individual to be treated and the particular disease.

[0316] Further, any of the above-mentioned pharmaceutical composition, nucleic acid or recombinant binding protein is considered for use in the treatment of a disorder.

[0317] In one embodiment, said recombinant binding protein or such other pharmaceutical composition described herein is applied intravenously. For parenteral application, the recombinant binding protein or said pharmaceutical composition can be injected as bolus injection or by slow infusion at a therapeutically effective amount.

[0318] In one embodiment, the invention relates to the use of the recombinant binding protein of the invention, the nucleic acid of the invention or the pharmaceutical composition of the invention for manufacturing of a medicament. In one embodiment, the invention relates to the use of the recombinant binding protein of the invention, the nucleic acid of the invention orthe pharmaceutical composition of the invention, for manufacturing of a medicament for the treatment of a disease. In one embodiment, the invention relates to a process for the manufacturing of a medicament for the treatment of a disease, wherein the recombinant binding protein of the invention, the nucleic acid of the invention or the pharmaceutical composition of the invention is an active ingredient of the medicament. In one embodiment, the invention relates to a method of treatment of a disease using the recombinant binding protein of the invention, the nucleic acid of the invention or the pharmaceutical composition of the invention.

[0319] The use of a recombinant binding protein of the present invention, a nucleic acid of the invention or a pharmaceutical composition of the invention for the treatment of cancer can also be in combination with one or more other therapies known in the art. The term “use in combination with”, as used herein, shall refer to a co-administration, which is carried out under a given regimen. This includes synchronous administration of the different compounds as well as time-shifted administration of the different compounds (e.g. compound A is given once and compound B is given several times thereafter, or vice versa, or both compounds are given synchronously and one of the two is also given at later stages).

[0320] In another aspect, the invention provides a method for treating a medical condition in a human patient, the method comprising administering to said patient a therapeutically effective amount of the binding protein of the invention, the nucleic acid of the invention or the pharmaceutical composition of the invention. In one embodiment said medical condition is conditioning of a mammal, preferably human, in need thereof. In one embodiment said medical condition is cancer.

[0321] In one particular embodiment, the medical condition is cancer, wherein the cancer or tumor tissue comprises cells that express or display a tumor-associated antigen, and said binding agent with binding specificity for a tumor-associated antigen binds said tumor-associated antigen expressed or displayed in said cells. In one particular embodiment, said tumor associated antigen is the extracellular domain of a cell surface protein expressed or overexpressed in said cancer or tumor tissue. In one embodiment, said cancer is selected from adenocarcinoma and squamous cell carcinoma. In one embodiment, said cancer is selected from osteosarcoma or osteogenic sarcoma (bone), chondrosarcoma (cartilage), leiomyosarcoma (smooth muscle), rhabdomyosarcoma (skeletal muscle), mesothelial sarcoma or mesothelioma (membranous lining of body cavities), fibrosarcoma (fibrous tissue), angiosarcoma or hemangioendothelioma (blood vessels), liposarcoma (adipose tissue), glioma or astrocytoma (neurogenic connective tissue found in the brain), myxosarcoma (primitive embryonic connective tissue), and mesenchymous or mixed mesodermal tumor (mixed connective tissue types). In one embodiment, said cancer is selected from myelogenous or granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series), lymphatic, lymphocytic, or lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series), and polycythemia vera or erythremia (malignancy of various blood cell products, but with red cells predominating). In one embodiment, said cancer is selected from Hodgkin lymphoma and non-Hodgkin lymphoma. In one embodiment, said cancer is selected from adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma and teratocarcinoma. In one embodiment, said cancer is selected from colorectal cancers, gastric cancers e.g gastrointestinal stromal tumors (GISTs), non-small cell lung cancers, breast cancers, head and neck cancer, ovarian cancers, lung cancers, invasive bladder cancers, pancreatic cancers, metastatic cancers of the brain, head and neck squamous cell carcinoma, esophagus squamous cell carcinoma, lung squamous cell carcinoma, skin squamous cell carcinoma, melanoma, breast adenocarcinoma, lung adenocarcinoma, cervix squamous cell carcinoma, pancreas squamous cell carcinoma, colon squamous cell carcinoma, or stomach squamous cell carcinoma, prostate cancer, osteosarcoma or soft tissue sarcoma and benign tumors. In one embodiment, such cancer is selected from epithelial malignancies (primary and metastatic), including lung, colorectal, gastric, bladder, ovarian and breast carcinomas, and bone and soft tissue sarcomas.

[0322] In another aspect, the invention provides a method of tumor-localized activation of immune cells, in a subject, preferably a human, the method comprising the step of administering to said mammal the CD117-specific recombinant binding protein or nucleic acid of the invention, wherein said binding protein further comprises a binding agent with binding specificity for a protein expressed on the surface of said immune cell.

[0323] In another aspect, the invention provides a method of diagnosing a medical condition in a mammal, preferably a human, the method comprising the steps of:

[0324] (i) contacting a cell or tissue sample obtained from said mammal with the CD117-specific recombinant binding protein of the invention; and

[0325] (ii) detecting specific binding of said binding protein to said cell or tissue sample.

[0326] In one embodiment, the invention relates to a kit comprising the recombinant binding protein of the invention. In one embodiment, the invention relates to a kit comprising a nucleic acid encoding the recombinant binding protein of the invention. In one embodiment, the invention relates to a kit comprising the pharmaceutical composition of the invention. In one embodiment, the invention relates to a kit comprising the recombinant binding protein of the invention, and / or the nucleic acid of the invention, and / or the pharmaceutical composition of the invention. In one embodiment, the invention relates to a kit comprising the recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117 of the invention, for example comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 32 and / or a nucleic acid encoding the recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117, for example comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 32, and / or a pharmaceutical composition comprising the recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117, for example comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 32.

[0327] In one embodiment, the invention relates to a method for producing a recombinant binding protein of the present invention. In one embodiment, the invention relates to a method for producing a recombinant binding protein, for example a recombinant binding protein comprising the amino acid sequence of any one of SEQ ID NOs: 1 to 32, the method comprising the steps of (i) expressing said recombinant binding protein in a suitable host cell (e.g., bacteria), and (ii) purifying said recombinant binding protein (e.g., using chromatography). Said method may comprise additional steps. Such a method of producing a recombinant binding protein of the present invention is described in Example 1.

[0328] The invention is not restricted to the particular embodiments described in the Examples. This specification refers to a number of amino acid sequences, nucleic acid sequences and SEQ ID NOs: 1 to 205 that are disclosed in the appended Sequence Listing, which forms part of the specification.

[0329] DEFINITIONS

[0330] Unless defined otherwise herein, all technical and scientific terms used herein shall have the meanings that are commonly understood by those of ordinary skill in the art to which the present invention belongs.

[0331] As used in the specification and claims, the singular form “a”, “an” and “the” include plural references unless the context clearly dictates otherwise.

[0332] Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", are used herein in their open- ended and non-limiting sense unless otherwise noted.

[0333] In each instance herein any of the terms "comprising", "consisting essentially of and "consisting of may be replaced with either of the other two terms.

[0334] All numerical designations, e.g., pH, temperature, time, concentration, and molecular weight, including ranges, are approximations which are varied (+) or (-) by increments of 0.1. It is to be understood, although not always explicitly stated that all numerical designations are preceded by the term “about”. It also is to be understood, although not always explicitly stated, that the reagents described herein are merely examples and that equivalents of such are known in the art.

[0335] In the context of the present invention the term "protein" refers to a molecule comprising a polypeptide, wherein at least part of the polypeptide has, or is able to acquire, a defined three-dimensional arrangement by forming secondary, tertiary, and / or quaternary structures within a single polypeptide chain and / or between multiple polypeptide chains. If a protein comprises two or more polypeptide chains, the individual polypeptide chains may be linked non-covalently or covalently, e.g. by a disulfide bond between two polypeptides. A part of a protein, which individually has, or is able to acquire, a defined three-dimensional arrangement by forming secondary and / or tertiary structure, is termed "protein domain". Such protein domains are known to the practitioner skilled in the art.

[0336] The term “recombinant” as used in recombinant protein, recombinant polypeptide and the like, means that said protein or polypeptide is produced by the use of recombinant DNA technologies known to the practitioner skilled in the art. For example, a recombinant DNA molecule (e.g. produced by gene synthesis) encoding a polypeptide can be cloned into a bacterial expression plasmid (e.g. pQE30, QIAgen), yeast expression plasmid, mammalian expression plasmid, or plant expression plasmid, or a DNA enabling in vitro expression. If, for example, such a recombinant bacterial expression plasmid is inserted into appropriate bacteria (e.g. Escherichia coli), these bacteria can produce the polypeptide(s) encoded by this recombinant DNA. The correspondingly produced polypeptide or protein is called a recombinant polypeptide or recombinant protein. In the context of the present invention, the term "binding protein" refers to a protein comprising a binding domain. A binding protein may also comprise two, three, four, five or more binding domains. Preferably, said binding protein is a recombinant binding protein. Binding proteins of the instant invention comprise an ankyrin repeat domain with binding specificity for CD117.

[0337] Furthermore, any such binding protein may comprise additional polypeptides (such as e.g. polypeptide tags, peptide linkers, fusion to other proteinaceous domains with binding specificity, cytokines, hormones, or antagonists), or chemical modifications (such as coupling to polyethylene-glycol, toxins (e.g. DM1 from Immunogen), small molecules, antibiotics and alike) known to the person skilled in the art.

[0338] The term “binding domain” means a protein domain exhibiting binding specificity for a target. Preferably, said binding domain is a recombinant binding domain.

[0339] The term "target" refers to an individual molecule such as a nucleic acid molecule, a polypeptide or protein, a carbohydrate, or any other naturally occurring molecule, including any part of such individual molecule, or to complexes of two or more of such molecules, or to a whole cell or a tissue sample, or to any non-natural compound. Preferably, a target is a naturally occurring or non-natural polypeptide or protein, or a polypeptide or protein containing chemical modifications, for example, naturally occurring or non-natural phosphorylation, acetylation, or methylation. In the context of the present invention, CD117 expressed in cancer cells or hematopoietic stem cells is the target of the CD117-specific binding proteins.

[0340] In the context of the present invention, the term "polypeptide" relates to a molecule consisting of a chain of multiple, i.e. two or more, amino acids linked via peptide bonds. Preferably, a polypeptide consists of more than eight amino acids linked via peptide bonds. The term “polypeptide” also includes multiple chains of amino acids, linked together by S-S bridges of cysteines. Polypeptides are known to the person skilled in the art.

[0341] Furthermore, the term “peptide” also encompasses peptides modified by, e.g, glycosylation, and proteins comprising two or more polypeptide chains, each of length of 4 to 600 amino acids long, crosslinked by, e.g., disulfide bonds, such as, e.g., insulin and immunoglobulins. The term "chemical or biochemical agent" is intended to include any naturally occurring or synthetic compound that may be administered to a recipient.

[0342] Patent application W02002 / 020565 and Forrer et al., 2003 (Forrer, P., Stumpp, M.T., Binz, H.K., Pluckthun, A., 2003. FEBS Letters 539, 2-6), contain a general description of repeat protein features and repeat domain features, techniques and applications. The term "repeat protein" refers to a protein comprising one or more repeat domains. Preferably, a repeat protein comprises one, two, three, four, five or six repeat domains. Furthermore, said repeat protein may comprise additional non-repeat protein domains, polypeptide tags and / or peptide linkers. The repeat domains can be binding domains.

[0343] The term "repeat domain" refers to a protein domain comprising two or more consecutive repeat modules as structural units, wherein said repeat modules have structural and sequence homology. Preferably, a repeat domain further comprises an N-terminal and / or a C-terminal capping module. For clarity, a capping module can be a repeat module. Such repeat domains, repeat modules, and capping modules, sequence motives, as well as structural homology and sequence homology are well known to the practitioner in the art from examples of ankyrin repeat domains (W02002 / 020565), leucine-rich repeat domains (W02002 / 020565), tetratricopeptide repeat domains (Main, E.R., Xiong, Y., Cocco, M.J., D'Andrea, L., Regan, L., Structure 11 (5), 497-508, 2003), and armadillo repeat domains (W02009 / 040338). It is further known to the practitioner in the art that such repeat domains are different from proteins comprising repeated amino acid sequences, where every repeated amino acid sequence is able to form an individual domain (for example FN3 domains of Fibronectin).

[0344] The term "designed" as used in designed repeat protein, designed repeat domain and the like refers to the property that such repeat proteins and repeat domains, respectively, are man-made and do not occur in nature. The binding proteins of the instant invention are designed ankyrin repeat proteins and they comprise at least one designed ankyrin repeat domain.

[0345] The term "target interaction residues" refers to amino acid residues of a repeat module, which contribute to the direct interaction with a target.

[0346] The term "framework residues" refers to amino acid residues of a repeat module, which contribute to the folding topology, i.e. which contribute to the fold of said repeat module or which contribute to the interaction with a neighboring module. Such contribution may be the interaction with other residues in the repeat module, or the influence on the polypeptide backbone conformation as found in a-helices or p-sheets, or the participation in amino acid stretches forming linear polypeptides or loops.

[0347] Such framework and target interaction residues may be identified by analysis of the structural data obtained by physicochemical methods, such as X-ray crystallography, NMR and / or CD spectroscopy, or by comparison with known and related structural information known to practitioners in structural biology and / or bioinformatics.

[0348] The term "repeat modules" refers to the repeated amino acid sequence and structural units of the designed repeat domains, which are originally derived from the repeat units of naturally occurring repeat proteins. Each repeat module comprised in a repeat domain is derived from one or more repeat units of a family or subfamily of naturally occurring repeat proteins, e.g. the family of ankyrin repeat proteins. Furthermore, each repeat module comprised in a repeat domain may comprise a “repeat sequence motif’ deduced from homologous repeat modules obtained from repeat domains selected on a target, e.g. as described in Example 1 , and having the same target specificity.

[0349] Accordingly, the term "ankyrin repeat module" refers to a repeat module, which is originally derived from the repeat units of naturally occurring ankyrin repeat proteins. Ankyrin repeat proteins are known to the person skilled in the art.

[0350] Repeat modules may comprise positions with amino acid residues which have not been randomized in a library for the purpose of selecting target-specific repeat domains ("non-randomized positions") and positions with amino acid residues which have been randomized in the library for the purpose of selecting target-specific repeat domains ("randomized positions"). The non-randomized positions comprise framework residues. The randomized positions comprise target interaction residues. “Have been randomized” means that two or more amino acids were allowed at an amino acid position of a repeat module, for example, wherein any of the usual twenty naturally occurring amino acids were allowed, or wherein most of the twenty naturally occurring amino acids were allowed, such as amino acids other than cysteine, or amino acids other than glycine, cysteine and proline. These positions are generally not substituted in the variants of the module sequences of SEQ ID NOs: 33 to 76 disclosed herein.

[0351] The term "repeat sequence motif refers to an amino acid sequence, which is deduced from one or more repeat modules. Preferably, said repeat modules are from repeat domains having binding specificity for the same target. Such repeat sequence motifs comprise framework residue positions and target interaction residue positions. Said framework residue positions correspond to the positions of framework residues of the repeat modules. Likewise, said target interaction residue positions correspond to the positions of target interaction residues of the repeat modules. Repeat sequence motifs comprise non-randomized positions and randomized positions.

[0352] The term “repeat unit” refers to amino acid sequences comprising sequence motifs of one or more naturally occurring proteins, wherein said "repeat units" are found in multiple copies, and exhibit a defined folding topology common to all said motifs determining the fold of the protein. Examples of such repeat units include leucine-rich repeat units, ankyrin repeat units, armadillo repeat units, tetratricopeptide repeat units, HEAT repeat units, and leucine-rich variant repeat units.

[0353] The term "antibody" means not only intact antibody molecules, but also any fragments and variants of antibody molecules that retain immunogen-binding ability. Such fragments and variants are also known in the art and are regularly employed both in vitro and in vivo. Accordingly, the term "antibody" encompasses intact immunoglobulin molecules, antibody fragments such as, e.g., Fab, Fab', F(ab')2, and single chain V region fragments (scFv), bispecific antibodies, chimeric antibodies, antibody fusion polypeptides, and unconventional antibodies.

[0354] Alternative scaffolds include any polypeptides or proteins comprising a binding domain that is capable of binding a target and that is not derived from an antibody or immunoglobulin molecule. The binding domain of alternative scaffolds may comprise or may be derived from a variety of different polypeptide or protein structures. Alternative scaffolds include, but are not limited to, adnectins (monobodies), affibodies, affilins, affimers and aptamers, affitins, alphabodies, anticalins, armadillo repeat proteinbased scaffolds, atrimers, avimers, ankyrin repeat protein-based scaffolds (such as DARPin proteins), fynomers, knottins, and Kunitz domain peptides. Alternative scaffolds are described, e.g., in Yu et al., Annu Rev Anal Chem (Palo Alto Calif). 2017 June 12; 10(1): 293-320. doi:10.1146 / annurevanchem- 061516-045205.

[0355] The term “binding specificity”, “has binding specificity for a target”, “specifically binding to a target”, “binding to a target with high specificity”, “specific for a target” or “target specificity” and the like means that a binding protein or binding domain binds to a target with a lower dissociation constant (i.e. it binds with higher affinity) than it binds to an unrelated protein such as the E. coli maltose binding protein (MBP). Preferably, the dissociation constant (“KD”) for the target is at least 102; more preferably, at least 103; more preferably, at least 104; or more preferably, at least 105times lower than the corresponding dissociation constant for MBP. Methods to determine dissociation constants of protein-protein interactions, such as surface plasmon resonance (SPR) based technologies (e.g. SPR equilibrium analysis) or isothermal titration calorimetry (ITC) are known to the person skilled in the art. The measured KD values of a particular protein-protein interaction can vary if measured under different conditions (e.g., salt concentration, pH). Thus, measurements of KD values are preferably made with standardized solutions of protein and a standardized buffer, such as PBS.

[0356] Binding of any molecule to another is governed by two forces, namely the association rate (kon) and the dissociation rate (koff). The affinity of any binder [B] to a target [T] can then be expressed by the equilibrium dissociation constant KD, which is the quotient of kotf / kon. kon is a second-order rate constant of the binding reaction, with the unit whereas the dissociation reaction koff is a first-order rate constant with the unit s~1. From this it becomes clear that the association reaction depends on the concentration of the reactants, whereas the dissociation is independent of the concentration, following a simple exponential decay function.

[0357] A variety of methods of measuring binding affinity are known in the art, any of which can be used for purposes of the present invention. For example, as exemplified herein, the binding affinity of a particular binding moiety to a drug molecule target can be expressed as KD value, which refers to the dissociation constant of the binding moiety and the drug molecule target. KD is the ratio of the rate of dissociation, also called the “off-rate (koff)”, to the association rate, or “on-rate (kon)”. Thus, KD equals k0ff / k0nand is expressed as a molar concentration (M), and the smaller the KD, the stronger the affinity of binding.

[0358] KD values can be determined using any suitable method. One exemplary method for measuring KD is surface plasmon resonance (SPR) (see, e.g., Nguyen et al. Sensors (Basel). 2015 May 5; 15(5):10481- 510). KD value may be measured by SPR using a biosensor system such as a BIACORE® system. BIAcore kinetic analysis comprises, e.g., analyzing the binding and dissociation of an antigen from chips with immobilized molecules (e.g., molecules comprising epitope binding domains), on their surface. Another method for determining the KD of a protein is by using Bio-Layer Interferometry (see, e.g., Shah et al. J Vis Exp. 2014; (84): 51383). A KD value may be measured using OCTET® technology (Octet QKe system, ForteBio). Alternatively, or in addition, a KinExA® (Kinetic Exclusion Assay) assay, available from Sapidyne Instruments (Boise, Id.) can also be used. Any method suitable for assessing the binding affinity between two binding partners is encompassed herein. Surface plasmon resonance (SPR) is particularly preferred. Most preferably, the KD values are determined in PBS and by SPR.

[0359] A typical and preferred determination of dissociation constants (KD) of the inventive recombinant binding proteins with binding specificity for CD117 by Surface Plasmon Resonance (SPR) analysis is described in Example 3.

[0360] The term “binding agent” refers to any molecule capable of specifically binding a target molecule. Binding agents include, for example, antibodies, antibody fragments, aptamers, peptides (e.g., Williams et al., J Biol Chem 266:5182-5190 (1991)), antibody mimics, repeat proteins, e.g. designed ankyrin repeat proteins, receptor proteins and any other naturally occurring interaction partners of the target molecule, and can comprise natural proteins and proteins modified or genetically engineered, e.g., to include non-natural residues and / or to lack natural residues.

[0361] The term “PBS” means a phosphate buffered water solution containing 137 mM NaCI, 10 mM phosphate and 2.7 mM KCI and having a pH of 7.4.

[0362] A “peptide linker” is an amino acid sequence, which is able to link, for example, two protein domains, a polypeptide tag and a protein domain, a protein domain and a non-proteinaceous compound or polymer such as polyethylene glycol, a protein domain and a biologically active molecule, a protein domain and a localizer, or two sequence tags. Peptide linkers are known to the person skilled in the art. A list of examples is provided in the description of patent application W02002 / 020565. Particular examples of such linkers are glycine-serine-linkers and proline-threonine-linkers of variable lengths. Examples of a glycine-serine-linker are the amino acid sequence GS and the amino acid sequence of SEQ ID NO: 152, and an example of a proline-threonine-linker is the amino acid sequences of SEQ ID NO: 151.

[0363] For the purpose of this disclosure, in order to determine the percent identity of two sequences (such as two polynucleotide or two polypeptide sequences), the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in a first sequence for optimal alignment with a second sequence). The nucleotides or amino acids at each position are then compared. When a position in the first sequence is occupied by the same amino acid or nucleotide as the corresponding position in the second sequence, then the amino acids or nucleotides are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions in the reference sequence x 100).

[0364] Typically, the sequence comparison is carried out over the length of the reference sequence. For example, if the user wished to determine whether a given (“test”) sequence is 95% identical to SEQ ID NO: 1 , SEQ ID NO: 1 would be the reference sequence. To assess whether a sequence is at least 80% identical to SEQ ID NO: 1 (an example of a reference sequence), the skilled person would carry out an alignment over the length of SEQ ID NO: 1 , and identify how many positions in the test sequence were identical to those of SEQ ID NO: 1. If at least 80% of the positions are identical, the test sequence is at least 80% identical to SEQ ID NO: 1 . If the sequence is shorter than SEQ ID NO: 1 , the gaps or missing positions should be considered to be non-identical positions.

[0365] The skilled person is aware of different computer programs that are available to determine the homology or identity between two sequences. For instance, a comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm. For example, the percent identity between two amino acid or nucleic acid sequences can be determined using the Needleman and Wunsch (1970) algorithm which has been incorporated into the GAP program in the Accelrys GCG software package (available at http: / / www.accelrys.com / products / gcg / ), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1 , 2, 3, 4, 5, or 6. One suitable set of parameters are a Blossum 62 scoring matrix with a gap penalty of 12, a gap extend penalty of 4, and a frameshift gap penalty of 5. The term “mouse serum albumin” refers to UniProt accession number P07724, the term “cynomolgus monkey serum albumin” (i.e. Macaca fascicularis) refers to UniProt accession number A2V9Z4, and the term “human serum albumin” refers to UniProt accession number P02768.

[0366] Preferably, clearance, and / or exposure, and / or terminal half-life are assessed in a mammal, more preferably mouse and / or cynomolgus monkey, more preferably cynomolgus monkey. Clearance, and / or exposure, and / or terminal half-life may be assessed as described in Example 3. Preferably, when measuring the clearance, and / or exposure, and / or terminal half-life in mouse, the evaluation is done considering the data up to 48 h post-injection. More preferably, the evaluation of terminal half-life in mouse is calculated from 24 h to 48 h. Preferably, when measuring the clearance, and / or exposure, and / or terminal half-life in cynomolgus monkey, the evaluation is done considering the data up to day 7 post-injection. More preferably, the evaluation of terminal half-life in cynomolgus monkey is calculated from day 1 to day 5. The person skilled in the art further is able to identify effects such as target- mediated clearance and consider them when calculating the terminal half-life. The term “terminal halflife” of a drug such as a recombinant binding protein of the invention refers to the time required to reach half the plasma concentration of the drug applied to a mammal after reaching pseudo-equilibrium (for example calculated from 24 hours to 48 hours in mouse or calculated from day 1 to day 5 in cynomolgus monkey). Terminal half-life is not defined as the time required to eliminate half the dose of the drug administered to the mammal. The term terminal half-life is known to the person skilled in the art. Preferably, pharmacokinetic comparison is done at any dose, more preferably at equivalent dose (i.e. same mg / kg dose) or equimolar dose (i.e. same mol / kg dose), more preferably at equimolar dose (i.e. same mol / kg dose). It is understood by the person skilled in the art that equivalent and / or equimolar dosing in animals is subject to experimental dose variations of at least 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100%. Preferably, a dose used for pharmacokinetic measurement is selected from 0.001 to 1000 mg / kg, more preferably 0.01 to 100 mg / kg, more preferably 0.1 to 50 mg / kg, more preferably 0.5 to 10 mg / kg.

[0367] The term “tumor-localized activation of immune cells” means that immune cells are activated preferentially in tumor tissue as compared to a non-tumor tissue.

[0368] The term “treat” and “treatment” refer to both therapeutic treatment and prophylactic or preventive measures, wherein the object is to prevent or slow down an undesired physiological change or disorder. For purpose of this invention, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. “Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. In other embodiments the terms “treat”, “treatment” and “treating” refer to the inhibition of the progression of a proliferative disorder, either physically by, e.g., stabilization of a discernible symptom, physiologically by, e.g., stabilization of a physical parameter, or both. In other embodiments the terms “treat”, “treatment” and “treating” refer to the reduction or stabilization of tumor size or cancerous cell count.

[0369] The term “medical condition" (or disorder or disease) includes autoimmune disorders, inflammatory disorders, retinopathies (particularly proliferative retinopathies), neurodegenerative disorders, infections, metabolic diseases, and neoplastic diseases. Any of the recombinant binding proteins described herein may be used for the preparation of a medicament for the treatment of such a disorder, particularly a disorder selected from the group comprising: an autoimmune disorder, an inflammatory disorder, an immune disorder, and a neoplastic disease. A “medical condition” may be one that is characterized by inappropriate cell proliferation. A medical condition may be a hyperproliferative condition. The invention particularly relates to a method of treating a medical condition, the method comprising the step of administering, to a patient in need of such treatment, a therapeutically effective amount of a recombinant binding protein or said pharmaceutical composition of the invention. In a preferred embodiment said medical condition is a neoplastic disease. The term "neoplastic disease", as used herein, refers to an abnormal state or condition of cells or tissue characterized by rapidly proliferating cell growth or neoplasm. In one embodiment said medical condition is a malignant neoplastic disease. In one embodiment said medical condition is a need for conditioning of a mammal, preferably a human, for a stem cell transplant, e.g. a hematopoietic stem cell transplant. In one embodiment said medical condition is a cancer. The term “therapeutically effective amount” means an amount that is sufficient to produce a desired effect on a patient.

[0370] The terms "cancer" and "cancerous" are used herein to refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth. Cancer encompasses solid tumors and liquid tumors, as well as primary tumors and metastases. A "tumor" comprises one or more cancerous cells. Solid tumors typically also comprise tumor stroma. Examples of cancer include, but are not limited to, primary and metastatic carcinoma, lymphoma, blastoma, sarcoma, and leukemia, and any other epithelial and lymphoid malignancies. More particular examples of such cancers include brain cancer, bladder cancer, breast cancer, ovarian cancer, clear cell kidney cancer, head / neck squamous cell carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, malignant melanoma, non-small-cell lung cancer (NSCLC), ovarian cancer, pancreatic cancer, prostate cancer, renal cell carcinoma, small-cell lung cancer (SCLC), breast cancer, acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, Hodgkin's lymphoma (HL), mantle cell lymphoma (MCL), multiple myeloma (MM), myelodysplastic syndrome (MDS), non-Hodgkin's lymphoma (NHL), Squamous Cell Carcinoma of the Head and Neck (SCCHN), chronic myelogenous leukemia (CML), small lymphocytic lymphoma (SLL), malignant mesothelioma, colorectal cancer, or gastric cancer.

[0371] EXAMPLES

[0372] Starting materials and reagents disclosed below are known to those skilled in the art, are commercially available and / or can be prepared using well-known techniques. Materials

[0373] Chemicals were purchased from Sigma-Aldrich (USA). Oligonucleotides were from Microsynth (Switzerland). Unless stated otherwise, DNA polymerases, restriction enzymes and buffers were from New England Biolabs (USA) or Fermentas / Thermo Fisher Scientific (USA). Inducible E. coli expression strains were used for cloning and protein production, e.g. E. coli XL1-blue (Stratagene, USA) or BL21 (Novagen, USA).

[0374] Molecular Biology

[0375] Unless stated otherwise, methods are performed according to known protocols (see, e.g., Sambrook J., Fritsch E.F. and Maniatis T., Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory 1989, New York).

[0376] Designed ankyrin repeat protein libraries

[0377] Methods to generate designed ankyrin repeat protein libraries have been described, e.g. in U.S. Patent No. 7,417,130; Binz et al. 2003, loc. cit.; Binz et al. 2004, loc. cit. By such methods designed ankyrin repeat protein libraries having randomized ankyrin repeat modules and / or randomized capping modules can be constructed. For example, such libraries could accordingly be assembled based on a fixed N- terminal capping module (e.g. the N-terminal capping module of any of SEQ ID NOs: 77 to 98) or a randomized N-terminal capping module (e.g. the N-terminal capping module of SEQ ID NO: 99), and a fixed C-terminal capping module (e.g. the C-terminal capping module of SEQ ID NOs: 100 to 144) or a randomized C-terminal capping module (e.g. the Ce-terminal capping module of SEQ ID NO: 145). Preferably, such libraries are assembled to not have any of the amino acids C, G, M, N (in front of a G residue) and P at randomized positions of repeat or capping modules.

[0378] Furthermore, such randomized modules in such libraries may comprise additional polypeptide loop insertions with randomized amino acid positions. Examples of such polypeptide loop insertions are complementarity determining region (CDR) loop libraries of antibodies or de novo generated peptide libraries. For example, such a loop insertion could be designed using the structure of the N-terminal ankyrin repeat domain of human ribonuclease L (Tanaka, N., Nakanishi, M, Kusakabe, Y, Goto, Y., Kitade, Y, Nakamura, K.T., EMBO J. 23(30), 3929-3938, 2004) as guidance. In analogy to this ankyrin repeat domain where ten amino acids are inserted in the beta-turn present close to the boarder of two ankyrin repeats, ankyrin repeat proteins libraries may contain randomized loops (with fixed and randomized positions) of variable length (e.g. 1 to 20 amino acids) inserted in one or more beta-turns of an ankyrin repeat domain.

[0379] Any such N-terminal capping module of an ankyrin repeat protein library preferably possesses the RILLAA, RILLKA or RELLKA motif (e.g. present from position 21 to 26 in SEQ ID NO: 1) and any such C-terminal capping module of an ankyrin repeat protein library preferably possesses the KLN, KLA or KAA motif (e.g. present at the last three amino acids in SEQ ID NO: 1). SEQ ID NOs: 77 to 98 provide examples of N-terminal capping modules comprising the RILLAA, RILLKA or RELLKA motif, and SEQ ID NOs: 100 to 144 provide examples of C-terminal capping modules comprising the KLN, KLA or KAA motif. The design of such an ankyrin repeat protein library may be guided by known structures of an ankyrin repeat domain interacting with a target. Examples of such structures, identified by their Protein Data Bank (PDB) unique accession or identification codes (PDB-IDs), are 1 WDY, 3V31 , 3V30, 3V2X, 3V2O, 3UXG, 3TWQ-3TWX, 1 N11 , 1 S70 and 2ZGD.

[0380] Examples of designed ankyrin repeat protein libraries, such as N2C and N3C designed ankyrin repeat protein libraries, have been described (U.S. Patent No. 7,417,130; Binz et al. 2003, loc. cit.; Binz et al. 2004, loc. cit.). The digit in N2C and N3C describes the number of randomized repeat modules present between the N-terminal and C-terminal capping modules.

[0381] The nomenclature used to define the positions inside the repeat units and modules is based on Binz et al. 2004, loc. cit. with the modification that borders of the ankyrin repeat modules and ankyrin repeat units are shifted by one amino acid position. For example, position 1 of an ankyrin repeat module of Binz et al. 2004 (loc. cit.) corresponds to position 2 of an ankyrin repeat module of the current disclosure and consequently position 33 of an ankyrin repeat module of Binz et al. 2004, loc. cit. corresponds to position 1 of a following ankyrin repeat module of the current disclosure.

[0382] All the DNA sequences were confirmed by sequencing, and the calculated molecular weight of selected proteins was confirmed by mass spectrometry.

[0383] Example 1 : Selection of binding proteins comprising an ankyrin repeat domain with binding specificity for CD117

[0384] Using ribosome display (Hanes, J. and Pluckthun, A., PNAS 94, 4937-42, 1997), many ankyrin repeat proteins with binding specificity for human CD117 were selected from DARPin libraries similar as described by Binz et al. 2004 (loc. cit.). The binding of the selected clones towards recombinant human CD117 target was assessed by crude extract Homogeneous Time Resolved Fluorescence (HTRF), indicating that hundreds of human CD117-specific binding proteins were successfully selected. For example, the ankyrin repeat domain of SEQ ID NO: 1 constitutes an amino acid sequence of a selected binding protein comprising an ankyrin repeat domain with binding specificity for CD117. Individual ankyrin repeat modules from such ankyrin repeat domains with binding specificity to CD117 are provided, e.g., in SEQ ID NOs: 1 to 32.

[0385] Human recombinant CD117 target preparation

[0386] Two target formats were used (purchased from AcroBiosystems). Both are based on single chain, consisting of the extracellular domain of human CD117 protein (UniProt Accession Nr: P10721-2, residues 26 to 516).

[0387] The extracellular domain was linked in the first format to a human IgG 1 Fc domain and in the second format to a polyhistidine tag followed by a C-terminal Avi-tag (SEQ ID NO: 154 for CD117-Fc and SEQ ID NO:153 for CD117-His). Both target formats were expressed in HEK293 cells (Human Embryonic Kidney cells) and purified by the provider. The Fc-tagged material was in vitro biotinylated using recombinant BirA and the final material was stored at the final concentration of 0.18 mg / ml. The storage buffer was 50 mM Tris, 100 mM glycine, 25 mM arginine, 150 mM NaCI, pH7.5. The His-tagged material was purchased biotinylated and stored at the final concentration of 0.23 mg / ml. The storage buffer was PBS pH7.4 with 10% Trehalose.

[0388] Selection of CD117-specific ankyrin repeat proteins by ribosome display

[0389] The selection of CD117-specific ankyrin repeat proteins was performed by ribosome display (Hanes and Pluckthun, loc. cit.) using the extracellular domain of CD117 (SEQ ID NO:155) as target protein, libraries of ankyrin repeat proteins as described above, and established protocols (see, e.g., Zahnd, C., Amstutz, P. and Pluckthun, A., Nat. Methods 4, 69-79, 2007). The number of reverse transcription (RT)- PCR cycles after each selection round was constantly reduced, adjusting to the yield due to enrichment of binders. The first four rounds of selection employed standard ribosome display selection, using decreasing target concentration (389 nM (hCD117-Fc) or 226 nM (hCD117-His), 100 nM, 25 nM and 5 nM, respectively), followed by a 5thoff rate round using a target concentration of 1 nM and a 6threcovery round at a target concentration of 5 nM.

[0390] The ribosome display output was subcloned into a derivative of the pQE30 (Qiagen) expression vector containing an N-terminal His-tag followed by a Flag-tag. Ribosome display rounds 4 and 6 were screened by HTRF of ankyrin repeat proteins crude extracts expressed in E. coli. Selected hits were re-arrayed on 4 plates, purified using their His-tag in 96 well format and binding was confirmed by HTRF. 16 selected binders were subcloned into a derivative of the pQE30 (Qiagen) expression vector containing an N-terminal His-tag (SEQ ID NO: 146) and purified on an AKTAxpress™ system for in- depth characterization.

[0391] For example, expression vectors encoding the following ankyrin repeat proteins were constructed: DARPin protein #1 (SEQ ID NO: 1 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0392] DARPin protein #2 (SEQ ID NO: 2 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0393] DARPin protein #3 (SEQ ID NO: 3 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0394] DARPin protein #4 (SEQ ID NO: 4 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0395] DARPin protein #5 (SEQ ID NO: 5 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0396] DARPin protein #6 (SEQ ID NO: 6 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0397] DARPin protein #7 (SEQ ID NO: 7 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0398] DARPin protein #8 (SEQ ID NO: 8 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0399] DARPin protein #9 (SEQ ID NO: 9 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0400] DARPin protein #10 (SEQ ID NO: 10 with a His-tag (SEQ ID NO: 146) fused to its N terminus) DARPin protein #11 (SEQ ID NO:11 with a His-tag (SEQ ID NO: 146) fused to its N terminus) DARPin protein #12 (SEQ ID NO: 12 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0401] DARPin protein #13 (SEQ ID NO: 13 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0402] DARPin protein #14 (SEQ ID NO: 14 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0403] DARPin protein #15 (SEQ ID NO: 15 with a His-tag (SEQ ID NO: 146) fused to its N terminus)

[0404] DARPin protein #16 (SEQ ID NO: 16 with a His-tag (SEQ ID NO: 146) fused to its N terminus) Selected clones show binding to CD117 target (shown by HTRF)

[0405] In a first screening step, the pools from the ribosome display were expressed in Escherichia coli cells in 96 well plates. 16 plates with designed ankyrin repeat proteins from ribosome display round 4 and 24 plates from round 6 were expressed with a Flag-tag and a His-tag. Crude extracts thereof were prepared to test binding of the Flag-tagged designed ankyrin repeat proteins to human CD117 target protein in an HTRF (Homogeneous Time Resolved Fluorescence) assay. Briefly, E. coli XL1 blue cells were transformed with the ankyrin repeat proteins, plated on LB-agar (containing 1 % glucose and 50 pg / ml ampicillin) and then incubated overnight at 37°C. For each construct, a single colony was picked into an individual well of a 96-deep-well plate with 1.2 mL TB medium (containing 1 % glucose and 50 pg / ml ampicillin) and incubated overnight at 37°C, under shaking at 230 rpm. Fresh TB medium (containing 50 pg / ml ampicillin; 0.99 mL per well of a 96-deep-well plate) was inoculated with overnight culture (1 :10) and incubated at 37°C at 230 rpm. After 2 h the culture was induced by addition of IPTG (Isopropyl p-D-thiogalactoside, 0.5 mM final concentration) and incubated for further 5-6 h at 37°C 230 rpm. Cell harvest was done by centrifugation (6 min 5000 x g) followed by cell disruption with 10 pl B- PER™ II Bacterial Protein Extraction Reagent (Cat. No. 78260; Thermo Fisher Scientific, Waltham, Massachusetts, United States; supplemented with DNAse I (200 Units / ml) and lysozyme (0.4 mg / ml)) according to the manufacturer’s protocol and addition of 150 pl PBS, pH7.4. The crude extracts were used at 1 :3000 dilution (final) in the assay. Protein binding was performed against 5 nM (final concentration) of human biotinylated CD117-His with 1 :400 (final concentration) of streptavidin-Tb FRET donor conjugate (Cisbio) and 1 :400 (final concentration) of mAb Anti Flag M2-d2 FRET acceptor conjugate (Cisbio) in a well of a 384-well plate and incubated for 60 minutes at room temperature (RT). The HTRF was read-out on a Tecan M1000 using a 340 nm excitation wavelength and a 665 ±10 nm emission filter. All dilutions were prepared in PBS-TB (PBS, pH 7.4 containing 0.2% BSA and 0.1 % Tween 20®).

[0406] Four plates with ankyrin repeat proteins were again expressed in E. coli cells and purified on 96 well plates using their His-tag according to standard protocols. Briefly, E. coli XL1 blue cells were transformed with the ankyrin repeat proteins, plated on LB-agar (containing 1 % glucose and 50 pg / ml ampicillin) and then incubated overnight at 37°C. For each construct, a single colony was picked into an individual well of a 96-deep-well plate with 1 .2 mL TB medium (containing 1 % glucose and 50 pg / ml ampicillin) and incubated overnight at 37°C, shaking at 230 rpm. Fresh TB medium (containing 50 pg / ml ampicillin; 0.99 mL per well of a 96-deep-well plate) was inoculated with overnight culture (1 :10) and incubated at 37°C at 230 rpm. After 2 h the culture was induced by addition of IPTG (0.5 mM final concentration) and incubated for further 5-6 h at 37°C 230 rpm. Harvest was done by centrifugation (6 min 5000 x g). After cell disruption with 50 pl B-PER™ II Bacterial Protein Extraction Reagent (Cat. No. 78260; Thermo Fisher Scientific, Waltham, Massachusetts, United States; supplemented with DNAse I (200 Units / ml) and lysozyme (0.4 mg / ml)) according to the manufacturer’s protocol and addition of 60 pl IMAC adjusting buffer (Na2HPO4 x 2H2O 50 mM, NaCI 300 mM, pH7.4), the clones were purified with via 96-well column IMAC plate (HisPur™ Cobalt Spin Plates, Cat. No: 90095; Thermo Fisher Scientific, Waltham, Massachusetts, United States) and re-buffered into PBS, pH7.4 with a Zeba Spin de-salting 96-well plate (Cat. No: 89807; Thermo Fisher Scientific, Waltham, Massachusetts, United States), all according to the manufacturer’s protocol. The purified DARPin proteins were tested again in HTRF. The biotinylated human target and the DARPins were used at 2.5nM with 1 :400 (final concentration) of streptavidin-Tb donor conjugate (Cisbio) and 1 :400 (final concentration) of MAb Anti Flag M2-d2 HTRF FRET acceptor conjugate (Cisbio) in a well of a 384-well plate and incubated for 60 minutes at RT. The HTRF was read-out on a Tecan M1000 using a 340 nm excitation wavelength and a 665 ±10 nm emission filter. All dilutions were prepared in PBS-TB (PBS, pH 7.4 containing 0.2% BSA and 0.1 % Tween 20®). Amino acid sequences of selected ankyrin repeat domains that specifically bind to CD117 are provided in SEQ ID NOs: 1 to 16.

[0407] Sequence engineering of selected CD117 binding designed ankyrin repeat proteins

[0408] In a further step, five of the above selected designed ankyrin repeat proteins with binding specificity for CD117, namely DARPin proteins #1 to #5, were sequence engineered in order to improve serum halflife and biophysical properties and the following designed ankyrin repeat proteins were produced:

[0409] DARPin protein #17 (SEQ ID NO: 17) DARPin protein #18 (SEQ ID NO: 18) DARPin protein #19 (SEQ ID NO: 19) DARPin protein #20 (SEQ ID NO: 20) DARPin protein #21 (SEQ ID NO: 21) DARPin protein #22 (SEQ ID NO: 22) DARPin protein #23 (SEQ ID NO: 23) DARPin protein #24 (SEQ ID NO: 24) DARPin protein #25 (SEQ ID NO: 25) DARPin protein #26 (SEQ ID NO: 26) DARPin protein #27 (SEQ ID NO: 27) DARPin protein #28 (SEQ ID NO: 28) DARPin protein #29 (SEQ ID NO: 29) DARPin protein #30 (SEQ ID NO: 30) DARPin protein #31 (SEQ ID NO: 31) DARPin protein #32 (SEQ ID NO: 32)

[0410] Cell binding by selected CD117-binding designed ankyrin repeat proteins

[0411] Several of the above selected designed ankyrin repeat proteins were further tested for CD117 specific cell binding. CD117 binding was confirmed by a cell binding assay using a cancer cell line expressing CD117, TF-1 cells (CL0022, ATCC). In brief, the CD117 expressing cells were washed Ix with 500 pl PBS, spun at 350xg for 5 minutes and the supernatant was discarded. Then, a titration of selected CD117 designed ankyrin repeat proteins diluted in FACS buffer was added to the pellet of cells, resuspended and incubated for 30 minutes at 4°C. The cells were washed twice with 200 pl cold PBS, spun at 350g for 5 minutes and the supernatant was discarded. 50 pl of anti-DARPin antibody AF-647 with live / dead aqua (1 :3000), was added to the cells and incubated for 30 mins at 4°C, in the dark. Then the cells were washed twice in 200 pl ice cold PBS and spun for 4 min at 400g. 50 pl of cell fix was added and the cells were incubated for 60 min at 4°C, then they were washed with PBS / 2mM EDTA, spun for 5 min at 500g and resuspended in 200 pl of PBS / 2mM EDTA. Flow cytometry analysis was performed using a Attune Nxt Flow Cytometer. All tested proteins show specific binding to the CD117 target on cells as shown in Figure 2 and Table 2.

[0412] Table 2: Cell binding of selected CD117-binding designed ankyrin repeat proteins.

[0413] Additionally, CD117 specific DARPin proteins #1 to 5 and engineered variants thereof were also tested in a cell binding assay, as described above, using a cancer cell line expressing CD117 (Kasumi-1 cells). As shown in the Figure 3 and Table 3, no loss of their binding capacity to its target on cells was observed for the engineered ankyrin repeat protein variants compared to the parental ankyrin repeat protein.

[0414] Table 3: EC50 values for CD117 parental and engineered DARPin proteins.

[0415] Example 2: Stability assessment of exemplary CD117-specific ankyrin repeat proteins

[0416] The above selected CD117-specific designed ankyrin repeat proteins were subcloned into a derivative of the pQE30 (Qiagen) expression vector containing an N-terminal His-tag. They were expressed in E. coli cells and purified using their His-tag according to standard protocols. Briefly, E. coli BL21 cells were transformed with the ankyrin repeat proteins, plated on LB-agar (containing 1 % glucose and 50 pg / ml ampicillin) and then incubated overnight at 37°C. For each construct, a single colony was picked into 25 ml of TB medium (containing 1 % glucose and 50 pg / ml of ampicillin) and incubated overnight at 37°C, shaking at 220 rpm. The stationary overnight cultures were used to inoculate 500 ml TB medium (containing 50 pg / ml ampicillin) and incubated at 37°C, shaking at 220 rpm. At an absorbance of 1 .0 to 1 .5 at 600 nm, the cultures were induced with 0.5 mM IPTG and incubated further for 4-5 h. The cultures were centrifuged, and the resulting pellets were re-suspended in 25 ml of TBS500 (50 mM Tris-HCI, 500 mM NaCI, pH 8) and lysed (sonication). Following the lysis, the samples were mixed with 50 KU DNase / ml and incubated for 15 minutes prior to a heat-treatment step for 30 minutes at 62.5°C, centrifuged and the supernatant was collected and filtrated. Tergitol (1 % (v / v) final concentration) and imidazole (20 mM final concentration) were added to the homogenate. Proteins were purified over a Ni- nitrilotriacetic (Ni-NTA) acid column followed by a size exclusion chromatography on an AKTAxpress™ system according to standard protocols and resins known to the person skilled in the art. The proteins were soluble and monomeric when concentrated to 10 mg / ml.

[0417] The proteins were further analysed in-depth to assess their biophysical properties. In brief, KTA purified CD117-specific ankyrin repeat proteins in PBS, pH7.4 were aliquoted into sterile glass vials (Schmidlin: LPP 11 09 0620) and stressed by incubation at 60°C for 1 week or 50°C for 18 days. The applied stress conditions allow a prediction of the biophysical properties after 2 years storage at 4°C. For each CD117-specific ankyrin repeat protein, an aliquot was stored at -70°C as a reference. The reference and the heat-stressed samples were exposed to one freeze-thaw cycle before analysis. The samples were evaluated for multimerization, aggregation and fragmentation by SDS-PAGE and analytic SEC. Stressed samples were then compared to the respective reference samples. No colour change, turbidity or precipitation was detected by visual inspection. Furthermore, no significant degradation or multimerization was detected for most of the tested proteins. The experimental data demonstrated that samples were stable in the applied stress conditions. Thermal stability assessment of exemplary CD117-specific ankyrin repeat proteins using Circular Dichroism (CD) spectroscopy

[0418] The same CD117-specific ankyrin repeat proteins were also assessed for their thermal stability and unfolding / refolding propensity using a Jasco J-815 spectrophotometer (non-stressed proteins only). The Tm (melting temperature) of the selected proteins was determined by CD as a parameter for thermal stability. The ellipticity was recorded at 222 nM and a temperature range from 20°C to 90°C was applied followed by reverse scan to record the refolding behaviour. The Tm of the selected CD117-specific ankyrin repeat proteins is the midpoint of the protein unfolding. Spectra from 190-250nm were recorded before and after the temperature scan. Samples were prepared at a concentration of 2 pM in PBS, pH7.4. As can be seen in Table 4 for all tested proteins, a Tm higher than 70°C was obtained.

[0419] Table 4: Tm(melting temperature) of eleven ex...

Claims

CLAIMS1 . A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117, wherein said ankyrin repeat domain comprises an ankyrin repeat module comprising an amino acid sequence selected from the group consisting of (1) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any of SEQ ID NOs: 33 to 76 are substituted by other amino acids.

2. The recombinant binding protein of claim 1 , wherein said ankyrin repeat domain comprises a first ankyrin repeat module and a second ankyrin repeat module, optionally wherein said first ankyrin repeat module is located N-terminally of said second ankyrin repeat module within said ankyrin repeat domain.

3. The recombinant binding protein of claim 2, wherein(i) 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids;(ii) said first 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 in SEQ ID NO: 33 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: 34 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 34 are substituted by other amino acids;(iii) said first 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 in SEQ ID NO: 35 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids;(iv) said first 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 in SEQ ID NO: 37 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: 38 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 38 are substituted by other amino acids;(v) said first 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 in SEQ ID NO: 39 are substituted by other amino acids, and wherein said second ankyrin repeat module comprisesan amino acid sequence selected from the group consisting of (1) SEQ ID NO: 40 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 40 are substituted by other amino acids;(vi) said first 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 in SEQ ID NO: 41 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: 42 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 42 are substituted by other amino acids;(vii) first 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 in SEQ ID NO: 43 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: 44 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 44 are substituted by other amino acids;(viii) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 56 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 56 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: 57 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 57 are substituted by other amino acids.(ix) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 58 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 58 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: 59 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 59 are substituted by other amino acids;(x) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 60 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 60 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: 61 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 61 are substituted by other amino acids;(xi) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 71 and (2) sequences in which up to 9 amino acids in SEQ ID NO:71 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids;(xii) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 72 and (2) sequences in which up to 9 amino acids in SEQ ID NO:72 are substituted by other amino acids, and wherein said second ankyrin repeat module comprisesan amino acid sequence selected from the group consisting of (1) SEQ ID NO: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids;(xiii) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 73 and (2) sequences in which up to 9 amino acids in SEQ ID NO:73 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids;(xiv) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 74 and (2) sequences in which up to 9 amino acids in SEQ ID NO:74 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids;(xv) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 75 and (2) sequences in which up to 9 amino acids in SEQ ID NO:75 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: 36 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 36 are substituted by other amino acids; or(xvi) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 76 and (2) sequences in which up to 9 amino acids in SEQ ID NO:76 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: 42 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 42 are substituted by other amino acids.

4. The recombinant binding protein of claim 1 , wherein said ankyrin repeat domain comprises a first ankyrin repeat module, a second ankyrin repeat module and a third ankyrin repeat module, optionally wherein 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.

5. The recombinant binding protein of claim 4, 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) any one of SEQ ID NOs: 33 to 76 and (2) sequences in which up to 9 amino acids in any one of SEQ ID NOs: 33 to 76 are substituted by other amino acids.

6. The recombinant binding protein of any one of claims 4 to 5, wherein(i) said first 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 in SEQ ID NO: 45 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: 46 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 46 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: 47 and (2) sequences in which up to 9 amino acids of SEQ ID NO:47 are substituted by other amino acids;(ii) 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, 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, and wherein said third 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 of SEQ ID NO:50 are substituted by other amino acids;(iii) said first 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 in SEQ ID NO:51 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: 52 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 52 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: 53 and (2) sequences in which up to 9 amino acids of SEQ ID NO:53 are substituted by other amino acids;(iv) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 54 and (2) sequences in which up to 9 amino acids in SEQ ID NO:54 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: 55 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 55 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: 53 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 53 are substituted by other amino acids;(v) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 62 and (2) sequences in which up to 9 amino acids in SEQ ID NO: 62 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: 63 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 63 are substituted by other amino acids, and whereinsaid third ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 64 and (2) sequences in which up to 9 amino acids of SEQ ID NO:64 are substituted by other amino acids;(vi) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 65 and (2) sequences in which up to 9 amino acids in SEQ ID NO:65 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: 66 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 66 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: 67 and (2) sequences in which up to 9 amino acids of SEQ ID NO:67 are substituted by other amino acids;(vii) said first ankyrin repeat module comprises an amino acid sequence selected from the group consisting of (1) SEQ ID NO: 68 and (2) sequences in which up to 9 amino acids in SEQ ID NO:68 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: 69 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 69 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: 70 and (2) sequences in which up to 9 amino acids of SEQ ID NO: 70 are substituted by other amino acids.

7. A recombinant binding protein comprising an ankyrin repeat domain with binding specificity for CD117, 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 32, and wherein A at the second last position of SEQ ID NOs: 1 to 32 is optionally substituted by L, and / or A at the last position of SEQ ID NOs: 1 to 32 is optionally substituted by N.

8. The recombinant binding protein of claim 7, wherein(i) said recombinant binding protein competes with Stem Cell Factor in binding to CD117 target, 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 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 and wherein A at the second last position of any one of SEQ ID NOs: 1 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 is optionally substituted by L, and / or A at the last position of any one of SEQ ID NOs: 1 , 2, 5, 6, 7, 9, 10, 12, 14 or 15 is optionally substituted by N; or(ii) said recombinant binding protein does not compete with Stem Cell Factor in binding to CD117 target, 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: 3, 4, 11 or 13 and wherein A at the second last position of any one of SEQ ID NOs: 3, 4, 11 or 13 is optionallysubstituted by L, and / or A at the last position of any one of SEQ ID NOs: 3, 4, 11 or 13 is optionally substituted by N.

9. The recombinant binding protein of any one of the preceding claims, wherein said binding protein binds human CD117 in PBS with a dissociation constant (KD) of or below about 10-8M.

10. The recombinant 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 wherein said protein expressed on the surface of an immune cell is CD16a.11 . The recombinant binding protein of claim 10, wherein said binding agent with binding specificity for a protein expressed on the surface of an immune cell is an ankyrin repeat domain, 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 SEQ ID NO: 156.

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

13. The recombinant binding protein of claim 12, wherein said half-life extending moiety comprises a binding agent with binding specificity for human serum albumin, optionally wherein said binding agent with binding specificity for human serum albumin is an ankyrin repeat domain.

14. The recombinant binding protein of claim 13, 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: 148 to 150.

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

16. A cloning or expression vector comprising the nucleic acid according to claim 15.

17. A host cell comprising the nucleic acid according claim 15 or the vector according to claim 16.

18. A method of producing a recombinant binding protein of any one of claims 1 to 14, the method comprising culturing the cell of claim 17 and collecting the recombinant binding protein from the cell and / or the culture medium.

19. A pharmaceutical composition comprising the binding protein of any one of claims 1 to 14 or the nucleic acid of claim 15, and optionally a pharmaceutically acceptable carrier and / or diluent.20 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 binding protein of any one of claims 1 to 14, the nucleic acid of claim 15 or the pharmaceutical composition of claim 19.

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