CLAIMS

1. A binding agent specifically binding the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), which upon binding increases the thermal stability of CFTR with at least 5°C as compared to non-bound CFTR under the same conditions, and wherein the CFTR binding site comprises amino acid residues 457, 459, 550-551, 576-581, 605-608, 610, 618, 625, and 633, or comprises amino acid residues 472, 474, 490, 494-499, 508-510, 560, and 564 as set forth in SEQ ID NO:l.

2. The binding agent according to claim 1, wherein said binding agent is a small compound, a chemical, a peptide, a peptidomimetic, an antibody mimetic, an immunoglobulin single variable domain (ISVD) or an active antibody fragment.

3. The binding agent of claims 1 or 2, wherein said binding agent is an ISVD comprising 4 framework regions (FR) and 3 complementarity determining regions (CDR) according to the following formula (1): FR1-CDR1-FR2-CDR2-FR3-CDR3-FR4 (1);

and wherein CDR1 consists of a sequence selected from the group of SEQ I D NO: 9, 16, 23, 30, 37, 44; CDR2 consists of a sequence selected from the group of SEQ ID NO: 11, 18, 25, 32, 39, 46; and CDR3 consists of a sequence selected from the group of SEQ ID NO: 13, 20, 27, 34, 41, 48.

4. The ISVD of claim 3, comprising a sequence selected from the group of SEQ ID NOs: 2 to 7, or a sequence with at least 90 % amino acid identity to SEQ ID NOs: 2-7, or a humanized variant of anyone thereof.

5. A multi-specific binding agent, comprising at least one binding agent according to any one of claims 1 to 4, coupled via a linker or spacer.

6. A multi-specific binding agent according to claim 5, which is a bispecific binding agent wherein the binding site of the second binding agent is different from the binding site of the first binding agent.

7. A vector for expression of the binding agent according to any of claims 1 to 4, or the multi-specific agent of claims 5 or 6 in a cell or a subject, preferably a viral vector: lentiviral, adenoviral or adeno- associated viral vector.

8. A composition comprising the binding agent of any of claims 1 to 4, or the multi-specific binding agent of claims 5 or 6.

9. The composition of claim 8, further comprising a small molecule compound, wherein said small molecule compound is a CFTR corrector and/or a CFTR potentiator.

10. The binding agent according to any of claims 1 to 4, the multi-specific binding agent according to claims 5 or 6, the vector according to claim 7, or the composition according to claims 8 or 9, for use as a medicament.

11. The binding agent according to any of claims 1 to 4, the multi-specific binding agent according to claims 5 or 6, the vector according to claim 7, or the composition according to claims 8 or 9, for use in treatment of cystic fibrosis.

12. A complex comprising CFTR NBD1, and a binding agent according to any one of claims 1 to 4, or the multi-specific binding agent according to claims 5 or 6.

13. The complex according to claim 12, wherein said binding agent or multi-specific binding agent comprises an ISVD according to claims 3 or 4, and wherein said complex is crystalline.

14. A crystal comprising the complex according to claim 13, wherein the NBD1 domain is a domain with an amino acid sequence with at least 90 % identity to SEQ I D NO:58 or SEQ ID NO:59, and characterized in that the crystal is:

i) a crystal between the NBD1 domain and said binding agent in the space group C121, with the following crystal lattice constants: a=152.2 A ± 5%, b=41.6 A ± 5%, c=99.3 A ± 5%, a=90°, b= 120.56°, y=90°, or

ii) a crystal between the NBD1 domain and said binding agent in the space group C222i, with the following crystal lattice constants: a=38.68 A ± 5%, b=135.78 A ± 5%, c=190.65 A ± 5%, a=b=n=90°, or

iii) a crystal between the NBD1 domain, and said binding agent in the space group P2i2i2i, with the following crystal lattice constants: a=64.49 A ± 5%, b=118.15 A ± 5%, c=180.21 A ± 5%, a=b=n=90°, or

iv) a crystal between the NBD1 domain, and said binding agent in the space group P12il, with the following crystal lattice constants: a=80.94 A ± 5%, b=55.19 A ± 5%, c=114.99 A ± 5%, a=90°, b= 103.96°, y=90°.

15. The crystal of claim 14, which has a three-dimensional structure wherein the crystal i) comprises an atomic structure characterized by the coordinates of PDB: 6GJS, or wherein the crystal ii) comprises an atomic structure characterized by the coordinates of PDB: 6GJU or a subset of atomic coordinates thereof, or wherein the crystal iii) comprises an atomic structure characterized by the coordinates of PDB: 6GJQ or a subset of atomic coordinates thereof, or wherein the crystal iv) comprises an atomic structure characterized by the coordinates of PDB: 6GK4 or a subset of atomic coordinates thereof.

16. A binding site, consisting of a subset of atomic coordinates, present in the crystals i), ii) , iii) or iv) as defined in claims 14 and 15, wherein said binding site consists of the amino acid residues:

457, 459, 550-551, 576-581, 605-608, 610, 618, 625, 633 and 636, or

457- 460, 550-551, 576-581, 605-608, 610, 618, 620, 625, and 633, or

469, 472, 474, 488-490, 494-499, 508-510, 553, 560, and 564, or

472, 474, 490, 492, 494-499, 504, 506, 508-510, 560, and 564,

as set forth in SEQ ID NO : 1,

and wherein said amino acid residues represent the binding agent's CFTR binding site.

17. A computer-assisted method of identifying, designing or screening for a stabilizer of CFTR wherein said stabilizer is a binding agent selected from the group consisting of a small molecule compound, a chemical, a peptide, a peptidomimetic, an antibody mimetic, an ISVD, or an active antibody fragment, and comprising:

i. introducing into suitable computer program parameters defining the three- dimensional structure of the binding site of claim 15,

ii. creating a three-dimensional structure of a test compound in said computer program;

iii. displaying a superimposing model of said test compound on the three-dimensional model of the binding site; and

iv. assessing whether said test compound model fits spatially and chemically into a binding site.