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US 11,685,771 B2Granted
Recombinant factor VIII proteins
AssigneeBioverativ Therapeutics Inc.
InventorJohn Kulman
Life of this patent
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Abstract
Provided are recombinant Factor VIII proteins, e.g., human Factor VIII proteins with heterologous moieties inserted into flexible permissive loops located in the Factor VIII A domains, while retaining the procoagulant activity of Factor VIII.
Claims13
An isolated nucleic acid comprising a sequence encoding a recombinant FVIII protein, wherein the recombinant FVIII protein comprises:
- a first polypeptide comprising Formula I:
- (A1)-a1-(A2)-a2-[B];
- and a second polypeptide comprising Formula II:
- a3-(A3)-(C1);
- wherein the first polypeptide and the second polypeptide are fused or exist as a heterodimer;
- wherein, a) A1 is an A1 domain of FVIII;
- b) A2 is an A2 domain of FVIII;
- c) [B] is a B domain of FVIII, a fragment thereof, or is deleted;
- d) A3 is an A3 domain of FVIII;
- e) C1 is a C1 domain of FVIII;
- f) a1, a2, and a3 are acidic spacer regions;
- wherein the A1 domain comprises a permissive loop-1 (A1-1) region and a permissive loop-2 (A1-2) region;
- wherein the A2 domain comprises a permissive loop-1 (A2-1) region and a permissive loop-2 (A2-2) region;
- wherein the A3 domain comprises a permissive loop-1 (A3-1) region and a permissive loop-2 (A3-2) region;
- wherein a first half-life extending moiety and a second half-life extending moiety are inserted within the FVIII protein immediately downstream of amino acids which correspond to amino acids in mature native human FVIII selected from the group consisting of:
- a) amino acids 18 and 1656 of SEQ ID NO:1;
- b) amino acids 40 and 1656 of SEQ ID NO:1;
- c) amino acids 399 and 1656 of SEQ ID NO:1;
- d) amino acids 403 and 1656 of SEQ ID NO:1;
- e) amino acids 1656 and 1720 of SEQ ID NO:1;
- f) amino acids 1656 and 1900 of SEQ ID NO:1;
- g) amino acids 18 and 399 of SEQ ID NO:1;
- h) amino acids 26 and 399 of SEQ ID NO:1;
- and
- i) amino acids 40 and 399 of SEQ ID NO:1;
- wherein the first half-life extending moiety and the second half-life extending moiety are independently selected from the group consisting of:
- (a) albumin;
- (b) albumin-binding polypeptide;
- (c) Fe;
- (d) PAS;
- (e) the C-terminal peptide (CTP) of the β subunit of human chorionic gonadotropin;
- (f) polyethylene glycol (PEG);
- (g) hydroxyethyl starch (HES);
- (h) albumin-binding small molecules;
- (i) a clearance receptor, or fragment thereof, wherein the clearance receptor blocks binding of the recombinant FVIII protein to FVIII clearance receptors;
- (j) a low-density lipoprotein receptor-related protein 1 (LRP1) or a FVIII-binding fragment thereof;
- (k) an XTEN;
- and
- (l) any combination of (a)-(j);
- and
- wherein the recombinant FVIII protein exhibits procoagulant activity.
38 more elements
Dependencies are inferred from the claim text.