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US 2014/0348869 A1Published application
Modified meningococcal fhbp polypeptides
AssigneeNovartis AG
InventorsLucia BANCI, Francesca CANTINI, Sara DRAGONETTI, Maria Antonietta GENTILE, Daniele VEGGI, Maria SCARSELLI, Mariagrazia PIZZA
Life of this patent
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Abstract
The factor H binding activity of meningococcal fHBP can be uncoupled from its bactericidal sensitivity. NMR studies have identified various amino acid residues involved in the fHBP/fH interaction and one or more of these residues is modified in a fHBP to reduce or eliminate its ability to bind to fH.
Claims16
1:
- A polypeptide comprising an amino acid sequence:
- (a) which has at least 85% identity to any one of SEQ ID NOs:
- 4, 5 or 6, and/or comprises a fragment of SEQ ID NO:
- 4, 5 or 6;
- but (b) wherein one or more of the following amino acid residues from SEQ ID NO:
- 4, 5 or 6 is either absent or is substituted by a different amino acid:
- SEQ ID NO:
- 4
- SEQ ID NO:
- 5
- SEQ ID NO:
- 6
- Asp-37
- Asp-37
- Glu-42
- Lys-45
- Lys-45
- Thr-50
- Thr-56
- Thr-56
- Thr-61
- Glu-83
- Glu-83
- Glu-91
- Glu-95
- Glu-95
- Glu-103
- Glu-112
- Glu-112
- Glu-120
- Lys-122
- Ser-122
- Ser-130
- Val-124
- Ile-124
- Ile-132
- Arg-127
- Arg-127
- Arg-135
- Thr-139
- Thr-139
- Thr-147
- Phe-141
- Phe-141
- Phe-149
- Asp-142
- Asn-142
- Asn-150
- Lys-143
- Gln-143
- Gln-151
- Ile-198
- Leu-197
- Leu-205
- Ser-211
- Asp-210
- Asp-218
- Leu-213
- Arg-212
- Arg-220
- Lys-219
- Lys-218
- Lys-226
- Asn-43
- Asn-43
- Asn-48
- Asp-116
- Asn-116
- Asn-124
- His-119
- Lys-119
- Lys-127
- Ser-221
- Thr-220
- Thr-228
- Lys-241
- Lys-240
- Lys-248
- wherein the polypeptide (i) can, after administration to a host animal, elicit antibodies which can recognise a wild-type meningococcal polypeptide consisting of SEQ ID NO:
- 4, 5 or 6, and (ii) has a lower affinity for human factor H than the same polypeptide but without the modification(s) of (b).
77 more elements
2:
- The polypeptide of claim 1, comprising an amino acid sequence which has at least 85% identity to SEQ ID NO:
- 4 and/or comprises a fragment of SEQ ID NO:
- 4, and which can, after administration to a host animal, elicit antibodies which can recognise a wild-type meningococcal polypeptide consisting of SEQ ID NO:
- 4.
1 more element
3:
- A method for designing a modified fHBP amino acid sequence comprising steps of:
- (i) providing a starting amino acid sequence, wherein a protein consisting of or comprising the starting amino acid sequence can bind to human factor H;
- (ii) identifying within the starting amino acid sequence an amino acid residue which, using a pairwise alignment algorithm, aligns with a residue in SEQ ID NO:
- 4, 5 or 6 as listed in the table in claim 1;
- (iii) either deleting the amino acid identified in step (ii), or replacing it with a different amino acid, thereby providing the modified fHBP amino acid sequence.
2 more elements
4:
- A polypeptide comprising (i) a modified fHBP amino acid sequence designed by the method of claim 3, or (ii) an amino acid sequence selected from SEQ ID NOs:
- 23 to 32.
5:
- Nucleic acid encoding the polypeptide of claim 1.
6:
- A plasmid comprising a nucleotide sequence encoding the polypeptide of claim 1.
7:
- A host cell transformed with the plasmid of claim 6.
8:
- The host cell of claim 7, wherein the cell is a meningococcal bacterium.
9:
- Membrane vesicles, wherein the vesicles include a polypeptide of claim 1.
10:
- An immunogenic composition comprising a polypeptide of claim 1.
11:
- The composition of claim 10, including an adjuvant.
12:
- The composition of claim 11, wherein the adjuvant comprises an aluminium salt.
13:
- The composition of claim 10, further comprising a second polypeptide that, when administered to a mammal, elicits an antibody response that is bactericidal against meningococcus, provided that the second polypeptide is not a meningococcal fHBP.
14:
- The composition of claim 10, further comprising a conjugated capsular saccharide from N. meningitidis serogroup A, C, W135 and/or Y.
15:
- The composition of claim 10, further comprising a conjugated pneumococcal capsular saccharide.
16:
- A method for raising an antibody response in a mammal, comprising administering an immunogenic composition of claim 10.