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Compositions comprising streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof

一种肺炎链球菌、多糖蛋白的技术，应用在药物组合、含有效成分的医用配制品、非有效成分的医用配制品等方向，能够解决肺炎球菌流行率增加等问题

Pending Publication Date: 2021-09-28
MERCK SHARP & DOHME BV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prevalence of pneumococci expressing serotypes not present in currently available vaccines has been increasing

Method used

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  • Compositions comprising streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof
  • Compositions comprising streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof
  • Compositions comprising streptococcus pneumoniae polysaccharide-protein conjugates and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0438] Preparation of Streptococcus pneumoniae capsular polysaccharide

[0439] Methods of culturing pneumococci are well known in the art. See, eg, Chase, 1967, Methods of Immunology and Immunochemistry 1:52. Methods of preparing pneumococcal capsular polysaccharides are also well known in the art. See, eg, European Patent No. EP 0 497 524 B1. The method described below generally follows that described in European Patent No. EP0 497524 B1 and is generally applicable to all pneumococcal serotypes.

[0440] Isolation of pneumococcal strains of serotypes 1, 3, 4, 5, 6A, 6B, 7F, 8, 9V, 10A, 11A, 12F, 14, 15A, 15B, 18C, 19A, 19F, 22F, 23F, 33F, and 35B Strains were obtained from the Merck Culture Collection. Serotype 23B strains were obtained from the Centers for Disease Control and Prevention and the University of Alabama at Birmingham. Serotype 24F strains were obtained from the Merck Culture Collection and the University of Alabama at Birmingham. Subtypes can be different...

Embodiment 2

[0444] Purification of pneumococcal polysaccharide

[0445] Purification of pneumococcal polysaccharides consists of multiple centrifugation, depth filtration, concentration / diafiltration operations and precipitation steps. All steps were performed at room temperature unless otherwise stated.

[0446] Use cationic polymers (such as BPA-1000, (Baker Hughes Inc., Houston, TX), Spectrum 8160, poly(ethyleneimine), and Millipore pDADMAC) were flocculated of inactivated media from fermentor cultures of S. pneumoniae. Cationic polymers bind to impurity proteins, nucleic acids and cellular debris. After the flocculation step and aging phase, the flocculated solids are removed by centrifugation and multiple depth filtration steps. Clarified medium was concentrated and diafiltered using 100 kDa to 500 kDa MWCO (molecular weight cut off) filters. Diafiltration is using Tris, MgCl 2 buffer and sodium phosphate buffer. Diafiltration removes residual nucleic acids and proteins.

[0...

Embodiment 3

[0449] Preparation of serotype 1 conjugates for polyvalent studies of PCV23 (DMSO) using DMSO conjugation

[0450] Polysaccharides are solubilized, size reduced to target molecular weight, chemically activated and buffer exchanged by ultrafiltration. Activated polysaccharide and purified CRM197 were separately lyophilized and then redissolved in dimethyl sulfoxide (DMSO). The redissolved polysaccharide and CRM197 solutions were then combined and conjugated as described below. The resulting conjugate was purified by ultrafiltration before a final 0.2 micron filtration. Multiple process parameters such as pH, temperature, concentration and time are controlled in each step to produce conjugates with desired properties.

[0451] Polysaccharide size reduction and oxidation

[0452] The purified pneumococcal capsular Ps powder was dissolved in water and subjected to 0.45 micron filtration. The dissolved polysaccharides were homogenized to reduce the Ps molecular weight. The hom...

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Abstract

The invention is related to multivalent immunogenic compositions comprising more than one S. pneumoniae polysaccharide protein conjugates, wherein each of the conjugates comprises a polysaccharide from an S. pneumoniae serotype conjugated to a carrier protein, and the serotypes of S. pneumoniae are as defined herein. In some embodiments, at least one of the polysaccharide protein conjugates is formed by a conjugation reaction comprising an aprotic solvent. In further embodiments, each of the polysaccharide protein conjugates is formed by a conjugation reaction comprising an aprotic solvent. Also provided are methods for inducing the protective immune response in a human patient comprising administering the multivalent immunogenic compositions of the invention to the patient. The multivalent immunogenic compositions are useful for providing protection against S. pneumoniae infection and / or pneumococcal diseases caused by S. pneumoniae. The compositions of the invention are also useful as part of treatment regimes that provide complementary protection for patients that have been vaccinated with a multivalent vaccine indicated for the prevention of pneumococcal disease.

Description

technical field [0001] The present invention provides multivalent immunogenic compositions with different polysaccharide-protein conjugates. Each conjugate consists of a capsular polysaccharide prepared from a different serotype of Streptococcus pneumoniae conjugated to a carrier protein, preferably CRM197. Immunogenic compositions provide broad coverage against pneumococcal disease. [0002] This application contains a Sequence Listing, which has been filed electronically in ASCII format, the entire contents of which are hereby incorporated by reference. Said ASCII copy, created on December 3, 2019, is named 24683WOPCT-SEQTXT-03DEC2019 and is 6 kilobytes in size. Background technique [0003] Streptococcus pneumoniae is a Gram-positive bacterium that is the most common cause of invasive bacterial disease in infants and young children, such as pneumonia, bacteremia, meningitis, and otitis media. Pneumococci are coated with chemically linked polysaccharides that confer ser...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/09A61P31/04
CPCA61K39/092A61K2039/70A61K2039/55505A61K2039/6037A61P31/04A61K47/62A61K47/61A61K39/116A61P37/04A61K47/20A61K2039/55588A61K2039/6068
Inventor C·阿拜古纳瓦达纳Y·A·崔R·费雷罗何健L·穆西T·皮蒂贾拉J·M·斯金纳
Owner MERCK SHARP & DOHME BV
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