TRAILR2 CDH17 binding molecules for the treatment of cancer

1. A binding molecule comprising at least one antigen binding site that binds specifically to TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) and at least one antigen binding site that binds specifically to cadherin-17 (CDH17),

wherein the antigen binding site that binds specifically to TRAILR2 comprises heavy chain CDRs comprising of SEQ ID NO.:43 (CDR1), SEQ ID NO.:44 (CDR2) and SEQ ID NO.:48 (CDR3) and light chain CDRs comprising the amino acid sequences of SEQ ID NO.:49 (CDR1), SEQ ID NO.50 (CDR2) and SEQ ID NO.:54 (CDR3), and

wherein the antigen binding site that binds specifically to CDH17 comprises heavy chain CDRs comprising the amino acid sequences of SEQ ID NO.:70 (CDR1), SEQ ID NO.:71 (CDR2) and SEQ ID NO.:72 (CDR3) and light chain CDRs comprising the amino acid sequences of SEQ ID NO.:73 (CDR1), SEQ ID NO.74 (CDR2) and SEQ ID NO.:75 (CDR3).

2. The binding molecule of claim 1 , wherein the molecule is bispecific and tetravalent.

3. The binding molecule of claim 1 , wherein the at least one antigen binding site that binds specifically to cadherin-17 (CDH17) is an immunoglobulin (Ig) molecule and the at least one antigen binding site that binds specifically to TNF-related apoptosis-inducing ligand receptor 2 (TRAILR2) comprises one or more scFv(s).

4. The binding molecule of claim 3 , wherein the one or more scFv(s) have a VL-VH orientation from N- to C-terminus.

5. The binding molecule of claim 3 , wherein the one or more scFv(s) is fused to the C-terminus of the heavy chain of the Ig molecule.

6. The binding molecule of claim 3 , wherein the Ig molecule is IgG.

7. The binding molecule of claim 3 , wherein the one or more scFv(s) is fused to the Ig molecule by a peptide linker.

8. The binding molecule of claim 7 , wherein the peptide linker has a length of about 4 to 20 amino acids.

9. The binding molecule of claim 1 , wherein the antigen binding site that binds specifically to TRAILR2

comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:96 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:97; or

comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:98 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:99.

10. The binding molecule of claim 1 , wherein the antigen binding site that binds specifically to CDH17

comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:114 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:115; or

comprises a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:116 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:117.

11. A pharmaceutical composition comprising a binding molecule of claim 1 and a pharmaceutically acceptable carrier.

12. A pharmaceutical composition comprising a binding molecule of claim 9 and a pharmaceutically acceptable carrier.

13. A pharmaceutical composition comprising a binding molecule of claim 10 and a pharmaceutically acceptable carrier.

14. A binding molecule comprising at least one antigen binding site that binds specifically to TRAILR2 and at least one antigen binding site that binds specifically to CDH17, wherein said binding molecule comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 196, or a heavy chain comprising the amino acid sequence of SEQ ID NO. 197, and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 203.

15. A binding molecule comprising at least one antigen binding site that binds specifically to TRAILR2 and at least one antigen binding site that binds specifically to CDH17, wherein said binding molecule comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 211, or a heavy chain comprising the amino acid sequence of SEQ ID NO. 212; and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 218.

16. An isolated nucleic acid molecule encoding the heavy chain and/or the light chain of a binding molecule of claim 14 .

17. An isolated nucleic acid molecule encoding the heavy chain and/or the light chain of a binding molecule of claim 15 .

18. An expression vector comprising a nucleic acid molecule of claim 16 .

19. An expression vector comprising a nucleic acid molecule of claim 17 .

20. A host cell transfected with an expression vector of claim 18 .

21. A host cell transfected with an expression vector of claim 19 .

22. A method of manufacturing a binding molecule comprising:

(a) cultivating a host cell comprising an isolated nucleic acid molecule encoding the heavy chain of a binding molecule of claim 14 and an isolated nucleic acid molecule encoding the light chain of a binding molecule of claim 14 under conditions allowing expression of the binding molecule; and

(b) recovering the binding molecule; and optionally

(c) further purifying and/or modifying and/or formulating the binding molecule.

23. A method of manufacturing a binding molecule comprising:

(a) cultivating a host cell comprising an isolated nucleic acid molecule encoding the heavy chain of a binding molecule of claim 15 and an isolated nucleic acid molecule encoding the light chain of a binding molecule of claim 15 under conditions allowing expression of the binding molecule; and

(b) recovering the binding molecule; and optionally

(c) further purifying and/or modifying and/or formulating the binding molecule.

24. A pharmaceutical composition comprising a binding molecule of claim 14 and a pharmaceutically acceptable carrier.

25. A pharmaceutical composition comprising a binding molecule of claim 15 and a pharmaceutically acceptable carrier.

26. A binding molecule comprising at least one antigen binding site that binds specifically to TRAILR2 and at least one antigen binding site that binds specifically to CDH17, wherein the antigen binding site that binds specifically to TRAILR2 and the antigen binding site that binds specifically to CDH17 comprise:

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:96 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:97, and

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:114 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:115, respectively; or

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:96 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:97, and

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:116 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:117, respectively;

or

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:98 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:99, and

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:114 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:115, respectively;

or

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:98 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:99, and

a heavy chain variable domain comprising the amino acid sequence of SEQ ID NO.:116 and a light chain variable domain comprising the amino acid sequence of SEQ ID NO.:117, respectively.

27. The binding molecule of claim 26 , wherein the molecule is bispecific and tetravalent.

28. The binding molecule of claim 26 , wherein the at least one antigen binding site that binds specifically to CDH17 is an immunoglobulin (Ig) molecule and the at least one antigen binding site that binds specifically to TRAILR2 comprises one or more scFv(s).

29. The binding molecule of claim 28 , wherein the one or more scFv(s) have a VL-VH orientation from N- to C-terminus.

30. The binding molecule of claim 28 , wherein the one or more scFv(s) is fused to the C-terminus of the heavy chain of the Ig molecule.

31. The binding molecule of claim 28 , wherein the Ig molecule is IgG.

32. The binding molecule of claim 28 , wherein the one or more scFv(s) is fused to the Ig molecule by a peptide linker.

33. The binding molecule of claim 32 , wherein the peptide linker having a length of about 4 to 20 amino acids.

34. A pharmaceutical composition comprising a binding molecule of claim 26 and a pharmaceutically acceptable carrier.

35. A binding molecule comprising at least one antigen binding site that binds specifically to TRAILR2 and at least one antigen binding site that binds specifically to CDH17, wherein said binding molecule comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 196 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 203.

36. A pharmaceutical composition comprising a binding molecule of claim 35 and a pharmaceutically acceptable carrier.

37. A binding molecule comprising at least one antigen binding site that binds specifically to TRAILR2 and at least one antigen binding site that binds specifically to CDH17, wherein said binding molecule comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 197 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 203.

38. A pharmaceutical composition comprising a binding molecule of claim 37 and a pharmaceutically acceptable carrier.

39. A binding molecule comprising at least one antigen binding site that binds specifically to TRAILR2 and at least one antigen binding site that binds specifically to CDH17, wherein said binding molecule comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 211 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 218.

40. A pharmaceutical composition comprising a binding molecule of claim 39 and a pharmaceutically acceptable carrier.

41. A binding molecule comprising at least one antigen binding site that binds specifically to TRAILR2 and at least one antigen binding site that binds specifically to CDH17, wherein said binding molecule comprises (i) a heavy chain comprising the amino acid sequence of SEQ ID NO. 212 and (ii) a light chain comprising the amino acid sequence of SEQ ID NO. 218.

42. A pharmaceutical composition comprising a binding molecule of claim 41 and a pharmaceutically acceptable carrier.