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US 2016/0102123 A1Published application
Stabilized soluble prefusion rsv f polypeptides
AssigneeCrucell Holland B.V.
InventorsJohannes Petrus Maria Langedijk, Anders Krarup
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Abstract
Described are stable pre-fusion respiratory syncitial virus (RSV) F polypeptides, immunogenic compositions comprising the polypeptides and uses thereof for the prevention and/or treatment of RSV infection.
Claims53
A recombinant pre-fusion respiratory syncytial virus (RSV) Fusion (F) polypeptide, comprising:
- at least one epitope that is specific to the pre-fusion conformation F protein, wherein the at least one epitope is recognized by
- a pre-fusion specific monoclonal antibody comprising:
- a heavy chain CDR1 region of SEQ ID NO:
- 54,
- a heavy chain CDR2 region of SEQ ID NO:
- 55,
- a heavy chain CDR3 region of SEQ ID NO:
- 56, and
- a light chain CDR1 region of SEQ ID NO:
- 62,
- a light chain CDR2 region of SEQ ID NO:
- 63, and
- a light chain CDR3 region of SEQ ID NO:
- 64, and/or
- a pre-fusion specific monoclonal antibody comprising:
- a heavy chain CDR1 region of SEQ ID NO:
- 58,
- a heavy chain CDR2 region of SEQ ID NO:
- 59,
- a heavy chain CDR3 region of SEQ ID NO:
- 60 and
- a light chain CDR1 region of SEQ ID NO:
- 66,
- a light chain CDR2 region of SEQ ID NO:
- 67, and
- a light chain CDR3 region of SEQ ID NO:
- 68.
24 more elements
A method for stabilizing the pre-fusion conformation of an RSV F polypeptide, the method comprising:
- introducing one or more mutations in a RSV F1 and/or F2 domain, as compared to the wild-type RSV F1 and/or F2 domain, wherein the one or more mutations are selected from the group consisting of:
- (a) a stabilizing mutation in a region that locks the HRA domain from hinging adjacent to the conserved 69-212 disulfide bridge, said region comprising the amino acid residues 66-68 and 214-216,
- (b) a mutation in the helix comprising the amino acid residues 76-98 at the C-terminus of the F2 domain;
- (c) a mutation that reduces the negative charge repulsion between the top of the HRB stem region comprising amino acids 486, 487;
- and
- (d) a stabilizing mutation in the HRA region.
3 more elements
Dependencies are inferred from the claim text.