Fviii-vwf fusion proteins with improved pharmacokinetics
A fusion protein combining FVIII, VWF, and extended peptides with O-glycosylation sites addresses rapid clearance issues, improving stability and therapeutic efficacy for hemophilia treatment.
Patent Information
- Authority / Receiving Office
- HK · HK
- Patent Type
- Applications
- Current Assignee / Owner
- OCTAPHARMA AG
- Filing Date
- 2026-04-20
- Publication Date
- 2026-07-10
AI Technical Summary
Existing factor VIII (FVIII) and von Willebrand factor (VWF) proteins face challenges in drug metabolism, particularly in maintaining stability and efficacy due to their rapid clearance from the bloodstream, leading to suboptimal therapeutic outcomes in hemophilia treatment.
A fusion protein is developed comprising an FVIII heavy chain, an FVIII light chain, a fragment of VWF, and extended peptides (EPs) with specific O-glycosylation sites, enhancing drug metabolism properties.
The fusion protein exhibits improved stability and prolonged circulation time in the bloodstream, thereby enhancing therapeutic efficacy for hemophilia treatment.
Abstract
Description
HK Application no: 62026122103.5 Our Ref: HKP / 2026 / 95373 cc * (Draft) * May 22, 2026 Invention Title: FVIII-VWF Fusion Protein with Improved Drug Metabolism Abstract This invention relates to a fusion protein comprising: a factor VIII (FVIII) heavy chain; an FVIII light chain; a fragment of von Willebrand factor (VWF); and at least two copies of an extended peptide (EP); wherein the EP has at least 90% identical amino acid sequence to SEQ ID NO: 1 and contains a cluster of O-glycosylation sites, wherein the cluster contains at least two O-glycosylated amino acids. The complex exhibits improved drug metabolism properties compared to FVIII. This invention also relates to a polynucleotide encoding the fusion protein and a vector and host cell comprising the polynucleotide. Abstract
Claims
C l a i m s1 . A fusion protein comprising:• A Factor VIII (FVIII) heavy chain;• an FVIII light chain;• a fragment of von Willebrand Factor (VWF); and• at least two copies of an extension peptide (EP); wherein the EP has at least 90 % amino acid sequence identity to SEQ ID NO: 1 and contains a cluster of O-glycosylation sites, wherein the cluster contains at least two O-glycosylated amino acids.
2. The fusion protein according to claim 1 , wherein• the FVIII heavy chain does not contain the FVIII B-domain and preferably comprises an amino acid sequence with an identity of at least 90 %, more preferably at least 95 %, most preferably at least 98 % to SEQ ID NO: 2;• the FVIII light chain comprises an amino acid sequence with an identity of at least 90 %, preferably at least 95 %, more preferably at least 98 % to SEQ ID NO: 3; and / or• the fragment of VWF comprises an amino acid sequence with an identity of at least 90 %, preferably at least 95 %, more preferably at least 98 % to SEQ ID NO: 4.
3. The fusion protein according to claim 1 or 2, wherein• the C-terminus of the FVIII heavy chain is fused to the N-terminus of the FVIII light chain by a first linker, wherein the first linker preferably comprises a sequence derived from the B-domain of FVIII; and / or• the C-terminus of the FVIII light chain is fused to the N-terminus of the VWF fragment by a second linker.
4. The fusion protein according to claim 3, wherein the first linker and / or the second linker comprise(s) at least one copy, preferably at least two copies, more preferably at least three copies of the EP, wherein the EPs are preferably assembled in a consecutive order.
5. The fusion protein according to claims 1 to 4, further containing at least one half-life prolonging moiety, preferably selected from an immunoglobulin Fc-domain, serum albumin or parts thereof, an albumin binding antibody, an albumin binding protein domain, the most preferred half-life prolonging moiety being an albumin binding VHH domain.
6. The fusion protein according to claims 1 to 5, wherein the half-life prolonging moiety is either a) fused to the C-terminus of the protein by a third linker or b) forms part of the first linker.
7. The fusion protein according to claims 3 to 6, wherein the first, second and / or third linker are flexible and comprise (GGS)n, (GGGS)n, or (GGGGS)n, wherein n is an integer in the range of 1 and 10 and wherein G represents glycine and S represents serine.
8. The fusion protein according to any one of claims 3 to 7, wherein the second linker comprises a thrombin cleavage site, preferably wherein the thrombin cleavage site is defined by SEQ ID NO: 19.
9. The fusion protein according to claim 8, wherein two consecutive copies of the GGGGS motif are located at the N-terminus and / or the C-terminus of the second linker.
10. The fusion protein according to any of claims 3 to 9, wherein the amino acid sequence of the second linker is at least 95 %, more preferably at least 98 % to a sequence selected from SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10 and SEQ ID NO: 11.
11. The fusion protein according to any of claims 3 to 10, wherein the first linker comprises a furin cleavage site, wherein the furin cleavage site preferably has the amino acid sequence of SEQ ID NO: 20.
12. The fusion protein according to any of claims 3 to 11 , wherein the amino acid sequence of the first linker is at least 95 %, more preferably at least 98 % to asequence selected from SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17 or SEQ ID NO: 18.
13. The fusion protein according to any of claims 5 to 12, wherein the first and / or the second linker contain(s) at least two copies of the GGGGS motif on either side of an EP assembly and / or on either side of the half-life prolonging moiety.
14. The fusion protein according to any one of the previous claims, wherein at least two copies of the EPs are fused to the C-terminus of the VWF fragment.
15. The fusion protein according to any one of the previous claims, wherein the amino acid sequence of the fusion protein is at least 95 %, more preferably at least 98 % identical to a sequence selected from SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27 SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36.
16. A fusion protein for use in the treatment of a bleeding disorder, wherein the fusion protein is defined according to any of the preceding claims.
17. A polynucleotide encoding a fusion protein according to any of claims 1 to 16.
18. The polynucleotide according to claim 17, encoding an amino acid sequence with an identity of at least 90 %, preferably at least 95 %, more preferably at least 98 %, most preferably 100 % to a sequence selected from SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31 , SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35 and SEQ ID NO: 36.
19. A vector containing the polynucleotide according to claim 16 or 17, wherein the vector backbone is preferably selected from pCDNA3, pCDNA3.1 , pCDNA4, pCDNA5, pCDNA6, pCEP4, pCEP-puro, pCET1019, pCMV, pEF1 , pEF4, pEF5, pEF6, pExchange, pEXPR, pIRES, and pSCAS.
20. A host cell containing the polynucleotide according to claim 17 or 18 or the vector according to claim 19, wherein the host cell is a cell of a mammalian cell line, preferably a human cell line, more preferably a human kidney cell line, most preferably a human embryonic kidney cell line, in particular a HEK293 cell line such as HEK293F.