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Hybrid polypeptides including meningococcal fHBP sequences

A meningococcal and sequence technology, applied in the field of immunity, can solve the problem of inactivity of bacterial strains

Inactive Publication Date: 2012-07-18
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The fHBP sequences are grouped into three families [4] (referred to herein as families I, II & III), and sera produced against a particular family are bactericidal in the same family, but inactive against strains expressing one of the other families, i.e. There is cross-protection within, not between, families

Method used

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  • Hybrid polypeptides including meningococcal fHBP sequences
  • Hybrid polypeptides including meningococcal fHBP sequences
  • Hybrid polypeptides including meningococcal fHBP sequences

Examples

Experimental program
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Effect test

Embodiment 1

[0249] Using the wild-type MC58 sequence (SEQ ID NO: 1) as a baseline, reference 15 produced 72 modified fHBP sequences. These are SEQ ID NO: 4-75. Using a similar approach, the inventors now provide SEQ ID NOs: 77 and 78.

[0250] The polypeptide expressed in E. coli has an N-terminal methionine followed by the amino acid sequence of SEQ ID NO. Combining the polypeptide with aluminum hydroxide adjuvant, sometimes including IC31 TM , and then used to immunize mice. Antisera in mice were tested in a bactericidal assay against a panel of meningococcal strains. Included in this panel were strains from each of the three fHBP families. Wild-type MC58 polypeptides from families I and II were also used to vaccinate mice for comparison.

[0251] Particularly good results were obtained for polypeptides comprising SEQ ID NO:78. Serum directed against this polypeptide was bactericidal against 5 different family I strains (MC58, NM008, M4030, GB185, NZ) and 4 different family II str...

Embodiment 2

[0253] Various modified fHBP sequences fused to:

[0254] (i) each other; (ii) the wild type fHBP sequence; or (iii) other meningococcal antigens. These were expressed with or without a C-terminal polyhistidine tag and purified from E. coli using IMAC.

[0255] Fusion proteins fall into four main categories: (a) fusions of two modified fHBP sequences that are the same or different; (b) fusions of three modified fHBP sequences that are the same or different; (c) fusions of wild-type fHBP sequences with one or a fusion of two modified fHBP sequences; and (d) a fusion of a modified fHBP sequence to a non-fHBP meningococcal antigen. These different fusion proteins comprise the following amino acid sequences:

[0256] (a) fusion of two modified fHBP sequences, identical or different,

[0257] 9C-9C........ SEQ ID NO: 132

[0258] 10A-10A...SEQ ID NO: 134

[0259] 10A-9C.......SEQ ID NO: 135

[0260] 8B-8B ......... SEQ ID NO: 138

[0261] 9C-10A.......SEQ ID NO: 133

[0262] ...

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Abstract

fHBP is a protein in Neisseria meningitidis. Three families of fHBP are known. To increase the ability of a fHBP protein to elicit antibodies that are cross-reactive between the families, fHBP is selected or engineered to have a sequence which can elicit broad-spectrum bactericidal anti-meningococcal antibodies after administration to a host animal.

Description

[0001] This application claims the benefit of US Provisional Application No. 61 / 237,576, filed August 27, 2009, the entire contents of which are incorporated herein by reference for all purposes. technical field [0002] The present invention belongs to the field of immunization, in particular, immunization against diseases caused by pathogenic bacteria of the genus Neisseria such as N. meningitidis (meningococcus). Background technique [0003] Neisseria meningitidis is a Gram-negative enveloped bacterial pathogen. While polysaccharide and conjugate vaccines exist for serogroups A, C, W135, and Y, this approach cannot be applied to serogroup B because capsular polysaccharide is a polymer of polysialic acid, an autologous antigen. To generate a vaccine against serogroup B, outer membrane vesicles (OMVs) are used. These vaccines elicit a serum bactericidal antibody response and protection against disease, but fail to induce cross-protection between strains [1]. Some invest...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/095C07K14/22
CPCC07K2319/00C07K14/22A61K39/00A61P31/04A61P37/04
Inventor M·皮萨M·斯卡塞利R·拉普奥利M·M·朱利亚尼M·阿科
Owner NOVARTIS AG