Amino acid sequences directed against a metalloproteinase from the ADAM family and polypeptides comprising the same for the treatment of ADAM-related diseases and disorders

1. A compound or VHH construct, that comprises or essentially consists of:

a) an amino acid sequence that specifically binds to A Disintegrin And Metalloprotease Thrombospondin 5 (ADAMTS5), and inhibit the proteinase activity of ADAMTS5, and that essentially consists of a VHH sequence, which consists of 4 framework regions (FR1 to FR4 respectively) and 3 complementarity determining regions (CDR1 to CDR3 respectively), in which:

CDR1 is SEQ ID NO: 313, CDR2 is SEQ ID NO: 525 and CDR3 is SEQ ID NO: 737;

CDR1 is SEQ ID NO: 314, CDR2 is SEQ ID NO: 526 and CDR3 is SEQ ID NO: 738;

CDR1 is SEQ ID NO: 315, CDR2 is SEQ ID NO: 527 and CDR3 is SEQ ID NO: 739;

CDR1 is SEQ ID NO: 316, CDR2 is SEQ ID NO: 528 and CDR3 is SEQ ID NO: 740;

CDR1 is SEQ ID NO: 317, CDR2 is SEQ ID NO: 529 and CDR3 is SEQ ID NO: 741;

CDR1 is SEQ ID NO: 318, CDR2 is SEQ ID NO: 530 and CDR3 is SEQ ID NO: 742;

CDR1 is SEQ ID NO: 319, CDR2 is SEQ ID NO: 531 and CDR3 is SEQ ID NO: 743;

CDR1 is SEQ ID NO: 320, CDR2 is SEQ ID NO: 532 and CDR3 is SEQ ID NO: 744;

CDR1 is SEQ ID NO: 321, CDR2 is SEQ ID NO: 533 and CDR3 is SEQ ID NO: 745;

CDR1 is SEQ ID NO: 322, CDR2 is SEQ ID NO: 534 and CDR3 is SEQ ID NO: 746;

CDR1 is SEQ ID NO: 323, CDR2 is SEQ ID NO: 535 and CDR3 is SEQ ID NO: 747;

CDR1 is SEQ ID NO: 324, CDR2 is SEQ ID NO: 536 and CDR3 is SEQ ID NO: 748;

CDR1 is SEQ ID NO: 325, CDR2 is SEQ ID NO: 537 and CDR3 is SEQ ID NO: 749;

CDR1 is SEQ ID NO: 326, CDR2 is SEQ ID NO: 538 and CDR3 is SEQ ID NO: 750;

CDR1 is SEQ ID NO: 327, CDR2 is SEQ ID NO: 539 and CDR3 is SEQ ID NO: 751;

CDR1 is SEQ ID NO: 328, CDR2 is SEQ ID NO: 540 and CDR3 is SEQ ID NO: 752;

CDR1 is SEQ ID NO: 329, CDR2 is SEQ ID NO: 541 and CDR3 is SEQ ID NO: 753;

CDR1 is SEQ ID NO: 330, CDR2 is SEQ ID NO: 542 and CDR3 is SEQ ID NO: 754;

CDR1 is SEQ ID NO: 331, CDR2 is SEQ ID NO: 543 and CDR3 is SEQ ID NO: 755;

CDR1 is SEQ ID NO: 332, CDR2 is SEQ ID NO: 544 and CDR3 is SEQ ID NO: 756;

CDR1 is SEQ ID NO: 333, CDR2 is SEQ ID NO: 545 and CDR3 is SEQ ID NO: 757;

CDR1 is SEQ ID NO: 334, CDR2 is SEQ ID NO: 546 and CDR3 is SEQ ID NO: 758;

CDR1 is SEQ ID NO: 335, CDR2 is SEQ ID NO: 547 and CDR3 is SEQ ID NO: 759;

CDR1 is SEQ ID NO: 336, CDR2 is SEQ ID NO: 548 and CDR3 is SEQ ID NO: 760;

CDR1 is SEQ ID NO: 337, CDR2 is SEQ ID NO: 549 and CDR3 is SEQ ID NO: 761; or

CDR1 is SEQ ID NO: 993, CDR2 is SEQ ID NO: 1013 and CDR3 is SEQ ID NO: 1033;

and further comprises

b) a serum protein, a VHH that specifically binds to human serum albumin, or an Fc portion.

2. The compound or VHH construct according to claim 1 , which is a multispecific construct.

3. The compound or VHH construct according to claim 1 , in which said serum protein is human serum albumin.

4. The compound or VHH construct according to claim 1 , that has a serum half-life that is at least 1.5 times greater than the half-life of the VHH sequence that specifically binds to ADAMTS5.

5. The compound or VHH construct according to claim 1 , that has a serum half-life that is increased than 1 hour compared to the VHH sequence that specifically binds to ADAMTS5.

6. The compound or VHH construct according to claim 1 , that has a serum half-life in human of at least about 12 hours.

7. A composition, comprising at least one compound or VHH construct according to claim 1 .

8. The compound or VHH construct according to claim 1 , wherein said VHH sequence is selected from the group consisting of SEQ ID NOs: 949-973 and 1053.

9. The compound or VHH construct according to claim 1 , wherein the serum protein, the VHH that specifically binds to human serum albumin, or the Fc portion is linked via a linker to the amino acid sequence that specifically binds to ADAMTS5.

10. The compound or VHH construct according to claim 1 , wherein the VHH sequence is a humanized VHH sequence, and wherein the framework region amino acid residue at position:

11 is selected from the group consisting of L, M, S, V, W;

37 is selected from the group consisting of F, Y, H, I, L and V;

44 is selected from the group consisting of G, E, A, D, Q, R, S, and L;

45 is selected from the group consisting of L, R, C, I, L, P, Q, and V;

47 is selected from the group consisting of W, L, F, A, G, I, M, R, S, V and Y;

83 is selected from the group consisting of R, K, N, E, G, I, M, Q and T;

84 is selected from the group consisting of P, A, L, R, S, T, D, and V;

103 is selected from the group consisting of W, P, R and S;

104 is selected from the group consisting of G and D; and

108 is selected from the group consisting of Q, L and R, with the proviso that when positions 44-47 are GLEW (SEQ ID NO:1054), position 108 is always Q in VHH sequences that also contain a W at 103;

wherein the amino acid residue position is according to the Kabat numbering.