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Recombinant polypeptide construct comprising multiple enterotoxigenic Escherichia coli fimbrial subunits

a technology of escherichia coli and polypeptides, which is applied in the direction of peptides, antibacterial agents, antibacterial ingredients, etc., can solve the problems of limited serologic cross-reactivity of native fimbriae, and achieve the effects of reducing amino acid sequence length, avoiding undesirable associations, and reducing protease cleavag

Active Publication Date: 2016-02-25
THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE NAVY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]The embodied multipartite construct can contain a deletion of the N-terminal region of one or more fimbrial subunits to avoid undesirable associations with other monomers or multimers and to remove reduce amino acid sequence length between polypeptides to reduce the protease cleavage.

Problems solved by technology

Serologic cross-reactivity of native fimbriae is, however, limited, and the pattern of cross-reactivity correlates with phylogenetically defined subtaxons of the major subunits (Gaastra, et al., Int. J. Med. Microbiol., 292: 43-50 (2002).

Method used

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  • Recombinant polypeptide construct comprising multiple enterotoxigenic Escherichia coli fimbrial subunits
  • Recombinant polypeptide construct comprising multiple enterotoxigenic Escherichia coli fimbrial subunits
  • Recombinant polypeptide construct comprising multiple enterotoxigenic Escherichia coli fimbrial subunits

Examples

Experimental program
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Effect test

example 1

Recombinant anti-ETEC Construct

[0053]Immunity to ETEC adhesin is important in reducing colonization of ETEC bacteria. However, the minor subunits (i.e., adhesin), the contact site of ETEC bacteria to the intestimal lumen, of ETEC Class 5 fimbriae are stoichiometrically represented in very low numbers relative to the major subunit. Therefore, in immunogenic compositions, it is important to enhance the immune recognition of the minor subunit over that not normally found in natural fimbriae.

[0054]Since fimbrial subunits, such as CfaE, are relatively susceptible to proteolytic degradation outside of the fimbrial structure, stabilization of the adhesin is also important. Therefore, constructs are designed to express ETEC subunits stabilized from misfolding and degradation by donor strand complementation. The donor β strand is provided by the major fimbrial subunit. For example, in the case of CfaE, stabilization is provided by the N-terminal region of CfaB. Engineering of dscCfaE by inco...

example 2

CS6 and CS3

[0068]Rabbit model (RITARD) studies suggest the colonization factor CS6 and CS3 has immune-protective potential (Svennerholm, et al., Infect. Immun. 56: 523-528 (1988); Svennerholm, et al., Infect. Immun. 58: 341-346 (1990)). As such, an important technical goal is to reproduce a stabilized CS6 expressing recombinant structure expressing CS6 antigens that maximally elicits antibody responses inhibitory to CS6-directed adhesion.

[0069]Unlike class 5 ETEC fimbriae, the fimbrial structures may function as polyadhesins rather than monadhesins (Zavialov, et al., FEMS Microbiol. Rev. 31: 478-514 (2007)). Extrapolation from related fimbriae, assembly of ETEC CS6 and CS3 may be mediated by a donor strand complementation mediated process through association of a CS6 or CS3 subunit with the N-terminal donor strand region of an adjacent subunit. Additionally, protection against misfolding and proteolytic degradation may also be afforded through donor strand complementation.

[0070]Asso...

example 4

Construction of Multipartite Fusion Constructs

[0096]Immunity to multiple strains of ETEC is important to obtain the greatest extent of anti-ETEC immunity. Toward this goal, recombinant polypeptide constructs were developed comprising two or more subunits derived from different ETEC fimbrial types according to the design illustrated in FIG. 2 to form multipartite fusion constructs. As used, herein, multipartite fusion or multipartite fusion constructs are recombinant polypeptide constructs according to FIG. 2. In this design, different ETEC fimbrial types are defined as fimbrial proteins derived from fimbriae of different strain ETEC types, as listed in Table 6, or deriviates of these polypeptides or DNA sequences. For example, the fimbrial type “CS3” comprises CstH and CstG. The fimbrial type “C56” comprises CssA and CssB. The fimbrial types of Class 5 ETEC include the fimbrial types Class 5a, Class 5b and Class 5c.

[0097]In a preferred embodiment, major and / or minor subunits, derive...

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Abstract

The inventive subject matter relates to a recombinant polypeptide construct comprising enterotoxigenic Escherichia coli fimbrial subunits. The recombinant polypeptide constructs comprise multiple subunits to the same or different ETEC fimbrial types. The constructs are useful for inclusion in immunogenic formulations for the inductin of immunity against entertoxigenic Escherichia coli. The inventive subject matter also relates to the use of the recombinant polypeptide constructs in induce anti-enterotoxigenic Escherichia coli.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS[0001]This application is a Continuation-in-Part to U.S. Nonprovisional application Ser. No. 11 / 340,003, filed Jan. 10, 2006, which claims priority to U.S. Provisional application 60 / 642,771 filed Jan. 11, 2005, and a Continuation-in-Part to National Stage of International Application No. PCT / US2007 / 000712, filed Jan. 11, 2007, which claims priority to provisional application 60 / 758,099 filed Jan. 11, 2006, the contents herein are incorporated by reference. This application also claims priority to U.S. Provisional application 61 / 727,943, filed Nov. 19, 2012, the contents herein are incorporated by reference.BACKGROUND OF INVENTION[0002]1. Field of the Invention[0003]The inventive subject matter relates to a method of inducing an immune response against enterotoxigenic Escherichia coli using bacterial fimbrial components. The method contemplates using enterotoxigenic Escherichia coli major and minor fimbrial subunits, incorporated into a stabil...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K14/245
CPCC07K14/245A61K39/0258A61K2039/523A61K2039/543A61K2039/545A61K2039/55544A61K2039/627A61K2039/70C07K2319/00A61P31/04Y02A50/30
Inventor SAVARINO, STEPHEN
Owner THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE NAVY
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