PELOSO PAUL (US)
Claims 1. A method for treatment of ankylosing spondylitis: the method comprising administering to a patient a therapeutically effective amount of pharmaceutical composition comprising a bispecific fusion protein, wherein the bispecific fusion protein comprises an IL-17A binding motif and an albumin binding motif. 2. A method claim 1, wherein the IL-17A binding motif consists of an amino acid sequence selected from: (i) EX2DX4AX6X7EIX10X11LPNL X16X17X18QX20X21AFIX25 X26LX28X29 (SEQ ID. No.1) wherein, independently from each other, X2 is selected from A, H, M and Y; X4 is selected from A, D, E, F, K, L, M, N, Q, R, S and Y; X6 is selected from A, Q and W; X7 is selected from F, I, L, M, V, W and Y; X10 is selected from A and W; X11 is selected from A, D, E, F, G, L, M, N, Q, S, T and Y; X16 is selected from N and T; X17 is selected from H, W and Y; X18 is selected from A, D, E, H and V; X20 is selected from A, G, Q, S and W; X21 is selected from A, D, E, F, H, K, N, R, T, V, W and Y; X25 is selected from A, D, E, G, H, I, L, M, N, Q, R, S, T and V; X26 is selected from K and S; X28 is selected from I, L, N and R; and X29 is selected from D and R; and (ii) an amino acid sequence which has at least 96% identity to the sequence defined in (i). 3. The method of claim 2, wherein the bispecific fusion protein is izokibep. 4. The method of claim 1, wherein the pharmaceutical composition comprises at least one additional excipient. 5. The method of claim 1, wherein the pharmaceutical composition is a solution. 6. The method of claim 5, wherein the solution is an injectable solution. 7. The method of claim 6, wherein the injectable solution is administered subcutaneously. 8. The method of claim 1, wherein the pharmaceutical compositions is administered once a week. 9. The method of claim 3, wherein the pharmaceutical composition is administered once a week. 10. The method of claim 3, wherein the pharmaceutical composition is administered once every two weeks. 11. The method of claim 3, wherein the pharmaceutical composition is administered once every four weeks. 12. The method of claim 1, wherein the pharmaceutical composition comprises from about 20 mg to about 300 mg izokibep. 13. The method of claim 1, wherein the pharmaceutical composition comprises about 40 mg izokibep. 14. The method of claim 1, wherein the pharmaceutical composition comprises about 80 mg izokibep. 15. The method of claim 1, wherein the pharmaceutical composition comprises about 160 mg izokibep. 16. The method of claim 3, wherein the patient is administered the pharmaceutical composition comprising 40 mg izokibep once every week. 17. The method of claim 3, wherein the patient administered the pharmaceutical composition comprising 40 mg izokibep once every two weeks. 18. The method of claim 3, wherein the patient is administered the pharmaceutical composition comprising 80 mg izokibep once every two weeks. 19. The method of claim 3, wherein the patient is administered the pharmaceutical composition comprising 160 mg izokibep once every week. 20. The method of claim 3, wherein the patient is administered pharmaceutical composition comprising 160 mg izokibep once every two weeks. 21. The method of claim 3, wherein the patient is administered pharmaceutical composition comprising 160 mg izokibep once every four weeks. 22. The method of claim 1, wherein the pharmaceutical composition is administered for at least 16 weeks. 23. The method of claim 1, wherein the pharmaceutical composition is administered for 52 weeks. 24. The method of claim 1, wherein the pharmaceutical composition is administered for 52 weeks. 25. The method of claim 1, wherein the patient is suffering from axial spondyloarthritis (AxSpA). 26. The method of claim 1, wherein the patient is suffering from radiographic axial spondyloarthritis (r-AxSpA). 27. The method of claim 1, wherein the patient is suffering from non-radiographic axial spondyloarthritis (nr-AxSpA). 28. A peptide comprising an IL-17A binding motif and an albumin binding motif for use in the treatment of ankylosing spondylitis (AS). 29. A peptide for use according to claim 28, wherein said peptide is defined in any one of claims 2-3. 30. A peptide for use according to any one of claims 28-29, wherein said peptide is included in a pharmaceutical composition, optionally wherein said pharmaceutical composition is as defined in any one of claims 4-9. 31. A peptide for use according to any one of claims 28-30, wherein said treatment is as defined in any one of claims 10-25. 32. Use of a peptide comprising an IL-17A binding motif and an albumin binding motif in the manufacture of a medicament for treatment of ankylosing spondylitis (AS). 33. Use according to claim 32, wherein said peptide is as defined in any one of claims 2-3. 34. Use according to any one of claims 32-33, wherein said medicament is a pharmaceutical composition, optionally wherein said pharmaceutical composition is as defined in any one of claims 4-9. 35. Use according to any one of claims 32-33, wherein said treatment is as defined in any one of claims 10-27. |
In a more specific embodiment, defining a sub-class of IL-17A binding polypeptides, sequence i) fulfills at least six of the eleven conditions I-XI: I. X 2 is A; II. X4 is selected from D, E and Q; III. X 6 is A; IV. X7 is selected from F and V; V. X 16 is T; VI. X17 is W; VII. X18 is selected from A and D; VIII. X 20 is W; IX. X 26 is K; X.X 28 is R; and XI. X 29 is D. In some examples of an IL-17A binding polypeptide of the invention, sequence i) fulfills at least seven of the eleven conditions I-XI. More specifically, sequence i) may fulfill at least eight of the eleven conditions I-XI, such as at least nine of the eleven conditions I-XI, such as at least ten of the eleven conditions I-XI, such as all of the eleven conditions I-XI. In some embodiments, for the IL-17A binding polypeptide, X 2 X 6 , X 2 X 10 or X 6 X 10 are independently AA. In some embodiments, X 2 X 17 , X 2 X 20 , X 6 X17, X 6 X 20 , X 10 X17 or X 10 X 20 are independently AW. In some embodiments, X 2 X 28 , X 6 X 28 or X 10 X 28 is AR. In some embodiments, X 17 X 28 or X 20 X 28 is WR. In some embodiments, X 17 X 20 is WW. In one embodiment, the sequences of individual IL-17A binding motifs correspond to amino acid positions 8-36 in SEQ ID NO:1-1216 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment of the IL-17A binding polypeptide, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-1216 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-66, 1200, 1206 and 1214, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-66 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-35 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-27 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-10 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-7 presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in a sequence selected from the group consisting of SEQ ID NO:1-4 presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence i) corresponds to the sequence from position 8 to position 36 in SEQ ID NO:1 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In some embodiments of the present disclosure, the BM as defined above “forms part of” a three-helix bundle protein domain. This is understood to mean that the sequence of the BM is “inserted” into or “grafted” onto the sequence of the original three-helix bundle domain, such that the BM replaces a similar structural motif in the original domain. For example, without wishing to be bound by theory, the BM is thought to constitute two of the three helices of a three-helix bundle, and can therefore replace such a two-helix motif within any three-helix bundle. As the skilled person will realize, the replacement of two helices of the three-helix bundle domain by the two BM helices has to be performed so as not to affect the basic structure of the polypeptide. That is, the overall folding of the Ca backbone of the polypeptide according to this embodiment of the invention is substantially the same as that of the three-helix bundle protein domain of which it forms a part, e.g. having the same elements of secondary structure in the same order etc. Thus, a BM according to the disclosure “forms part” of a three-helix bundle domain if the polypeptide according to this embodiment of the aspect has the same fold as the original domain, implying that the basic structural properties are shared, those properties e.g. resulting in similar CD spectra. The skilled person is aware of other parameters that are relevant. In particular embodiments, the IL-17A binding motif (BM) thus forms part of a three-helix bundle protein domain. For example, the BM may essentially constitute two alpha helices with an interconnecting loop, within said three-helix bundle protein domain. In particular embodiments, said three-helix bundle protein domain is selected from domains of bacterial receptor proteins. Non-limiting examples of such domains are the five different three-helical domains of Protein A from Staphylococcus aureus, such as domain B, and derivatives thereof. In some embodiments, the three-helical bundle protein domain is a variant of protein Z, which is derived from domain B of staphylococcal Protein A. In some embodiments where the IL-17A binding polypeptide as disclosed herein forms part of a three-helix bundle protein domain, the IL-17A binding polypeptide may comprise an amino acid sequence binding module (BMod) selected from: iii) K-[BM]-DPSQS X a X b LLX c EAKKL X d X e X f Q (SEQ ID NO:1296), as presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety, wherein [BM] is an IL-17A binding motif as defined herein, provided that X29 is D; X a is selected from A and S; Xb is selected from N and E; Xc is selected from A, S and C; X d is selected from E, N and S; X e is selected from D, E and S; X f is selected from A and S; and iv) an amino acid sequence which has at least 85% identity to a sequence defined by iii). It may be beneficial in some embodiments that said polypeptides exhibit high structural stability, such as resistance to chemical modifications, changes in physical conditions and proteolysis, during production or storage, as well as in vivo. Thus, in other embodiments where the IL-17A binding polypeptide as disclosed herein forms part of a three-helix bundle protein domain, the IL-17A binding polypeptide may comprise an amino acid sequence binding module (BMod) selected from: v) K-[BM]-QPEQS X a X b LLX c EAKKL X d X e X f Q (SEQ ID NO:1297), as presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety, wherein [BM] is an IL-17A binding motif as defined herein, provided that X29 is R; X a is selected from A and S; Xb is selected from N and E; Xc is selected from A, S and C; X d is selected from E, N and S; X e is selected from D, E and S; X f is selected from A and S; and vi) an amino acid sequence which has at least 85% identity to a sequence defined by v). As discussed above, polypeptides comprising minor changes as compared to the above amino acid sequences, which changes do not largely affect the tertiary structure or function of the polypeptide, are also within the scope of the present disclosure. Thus, in some embodiments, sequence iv and vi) have at least at least 87%, such as at least 89%, such as at least 91%, such as at least 93%, such as at least 95%, such as at least 97% identity to a sequence defined by iii) or v), respectively. In one embodiment, Xa in sequence iii) or v) is A. In one embodiment, Xa in sequence iii) or v) is S. In one embodiment, X b in sequence iii) or v) is N. In one embodiment, Xb in sequence iii) or v) is E. In one embodiment, Xc in sequence iii) or v) is A. In one embodiment, X c in sequence iii) or v) is S. In one embodiment, X c in sequence iii) or v) is C. In one embodiment, Xd in sequence iii) or v) is E. In one embodiment, X d in sequence iii) or v) is N. In one embodiment, X d in sequence iii) or v) is S. In one embodiment, Xe in sequence iii) or v) is D. In one embodiment, Xe in sequence iii) or v) is E. In one embodiment, X e in sequence iii) or v) is S. In one embodiment, X d X e in sequence iii) or v) is selected from EE, ES, SD, SE and SS. In one embodiment, X d X e in sequence iii) or v) is ES. In one embodiment, X d X e in sequence iii) or v) is SE. In one embodiment, X d X e in sequence iii) or v) is SD. In one embodiment, X f in sequence iii) or v) is A. In one embodiment, X f in sequence iii) or v) is S. In one embodiment, in sequence iii) or v), X a is A; X b is N; X c is A and X f is A. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is A and X f is A. In one embodiment, in sequence iii) or v), X a is A; X b is N; X c is C and X f is A. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is S and X f is S. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is S and X f is A. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is A and X f is S. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is C and X f is S. In one embodiment, in sequence iii) or v), Xa is A; Xb is N; Xc is A; X d X e is ND and X f is A. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is A; X d X e is ND and X f is A. In one embodiment, in sequence iii) or v), Xa is A; Xb is N; Xc is C; X d X e is ND and X f is A. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is S, X d X e is ND and X f is S. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is S, X d X e is ND and X f is A. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is C; X d X e is ND and X f is S. In one embodiment, in sequence iii) or v), X a is A; X b is N; X c is A; X d X e is SE and X f is A. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is A; X d X e is SE and X f is A. In one embodiment, in sequence iii) or v), X a is A; X b is N; X c is C; X d X e is SE and X f is A. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is S, X d X e is SE and X f is S. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is A; X d X e is SE and X f is S. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is C; X d X e is SE and X f is S. In one embodiment, in sequence iii) or v), Xa is A; Xb is N; Xc is A; X d X e is ES and X f is A. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is A; X d X e is ES and X f is A. In one embodiment, in sequence iii) or v), Xa is A; Xb is N; Xc is C; X d X e is ES and X f is A. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is S, X d X e is ES and X f is S. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is C; X d X e is ES and X f is S. In one embodiment, in sequence iii) or v), X a is A; X b is N; X c is A; X d X e is SD and X f is A. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is A; X d X e is SD and X f is A. In one embodiment, in sequence iii) or v), X a is A; X b is N; X c is C; X d X e is SD and X f is A. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is S, X d X e is SD and X f is S. In one embodiment, in sequence iii) or v), X a is S, X b is E; X c is A; X d X e is SD and X f is S. In one embodiment, in sequence iii) or v), Xa is S, Xb is E; Xc is C; X d X e is SD and X f is S. In yet a further embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-1216 presented in FIG.1 of U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-66, 1200, 1206 and 1214, presented in FIG. 1 of U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-66, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-35, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In another embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-27 presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-10 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In yet another embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-7 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in a sequence selected from the group consisting of SEQ ID NO:1-4 and in another embodiment, sequence iii) corresponds to the sequence from position 7 to position 55 in SEQ ID NO:1 presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. Also, in a further embodiment, there is provided an IL-17A binding polypeptide, which comprises an amino acid sequence selected from: vii) YA-[BMod]-AP (SEQ ID NO:1298), presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety wherein [BMod] is an IL-17A binding module as defined above; and viii) an amino acid sequence which has at least 86% identity to a sequence defined by vii). In an alternative further embodiment, there is provided an IL-17A binding polypeptide, which comprises an amino acid sequence selected from: ix) FA-[BMod]-AP (SEQ ID NO:1299), presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety, wherein [BMod] is an IL-17A binding module as defined above; and x) an amino acid sequence which has at least 86% identity to a sequence defined by ix). Alternatively, there is provided an IL-17A binding polypeptide, which comprises an amino acid sequence selected from: xi) FN-[BMod]-AP (SEQ ID NO:1300) presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety, wherein [BMod] is an IL-17A binding module as defined above; and xii) an amino acid sequence which has at least 86% identity to a sequence defined by xi). As discussed above, polypeptides comprising minor changes as compared to the above amino acid sequences without largely affecting the tertiary structure and the function thereof also fall within the scope of the present disclosure. Thus, in some embodiments, the IL-17A binding polypeptides as defined above may for example have a sequence which is at least 88%, such as at least 90%, such as at least 92%, such as at least 94%, such as at least 96%, such as at least 98% identical to a sequence defined by vii), ix) or xi). In some embodiments, the IL-17A binding motif may form part of a polypeptide comprising an amino acid sequence selected from: wherein [BM] is an IL-17A binding motif as defined above. In one embodiment, the IL-17A binding polypeptide comprises an amino acid sequence selected from: • xiii) VDAKYAK-[BM]-DPSQSSELLSEAKKLNDSQAPK (SEQ ID NO:1281), presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety wherein [BM] is an IL-17A binding motif as defined above; and • xiv) an amino acid sequence which has at least 86% identity to the sequence defined in xiii). Again, polypeptides comprising minor changes as compared to the above amino acid sequences without largely affecting the tertiary structure and the function thereof are also within the scope of the present disclosure. Thus, in some embodiments, the IL-17A binding polypeptides as defined above may for example have a sequence which is at least 87%, such as at least 89%, such as at least 91%, such as at least 93%, such as at least 94%, such as at least 96%, such as at least 98% identical to the sequence defined by xiii). Sequence xiii) in such a polypeptide may be selected from the group consisting of SEQ ID NO:1-1216, presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xiii) is selected from the group consisting of SEQ ID NO:1- 66, 1200, 1206 and 1214, presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xiii) is selected from the group consisting of SEQ ID NO:1-66, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xiii) is selected from the group consisting of SEQ ID NO:1-35, presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In another embodiment, sequence xiii) is selected from the group consisting of SEQ ID NO:1-27, presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xiii) is selected from the group consisting of SEQ ID NO:1- 10, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xiii) is selected from SEQ ID NO:1-7, presented in U.S. Patent No. 10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xiii) is selected from the group consisting of SEQ ID NO:1-4, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xiii) is SEQ ID NO:1, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, the IL-17A binding polypeptide comprises an amino acid sequence selected from: xv) AEAKYAK-[BM]-DPSQSSELLSEAKKLNDSQAPK (SEQ ID NO:1259), presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety, wherein [BM] is an IL-17A binding motif as defined above; and xvi) an amino acid sequence which has at least 86% identity to the sequence defined in xv). Again, polypeptides comprising minor changes as compared to the above amino acid sequences without largely affecting the tertiary structure and the function thereof are also within the scope of the present disclosure. Thus, in some embodiments, the IL-17A binding polypeptides as defined above may for example have a sequence which is at least 87%, such as at least 89%, such as at least 91%, such as at least 93%, such as at least 94%, such as at least 96%, such as at least 98% identical to the sequence defined by xv). Sequence xv) in such a polypeptide may be selected from the group consisting of SEQ ID NO:1217-1222, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xv) is selected from the group consisting of SEQ ID NO:1218-1222, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xv) is selected from the group consisting of SEQ ID NO:1219-1222, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In another embodiment, sequence xv) is selected from the group consisting of SEQ ID NO:1219 and SEQ ID NO:1222, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. In one embodiment, sequence xv) is SEQ ID NO:1219, presented in U.S. Patent No.10,934,335, which is incorporated by reference in its entirety. The small size and robustness of the IL-17A binding domains of the present disclosure confer several advantages over conventional monoclonal antibody-based therapies. Such advantages include the possibility of subcutaneous (s.c.) administration at higher doses than antibodies, alternative routes of administration, flexibility in formatting for superior potency and absence of Fc-mediated side effects. The small size combined with potential for very high solubility (>100 mg/ml) and stability allows for extreme molar amounts of drug in a small volume for s.c. injections. For systemic administration, this suggests outpatient “home use” treatment using convenient small prefilled syringes or auto-injectors, with low volume and well tolerated administration of doses. In addition, the capacity for high molar concentrations in drug preparations in combination with the ability to retain functional stability in diverse formulations opens up for topical (skin, eye, lung) administration routes. Psoriasis, asthma, uveitis and dry eye syndrome are examples of indications where alternative administration routes could be especially relevant in IL-17A mediated disease. The IL-17A binding motif for the bispecific fusion protein of the invention are disclosed in U.S. Patent No.10,934,335 and U.S. Patent Publication No.2021/0253659, which are hereby incorporated in their entirety by reference herein. Albumin binding motif In another embodiment of the invention, the albumin binding motif consists of an amino acid sequence selected from (SEQ ID. NO: 2) xvii) LAX 3 AKX 6 X 7 ANX 10 ELDX 14 YGVSDFYKRLIX 26 KAKTVEGVEALKX 39 X 40 IL X43X44LP; wherein independently of each other X 3 is selected from E, S, Q and C; X 6 is selected from E, S and C; X7 is selected from A and S; X 10 is selected from A, S and R; X 14 is selected from A, S, C and K; X26 is selected from D and E; X 39 is selected from D and E; X 40 is selected from A and E; X43 is selected from A and K; X44 is selected from A, S and E; L in position 45 is present or absent; and P in position 46 is present or absent; and xviii) an amino acid sequence which has at least 95% identity to the sequence defined in xvii). The above defined class of sequence related polypeptides having a binding affinity for albumin is derived from a common parent polypeptide sequence, which folds into a three alpha helix bundle domain. More specifically, the polypeptides as described above are derived from a model building based on a structure of a complex between serum albumin and the albumin binding domain G148-GA3 (Lejon et al, J Biol Chem 279:42924-8, 2004), as well as analyses of binding and structural properties of a number of mutational variants of the common parent polypeptide sequence. The above defined amino acid sequence xvii) comprises amino acid substitutions as compared to the parent polypeptide sequence that result in a class of polypeptides which are expected to fold into an almost identical three helix bundle domain. While the parent polypeptide sequence already comprises a binding surface for interaction with albumin, that binding surface is modified by some of the substitutions according to the above definition. The substitutions according to the above definition provide an improved albumin binding ability as compared to the parent polypeptide sequence. In certain embodiments, the albumin binding polypeptides exhibit a set of characteristics, which, for example, make them suitable for use as fusion or conjugate partners for therapeutic molecules for human administration. The albumin binding polypeptides according to the present disclosure demonstrate, for example in comparison with related albumin binding polypeptides such as the albumin binding domain G148-GA3 and the albumin binding polypeptides disclosed in WO 09/016,043, at least five of the following six characteristics: • The polypeptides display a different surface compared to, for example, G148-GA3 and other bacterially derived albumin binding domains. The difference may decrease or eliminate any risk for antibody reactions in a subject, such as a human, which has been previously exposed to such bacterial proteins. • The polypeptides comprise fewer potential T-cell epitopes than, for example, G148-GA3 and other related, but different, mutational variants of the common parent polypeptide sequence, and hence exhibit low immunogenicity when administered to a subject, such as a human. • The polypeptides display a lower reactivity with circulating antibodies when administered to a subject, such as a human. Thus, by amino acid substitutions in the surface of the polypeptides exposed to circulating antibodies, i.e. in the polypeptide surface not involved in the binding interaction with albumin, antibody cross-reactivity is reduced as compared to, for example, antibody cross-reactivity caused by G148-GA3 as measured in a test set of human sera. • The polypeptides have a high albumin binding ability, both in terms of a higher binding affinity, as defined by a KD value, and in terms of a slower off-rate, as defined by a k off value, than, for example, known naturally occurring albumin binding polypeptides, such as the albumin binding domains derived from bacterial proteins. • The polypeptides comprise fewer amino acid residues that are associated with stability problems of polypeptides than, for example, known naturally occurring albumin binding polypeptides, such as the albumin binding domains derived from bacterial proteins. Thus, the polypeptides comprise, for example, no oxidation-prone methionines or tryptophanes and only one asparagine. • The polypeptides have a higher structural stability, as defined by a melting point of above 55° C., than previous albumin binding polypeptides, such as those disclosed in WO 09/016,043. In another embodiment, the albumin binding motif displays all six of the above listed characteristics. In another embodiment, the albumin binding motif, when bound to albumin, a more hydrophilic profile than, for example, previous albumin binding polypeptides, such as those disclosed in WO 09/016,043. The surface of the albumin binding polypeptide which is exposed to the surroundings when the polypeptide interacts with albumin comprises fewer amino acid residues that confer surface hydrophobicity. As the skilled person will realize, the function of any polypeptide, such as the albumin binding capacity of the polypeptides, is dependent on the tertiary structure of the polypeptide. It is however possible to make changes to the sequence of amino acids in an α-helical polypeptide without affecting the structure thereof (Taverna and Goldstein, J Mol Biol 315(3):479-84, 2002; He et al, Proc Natl Acad Sci USA 105(38):14412-17, 2008). Thus, a person of ordinary skill in the art would recognize that the modified variants of i), which are such that the resulting sequence is at least 95% identical to a sequence belonging to the class defined by i), are also encompassed by the current invention. For example, it is possible that an amino acid residue belonging to a certain functional grouping of amino acid residues (e.g. hydrophobic, hydrophilic, polar etc) could be exchanged for another amino acid residue from the same functional group. The term “% identical” or “% identity”, as used in the specification and claims, is calculated as follows. The query sequence is aligned to the target sequence using the CLUSTAL W algorithm (Thompson, J. D., Higgins, D. G. and Gibson, T. J., Nucleic Acids Research, 22: 4673-4680 (1994)). A comparison is made over the window corresponding to the shortest of the aligned sequences. The shortest of the aligned sequences may in some instances be the target sequence, such as the albumin binding polypeptide disclosed herein. In other instances, the query sequence may constitute the shortest of the aligned sequences. The query sequence may for example consist of at least 10 amino acid residues, such as at least 20 amino acid residues, such as at least 30 amino acid residues, such as at least 40 amino acid residues, for example 45 amino acid residues. The amino acid residues at each position are compared, and the percentage of positions in the query sequence that have identical correspondences in the target sequence is reported as % identity. In one embodiment of the albumin binding motif, described in xvii), X 6 is E. In another embodiment of the albumin binding motif, described in xvii), X3 is S. In another embodiment of the albumin binding motif, described in xvii), X3 is E. In another embodiment of the albumin binding motif, described in xvii), X 7 is A. In another embodiment of the albumin binding motif, described in xvii), X14 is S. In another embodiment of the albumin binding motif, described in xvii), X14 is C. In another embodiment of the albumin binding motif, described in xvii), X 10 is A. In another embodiment of the albumin binding motif, described in xvii), X 10 is S. In another embodiment of the albumin binding motif, described in xvii), X 26 is D. In another embodiment of the albumin binding motif, described in xvii), X26 is E. In another embodiment of the albumin binding motif, described in xvii), X39 is D. In another embodiment of the albumin binding motif, described in xvii), X 39 is E. In another embodiment of the albumin binding motif, described in xvii), X 40 is A. In another embodiment of the albumin binding motif, described in xvii), X43 is A. In another embodiment of the albumin binding motif, described in xvii), X 44 is A. In another embodiment of the albumin binding motif, described in xvii), X 44 is S. In another embodiment of the albumin binding motif, the L residue in position 45 is present. In another embodiment of the albumin binding motif, described in xvii), the P residue in position 46 is present. In another embodiment of the albumin binding motif, described in xvii), the P residue in position 46 is absent. In another embodiment, the albumin binding polypeptide, described in xvii), is subject to the proviso that X7 is neither L, E nor D. The albumin binding polypeptide may be prepared for conjugation with a suitable conjugation partner by the replacement of surface exposed amino acid residues with, for example, either a cysteine or a lysine. These replacements may be introduced into the N-terminal helix, i.e. helix one, of the polypeptide, which is the helix situated furthest away from the serum albumin when the albumin binding polypeptide is bound to serum albumin. Thus, a lysine residue in position X14 of the sequence defined in i) may be used to enable site-directed conjugation. This may furthermore be advantageous when the molecule is made by chemical peptide synthesis, since orthogonal protection of the epsilon-amino group of said lysine may be utilized. Furthermore, a cysteine residue may be introduced into the amino acid sequence to enable site-directed conjugation. For example, a cysteine residue may be introduced into any one of the positions X3, X 6 and/or X 14 in accordance with the above definition. Coupling of a conjugation partner to the epsilon-amine of a lysine or the thiol group of a cysteine represents two chemically different alternatives to obtain site-directed conjugation using an amino acid residue within the amino acid sequence xvii). As the skilled person understands, other chemical alternatives for preparing an amino acid sequence for conjugation exist, and are as such also within the scope of the present disclosure. One example of such a chemistry is the click- like chemistry enabled by the introduction of a tyrosine as presented by Ban et al (J Am Chem Soc 132:1523-5, 2009). In one embodiment, the albumin binding polypeptide comprises one or more additional amino acid residues positioned at the N- and/or the C-terminal of the sequence defined in xvii). These additional amino acid residues may play a role in enhancing the binding of albumin by the polypeptide, and improving the conformational stability of the folded albumin binding domain, but may equally well serve other purposes, related for example to one or more of production, purification, stabilization in vivo or in vitro, coupling, labeling or detection of the polypeptide, as well as any combination thereof. Such additional amino acid residues may comprise one or more amino acid residue(s) added for purposes of chemical coupling, e.g. to a chromatographic resin to obtain an affinity matrix or to a chelating moiety for complexing with a radiometal. The amino acids directly preceding or following the alpha helix at the N- or C-terminus of the amino acid sequence xvii) may thus in one embodiment affect the conformational stability. One example of an amino acid residue which may contribute to improved conformational stability is a serine residue positioned at the N-terminal of the amino acid sequence i) as defined above. The N-terminal serine residue may in some cases form a canonical S-X-X-E capping box, by involving hydrogen bonding between the gamma oxygen of the serine side chain and the polypeptide backbone NH of the glutamic acid residue. This N-terminal capping may contribute to stabilization of the first alpha helix of the three helix domain constituting the albumin binding polypeptide. Thus, in one embodiment, the additional amino acids comprise at least one serine residue at the N-terminal of the polypeptide. The amino acid sequence is in other words preceded by one or more serine residue(s). In another embodiment of the albumin binding polypeptide, the additional amino acids comprise a glycine residue at the N-terminal of the polypeptide. It is understood that the amino acid sequence xvii) may be preceded by one, two, three, four or any suitable number of amino acid residues. Thus, the amino acid sequence may be preceded by a single serine residue, a single glycine residue or a combination of the two, such as a glycine-serine (GS) combination or a glycine-serine-serine (GSS) combination. Examples of albumin binding polypeptides comprising additional amino residues at the N-terminal are set out in SEQ ID NO:145-163, such as in SEQ ID NO:145-148 and SEQ ID NO:162-163, as presented in U.S. Patent No.9,211,344, which is incorporated by reference in its entirety. In yet another embodiment, the additional amino acid residues comprise a glutamic acid at the N-terminal of the polypeptide as defined by the sequence i). Similarly, C-terminal capping may be exploited to improve stability of the third alpha helix of the three helix domain constituting the albumin binding polypeptide. A proline residue, when present at the C-terminal of the amino acid sequence defined in i), may at least partly function as a capping residue. In such a case, a lysine residue following the proline residue at the C-terminal may contribute to further stabilization of the third helix of the albumin binding polypeptide, by hydrogen bonding between the epsilon amino group of the lysine residue and the carbonyl groups of the amino acids located two and three residues before the lysine in the polypeptide backbone, e.g., when both L45 and P46 are present, the carbonyl groups of the leucine and alanine residues of the amino acid sequence defined in xvii). Thus, in one embodiment, the additional amino acids comprise a lysine residue at the C-terminal of the polypeptide. As discussed above, the additional amino acids may be related to the production of the albumin binding polypeptide. In particular, when an albumin binding polypeptide according to an embodiment in which P46 is present is produced by chemical peptide synthesis, one or more optional amino acid residues following the C-terminal proline may provide advantages. Such additional amino acid residues may for example prevent formation of undesired substances, such as diketopiperazine at the dipeptide stage of the synthesis. One example of such an amino acid residue is glycine. Thus, in one embodiment, the additional amino acids comprise a glycine residue at the C-terminal of the polypeptide, directly following the proline residue or following an additional lysine and/or glycine residue as accounted for above. Alternatively, polypeptide production may benefit from amidation of the C-terminal proline residue of the amino acid sequence i), when present. In this case, the C-terminal proline comprises an additional amine group at the carboxyl carbon. In one embodiment of the polypeptides described herein, particularly those ending at its C-terminus with proline or other amino acid known to racemize during peptide synthesis, the above-mentioned addition of a glycine to the C-terminus or amidation of the proline, when present, can also counter potential problems with racemization of the C-terminal amino acid residue. If the polypeptide, amidated in this way, is intended to be produced by recombinant means, rather than by chemical synthesis, amidation of the C-terminal amino acid can be performed by several methods known in the art, e.g. through the use of amidating PAM enzyme. The albumin binding motifs for the bispecific fusion protein of the invention are disclosed in U.S. Patent Nos. 9,211,344, 10,329,331, 8,937,153, and 10,118,949, which are hereby incorporated in their entirety by reference herein. Pharmaceutical compositions Another aspect of the invention provides for a pharmaceutical composition comprising a bispecific fusion protein, preferably izokibep. In another aspect of the invention, the pharmaceutical composition comprises additional excipients. The pharmaceutical composition may be in a form suitable for oral use, for example, as tablets, troches, lozenges, fast-melts, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups, or elixirs. Compositions intended for oral use may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents, and preserving agents, in order to provide pharmaceutically elegant and palatable preparations. Depending on the specific conditions being treated, such agents may be formulated into liquid or solid dosage forms and administered systemically or locally. The agents may be delivered, for example, in a timed- or sustained-slow release form as is known to those skilled in the art. Techniques for formulation and administration may be found in Remington: The Science and Practice of Pharmacy (20 th ed.) Lippincott, Williams & Wilkins (2000). Suitable routes may include oral, buccal, by inhalation spray, sublingual, rectal, transdermal, vaginal, transmucosal, nasal or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intra- articullar, intra -sternal, intra-synovial, intra-hepatic, intralesional, intracranial, intraperitoneal, intranasal, or intraocular injections or other modes of delivery. For injection, the agents of the disclosure may be formulated and diluted in aqueous solutions, such as in physiologically compatible buffers such as Hank’s solution, Ringer’s solution, or physiological saline buffer. For such transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Use of pharmaceutically acceptable inert carriers to formulate the compounds herein disclosed for the practice of the disclosure into dosages suitable for systemic administration is within the scope of the disclosure. With proper choice of carrier and suitable manufacturing practice, the compositions of the present disclosure, in particular, those formulated as solutions, may be administered parenterally, such as by intravenous injection. The compounds can be formulated readily using pharmaceutically acceptable carriers well known in the art into dosages suitable for oral administration. Such carriers enable the compounds of the disclosure to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a subject (e.g., patient) to be treated. The composition may be provided according to a dosing regimen. A dosing regimen may include one or more of a dosage, a dosing frequency, and a duration. Dosing Regimen In one aspect of the invention, the aforementioned bispecific fusion protein, wherein the bispecific fusion protein comprises an IL-17A binding motif and an albumin binding motif is administered to the patients suffering from several chronic inflammatory diseases such as psoriasis, rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE) and multiple sclerosis (MS) (Miossec and Kolls, 2012, Nat Rev Drug Discov 11:763-7). Doses may be provided at any suitable interval. For example and without limitation, doses may be provided once per day, twice per day, three times per day, four times per day, five times per day, six times per day, eight times per day, once every 48 hours, once every 36 hours, once every 24 hours, once every 12 hours, once every 8 hours, once every 6 hours, once every 4 hours, once every 3 hours, once every two days, once every three days, once every four days, once every five days, once every week, twice per week, three times per week, four times per week, or five times per week. In another aspect of the invention, the aforementioned bispecific fusion protein, wherein the bispecific fusion protein comprises an IL-17A binding motif and an albumin binding motif is administered to the patients suffering from ankylosing spondylitis (AS). In another preferred aspect of the invention, a pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein is administered to a patient suffering from AS. In another aspect, there is provided a composition comprising a bispecific fusion protein, as described herein, and at least one pharmaceutically acceptable excipient or carrier. In one embodiment, said composition further comprises at least one additional active agent, such as at least two additional active agents, such as at least three additional active agents. Non- limiting examples of additional active agents that may prove useful in such a composition are the therapeutically active polypeptides, immune response modifying agents and toxic compounds described herein. In another aspect of the invention, a pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered to a patient suffering from AS. In another aspect of the invention, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered by a subcutaneous injection. In another aspect of the invention, the pharmaceutical composition comprises about 20 to about 400 mg izokibep. In another aspect of the invention, the pharmaceutical composition comprises about 40 mg, about 80 mg, or about 160 mg izokibep. In another aspect of the invention, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered as a subcutaneous injection once weekly, twice weekly, or once every four weeks. In another aspect of the invention, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered as a subcutaneous injection is administered for at least 16 weeks. In another aspect of the invention, the pharmaceutical composition comprising a therapeutically effective of amount of the bispecific fusion protein, preferably izokibep, is administered as a subcutaneous injection is administered for at least 52 weeks. In another aspect of the invention, the pharmaceutical composition comprising about 40 mg izokibep is administered once a week to a patient suffering from AS. In another aspect of the invention, the pharmaceutical composition comprising about 160 mg izokibep is administered once a week to a patient suffering from AS. In another aspect of the invention, the administration of the pharmaceutical compositions comprising izokibep leads to a clinical response as assessed by Assessment of Spondyloarthritis International Society 40 (ASAS40) response after 16 weeks or 52 weeks in subjects with active AS. In a preferred embodiment, the patient suffering from AS achieves a ASA40 response after 16 weeks. In another aspect of the invention, the patient is suffering from axial spondyloarthritis (AxSpA). In another aspect of the invention, the patient is suffering from radiographic axial spondyloarthritis (r-AxSpA). In another aspect of the invention, the patient is suffering from non-radiographic axial spondyloarthritis (nr-AxSpA). In another aspect of the invention, the patient is administered the pharmaceutical compositions comprising izokibep suffering from AS had an inadequate response or intolerance to at least 2 Non-steroidal anti-inflammatory drugs (NSAIDs), or contraindication to NSAID therapy. In another aspect of the invention, the patient is administered the pharmaceutical compositions comprising izokibep suffering from AS is TNFα inhibitor-naïve or may have received up to 2 prior TNFα inhibitor(s). In another aspect of the invention, the patient is administered the pharmaceutical compositions comprising izokibep suffering from AS had an inadequate response to any previous therapies, including a therapy by a biomolecule, or any other Janus Kinase (JAK) inhibitors. Examples The examples provided herein are representative for the dosing regimens disclosed in the invention. An exemplary clinical dosing in accordance with the present disclosure is provided below. The study will include the following 3 periods: 1. Screening Period: Up to 35 days prior to baseline randomization. 2. Treatment Period 1: (Placebo-Controlled, Double-Blind Period): Day 0 to Week 16 Cohort 1: Eligible subjects will be randomized 1:1:1:1 to receive 1 of 4 treatments (Izokibep 160 mg once every two weeks, izokibep 40 mg once every two weeks, izokibep 160 mg once every four weeks, or placebo Q2W), and will remain on their allowable background medication. Cohort 2: Eligible subjects will be randomized 1:1:1 to receive 1 of 3 treatments (izokibep 160 mg once a week, izokibep 40 mg once a week, or placebo once a week), and will remain on their allowable background medication. Treatment Period 1 ends at Week 16 after all trial assessments have been done and Treatment Period 2 starts at Week 16 with the IMP injection. 3. Treatment Period 2 (Open-label Extension Period): Week 16 to Week 52 Cohort 1: Subjects will receive izokibep 160 mg once every two weeks subcutaneous injection treatment in an open-label manner.; Cohort 2: Subjects will receive izokibep 160 mg once a week subcutaneous treatment in an open-label manner. At week 24, subjects who could not achieve an ASAS20 response from baseline are defined as non-responders and will discontinue the study treatment. Inclusion Criteria 1. Male or female at least 18 years of age. 2. Subjects with active AS, determined by documented radiologic evidence (X-ray) fulfilling the Modified New York criteria for AS (1984) and at least one SpA feature, according to ASAS criteria. 3. Subjects have moderate to severe active disease 4. Subjects must have inadequate response or intolerance to at least 2 NSAIDs, or contraindication to NSAID therapy. 5. Subjects may be TNFα inhibitor-naïve or may have received up to 2 prior TNFα inhibitor(s). Exclusion Criteria 1. Subjects have active fibromyalgia or total spinal ankylosis ('bamboo spine'), or any other inflammatory arthritis. 2. Subjects have used medications in the manner as detailed by the exclusion criteria as detailed in the study protocol. 3. Subjects have received technetium-99 conjugated with methylene diphosphonate other than for diagnostic purpose within 5 years prior to baseline. 4. Have received any live (includes attenuated) vaccination within the 12 weeks prior to the baseline. 5. Subjects have received any non-biological therapy for AS not listed as detailed in the study protocol within or outside a clinical study in the 3 months or within 5 half-lives prior to the Baseline Visit (whichever is longer). 6. Subject has an active infection or history of infections 7. Have evidence of or test positive for hepatitis B virus (HBV) 8. Have evidence of or test positive for hepatitis C virus (HCV). 9. Have a historically positive human immunodeficiency virus (HIV) test or test positive at screening for HIV. 10. Subjects have known tuberculosis (TB) infection, at high risk of acquiring TB infection, or current or history of nontuberculous mycobacterium (NTMB) infection, or LTB. 11. Have a history of a lymphoproliferative disorder including lymphoma or current signs and symptoms suggestive of lymphoproliferative disease. 12. Subjects have active Crohn's disease (CD) or active ulcerative colitis (UC). 13. Subjects have active uveitis within 6 weeks prior to baseline. 14. Subjects have laboratory abnormalities at Screening. Dosing Regimen The dosing regimen in the various arms of clinical trials are provided below.
Primary Outcome Measures: 1. Proportion of subjects achieving an ASAS40 response [ Time Frame: 16 weeks] Secondary Outcome Measures: 2. Change from baseline in BASDAI [ Time Frame: 16 weeks] 3. Change from baseline in BASFI [ Time Frame: 16 weeks] 4. Proportion of subjects reaching ASDAS-MI [ Time Frame: 16 weeks] 5. Incidence of AEs [ Time Frame: 74 weeks] 6. Incidence of serious adverse events (SAEs) [ Time Frame: 74 weeks ] 7. AEs leading to withdrawal from investigational medicinal product (IMP) [ Time Frame: 74 weeks ] 8. Proportion of subjects achieving an ASAS40 response at Week 2, 24 and 52 [ Time Frame: 52 weeks ] 9. Change from baseline in BASDAI at Week 2, 24 and 52 [Time Frame: 52 weeks] 10. Change from baseline in BASFI at Week 2, 24 and 52 [Time Frame: 52 weeks] 11. Proportion of subjects reaching ASDAS-MI at Week 24 and 52 [Time Frame: 52 weeks] Incorporation by Reference References and citations to other documents, such as patents, patent applications, patent publications, journals, books, papers, web contents, have been made throughout this disclosure. All such documents are hereby incorporated herein by reference in their entirety for all purposes. Equivalents Various modifications of the invention and many further embodiments thereof, in addition to those shown and described herein, will become apparent to those skilled in the art from the full contents of this document, including references to the scientific and patent literature cited herein. The subject matter herein contains important information, exemplification and guidance that can be adapted to the practice of this invention in its various embodiments and equivalents thereof.
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