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1. (WO2016061632) FN14-BINDING PROTEINS AND USES THEREOF
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CLAIMS:

1. An isolated or recombinant Fnl4-binding protein comprising an antigen binding domain, wherein the antigen binding domain binds specifically to Fnl4 or a cell expressing Fnl4, and wherein the antigen binding domain comprises:

i) a heavy chain variable region (VH) comprising CDRs 1 and 2 in the sequence set forth in SEQ ID NOs:2 and 3; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof; and/or ii) a light chain variable region (VL) comprising CDRs 1, 2 and 3 in the sequence set forth in any one of SEQ ID NOs:4, 5, 6, 7 or 8; or a sequence of at least

50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

2. An isolated or recombinant Fnl4-binding protein comprising an antigen binding domain of an anti-Fnl4 antibody, wherein the antigen binding domain binds specifically to Fnl4 or a cell expressing Fnl4, wherein the antigen binding domain comprises:

i) a VH comprising CDRs 1 and 2 in the sequence set forth in SEQ ID NOs:2 and 3; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof; and/or

ii) a VL comprising CDRs 1, 2 and 3 in the sequence set forth in any one of SEQ ID NOs:4, 5, 6, 7 or 8; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

3. The Fnl4-binding protein of claim 1 or 2, wherein the antigen binding domain comprises a VH comprising CDR3 in the sequence set forth in any one of SEQ ID NOs:9 to 23; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

4. The Fnl4-binding protein of any one of claims 1 to 3, wherein the Fnl4-binding protein binds specifically to an epitope in Fnl4 comprising residues contained within the sequence set forth in SEQ ID NO: 1.

5. The Fnl4-binding protein of any one of claims 1 to 4, wherein the Fnl4-binding protein binds specifically to the Fnl4 ectodomain.

6. The Fnl4-binding protein of any one of claims 1 to 5, wherein the Fnl4-binding protein when tested as a Fab binds to Fnl4 with a KD of between 5 and 220 nM.

7. The Fnl4-binding protein of any one of claims 1 to 6, wherein the Fnl4-binding protein when tested as a Fab binds to Fnl4 with a Kd of between 8xl0~4s_1 to 2.1 x lOV.

8. The Fnl4-binding protein of any one of claims 1 to 7, wherein the antigen binding domain comprises a VH sequence set forth in any one of SEQ ID NOs:9 to 23; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

9. The Fnl4-binding protein of any one of claims 1 to 8, wherein the antigen binding domain comprises a VL sequence set forth in SEQ ID NO:69; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

10. The Fnl4-binding protein of any one of claims 1 to 8, wherein the antigen binding domain comprises a VL sequence set forth in any one of SEQ ID NOs:24 to 48 or 70 to 75; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

11. The Fnl4-binding protein of any one of claims 1 to 7, wherein the antigen binding domain comprises:

i) a VH comprising a sequence set forth in any one of SEQ ID NOs:9 to 23; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof; and

ii) a VL comprising a sequence set forth in any one of SEQ ID NOs:24 to 48, 69, or 70 to 75; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

12. The Fnl4-binding protein of any one of claims 1 to 7, wherein the antigen binding domain comprises:

i) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:24;

ii) a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO:25;

iii) a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO: 26;

iv) a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO:27;

v) a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO:28;

vi) a VH comprising a sequence set forth in SEQ ID NO: 16 and a VL comprising a sequence set forth in SEQ ID NO:29;

vii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:30;

viii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:31 ;

ix) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:32;

x) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:33;

xii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:34;

xiii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:35;

xiv) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:36;

xv) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:37;

xvi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:38;

xvii) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO:39;

xviii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:40;

xix) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:41 ;

xx) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:42;

xxi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:43;

xxii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:44;

xxiii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:45;

xxiv) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:46;

xxv) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:47;

xxvi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:48;

xxvii) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO:70;

xxviii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:71;

xxix) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:72;

xxx) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:73;

xxxi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:74;

xxxii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:75.

13. The Fnl4-binding protein of any one of claims 1 to 7, wherein the antigen binding domain comprises a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in any one of SEQ ID NOs:24 to 48 or 70 to 75.

14. The Fnl4-binding protein of any one of claims 1 to 7, wherein the antigen binding domain comprises a VL comprising CDRs 1, 2 and 3 set forth in any one of SEQ ID NOs: 26, 45, 46, 48, 71, 73 or 74; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

15. The Fnl4-binding protein of any one of claims 1 to 7, wherein the antigen binding domain comprises a heavy chain set forth in SEQ ID NO:68; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

16. The Fnl4-binding protein of any one of claims 1 to 7, wherein the antigen binding domain comprises the light chain sequence set forth in any one of SEQ ID NOs:49 to 67 or 76 to 91 ; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

17. The Fnl4-binding protein of any one of claims 1 to 16, wherein the VH and the VL are in a single polypeptide chain and the Fnl4-Binding protein is:

i) a single chain Fv fragment (scFv);

ii) a dimeric scFv (di-scFV);

iii) at least one of i) and/or ii) linked to a heavy chain constant region or an Fc or a heavy chain constant domain (CH) 2 and/or CH3; or

iv) at least one of i) and/or ii) linked to a protein that binds to an immune effector cell; or wherein the VL and VH are in separate polypeptide chains and the Fnl4-binding protein is:

i) a diabody;

ii) a triabody;

iii) a tetrabody;

iv) a Fab;

v) a F(ab')2;

vi) a Fv;

vii) at least one of i) to vi) linked to a heavy chain constant region or an

Fc or a heavy chain constant domain (CH)2 and/or CR3;

viii) at least one of i) to vi) linked to a protein that binds to an immune effector cell; or

ix) an antibody.

18. The Fnl4-binding protein of claim 17, comprising an IgGl constant region or an IgG4 constant region or a stabilized IgG4 constant region.

19. The Fnl4-binding protein of claim 17, wherein the stabilized IgG4 constant region comprises a proline at position 241 according to the numbering system of Kabat.

20. An anti-Fnl4 antibody, wherein the antigen binding domain comprises a VH sequence set forth in any one of SEQ ID NOs:9 to 23; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

21. An anti-Fnl4 antibody, wherein the antigen binding domain comprises the VL sequence set forth in SEQ ID NO:69; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

22. An anti-Fnl4 antibody, wherein the antigen binding domain comprises the VL sequence set forth in any one of SEQ ID NOs:24 to 48 or 70 to 75; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

23. An anti-Fnl4 antibody, wherein the antigen binding domain comprises: i) a VH comprising a sequence set forth in any one of SEQ ID NOs:9 to 23; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof; and

ii) a VL comprising a sequence set forth in any one of SEQ ID NOs:24 to 48,

69, or 70 to 75; or a sequence of at least 50% identity thereto; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

24. An anti-Fnl4 antibody, the antibody comprising any one of the following: i) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:24;

ii) a VH comprising a sequence set forth in SEQ ID NO: 10 and a VL comprising a sequence set forth in SEQ ID NO:25;

iii) a VH comprising a sequence set forth in SEQ ID NO: 11 and a VL comprising a sequence set forth in SEQ ID NO:26;

iv) a VH comprising a sequence set forth in SEQ ID NO: 12 and a VL comprising a sequence set forth in SEQ ID NO:27;

v) a VH comprising a sequence set forth in SEQ ID NO: 14 and a VL comprising a sequence set forth in SEQ ID NO:28;

vi) a VH comprising a sequence set forth in SEQ ID NO: 16 and a VL comprising a sequence set forth in SEQ ID NO:29;

vii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:30;

viii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:31;

ix) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:32;

x) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:33;

xii) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO:34;

xiii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:35;

xiv) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:36;

xv) a VH comprising a sequence set forth in SEQ ID NO: 9 and a VL comprising a sequence set forth in SEQ ID NO:37;

xvi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:38;

xvii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:39;

xviii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:40;

xix) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:41;

xx) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:42;

xxi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:43;

xxii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:44;

xxiii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:45;

xxiv) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:46;

xxv) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:47;

xxvi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:48;

xxvii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:70;

xxviii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:71;

xxix) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:72;

xxx) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:73;

xxxi) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:74;

xxxii) a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in SEQ ID NO:75.

25. An anti-Fnl4 antibody, the antibody comprising a VH comprising a sequence set forth in SEQ ID NO:9 and a VL comprising a sequence set forth in any one of SEQ ID NOs:24 to 48 or 70 to 75.

26. The anti-Fnl4 antibody according to any of one claims 21 to 25, the antibody comprising an IgGl constant region or an IgG4 constant region or a stabilized IgG4 constant.

27. The anti-Fnl4 antibody according to claim 26, wherein the stabilized IgG4 constant region comprises a proline at position 241 according to the numbering system of Kabat.

28. An anti-Fnl4 antibody, the antibody comprising any one of the following: i) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:49;

ii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:50;

iii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:51 ;

iv) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:52;

v) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:53;

vi) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:54;

vii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:55;

viii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:56;

ix) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:57;

x) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:58;

xi) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:59;

xii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:60;

xiii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:61;

xiv) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:62;

xv) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:63;

xvi) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:64;

xvii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:65;

xviii) a heavy chain comprising a sequence set forth in SEQ ID NO :68 and a light chain comprising a sequence set forth in SEQ ID NO:66;

xix) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:67;

xx) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:76;

xxi) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:77;

xxii) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:78;

xxiii) a heavy chain comprising a sequence set forth in SEQ ID NO :68 and a light chain comprising a sequence set forth in SEQ ID NO:79;

xxiv) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:80;

xxv) a heavy chain comprising a sequence set forth in SEQ ID NO:68 and a light chain comprising a sequence set forth in SEQ ID NO:81.

29. An anti-Fnl4 antibody, the antibody comprising a heavy chain comprising a sequence set for in SEQ ID NO:68; or a deimmunized or germlined version thereof; or an affinity matured form thereof; and a light chain comprising a sequence set forth in any one of SEQ ID NOs:49 to 67 or 76 to 81 ; or a deimmunized or germlined version thereof; or an affinity matured form thereof.

30. A conjugate comprising the Fnl4-binding protein of any one of claims 1 to 19, or the anti-Fnl4 antibody of any one of claims 20 to 29 conjugated to a compound.

31. The conjugate of claim 30, wherein the compound is selected from the group consisting from; a radioisotope, a detectable label, a therapeutic compound, a colloid a toxin, a nucleic acid, a peptide, a protein, a compound that increases the half-life of the protein in a subject and mixtures thereof.

32. A composition comprising the Fnl4-binding protein of any one of claims 1 to 19, or the anti-Fnl4 antibody of any one of claims 20 to 29, or the conjugate of claims 30 or 31 and a suitable carrier.

33. A method for treating or preventing an Fnl4-mediated condition in a subject, the method comprising administering to a subject the Fnl4-binding protein of any one of claims 1 to 19, or the anti-Fnl4 antibody of any one of claims 20 to 29, or the conjugate of claims 30 or 31, or the composition of claim 33.

34. The method of claim 33 wherein the Fnl4-mediated condition is cancer, metastasis, excessive vascularization or angiogenesis, an autoimmune disease, an inflammatory disease, a neurodegenerative disease, a wasting disorder, a cardiovascular disease or ischemia.

35. The method of claim 34, wherein the Fnl4-mediated condition is cancer and the method reduces or prevents invasiveness of the cancer into tissue of a subject or reduces or prevents metastasis of the cancer.

36. A method of treating or preventing a wasting disorder which is associated with a condition, the method comprising administering to a subject the Fnl4-binding protein of any one of claims 1 to 19, or the anti-Fnl4 antibody of any one of claims 20 to29, or the conjugate of claims 30 or 31, or the composition of claim 32 to a subject.

37. The method of claim 36 wherein the wasting disorder is cachexia.

38. A method for detecting Fnl4 in a sample, the method comprising contacting a sample with the Fnl4-binding protein of any one of claims 1 to 19, or the anti-Fnl4

antibody of any one of claims 20 to 29, such that the antigen protein complex forms a detectable complex wherein detecting the complex is indicative of the amount of Fnl4 in a sample.

39. Use of the Fnl4-binding protein of any one of claims 1 to 19, or the anti-Fnl4 antibody of any one of claims 20 to 29, or the conjugate of claims 30 or 31, or the composition of claim 32 in the manufacture of a medicament for treating an Fnl4-mediated condition in a subject.

40. The use of claim 39 wherein the Fnl4-mediated condition is cancer, metastasis, excessive vascularization or angiogenesis, an autoimmune disease, an inflammatory disease, a neurodegenerative disease, a wasting disorder, a cardiovascular disease or ischemia.

41. The use of claim 40, wherein the Fnl4-mediated condition is cancer and the method reduces or prevents invasiveness of the cancer into tissue of a subject or reduces or prevents metastasis of the cancer.

42. The use of claim 41, wherein the Fnl4-mediated condition is a wasting disorder.