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Synthetic Antigen Constructs Against Campylobacter Jejuni

Active Publication Date: 2019-06-06
THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE NAVY +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about an immunogenic synthetic construct that can induce an immune response against Campylobacter jejuni (C. jejuni) in a subject. The immunogenic synthetic construct comprises one or more monosaccharides that have one or more MeOPN moieties. The MeOPN moieties can be selected from the group consisting of MeOPN-2-Gal, MeOPN-4-Gal, and MeOPN-6-Gal. The immunogenic synthetic construct can be administered to a subject in an effective amount, such as an amount ranging from 0.1 μg to 10 mg. The invention also relates to a composition comprising the immunogenic synthetic construct and a method of inducing an immune response against C. jejuni in a subject by administering the immunogenic synthetic construct.

Problems solved by technology

Diarrheal diseases are a major cause of morbidity and mortality in the developing world.
) It is believed that antibodies generated by a human subject against the LOS cores of C. jejuni may cause an undesirable autoimmune response to neural tissue in the subje
Notwithstanding the promise of prototype vaccines, and despite the importance of this organism to human disease, there are yet no licensed, commercially available vaccines against C. jejuni.

Method used

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  • Synthetic Antigen Constructs Against Campylobacter Jejuni
  • Synthetic Antigen Constructs Against Campylobacter Jejuni
  • Synthetic Antigen Constructs Against Campylobacter Jejuni

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of p-methoxyphenyl and aminopentyl glycosides of the MeOPN→6-Gal Construct: MeOPN→6-α-D-Galp-(1→OMP and MeOPN→6-β-D-Galp-(1→O(CH2)5NH2

[0142]Previously, using conventional methods and mass spectrometry, we detected a non-stoichiometric MeOPN unit at the 2 position of galactose (MeOPN-2-Gal) in C. jejuni 81-176 CPS, with a 31P resonance similar to that depicted in FIG. 20A (peak Y) (Kanipes M I, et al. (2006.) J. Bacteriol. 188:3273-3279.) We confirmed this MeOPN-2-Gal linkage by NMR (FIG. 21A) through the detection of a cross-peak between the 31P resonance Y (δP 14.45) of MeOPN and H-2 (δH 4.52) of the galactose unit in a 1H-31P correlation experiment. In some 81-176 CPS preparations, albeit of lower intensity, the 31P NMR spectrum displayed an additional resonance at δP 14.15 (designated peak Z) (FIG. 20B). A similar peak was also observed in another 81-176 CPS preparation (a mutant in gene CJJ81176_1420) that exhibited a cross-peak between the phosphorous of MeOPN and H-...

example 2

Synthesis of MeOPN→2-β-D-Galp-(1→OMP

Summary Synthesis of MeOPN→2-β-D-Galp-(1→OMP (FIG. 5, Scheme 3)

[0178]The synthesis of MeOPN→2-β-D-Galp-(1→OMP is depicted in FIG. 5, scheme 3. The synthesis of galactoside (product 7) began with a known compound, 4-methoxyphenyl 3,4-O-isopropylidene-6-O-trityl-β-D-galactopyranoside (product 1), which was prepared from D-galactose following published procedures (Scheme 1.) (Comfort D A, et al., Biochem 2007; 46:3319-3330.) To distinguish the C-2 position, O-allylation was performed generating product 2 in excellent yield. Since MeOPN can be removed by acidic media, suitable protecting groups needed to be installed. Thus, O-isopropylidene and O-trityl groups were removed giving product 3, which was then per-benzoylated affording product 4. Nast, the allyl group was removed yielding a free 2-OH for modification. The introduction of MeOPN group to product 5 followed a strategy developed in our lab, involving first a phosphorylation with commercially a...

example 3

Immunodetection of MeOPN→6-α-D-Galp-(1→OMP and MeOPN→6-β-D-Galp-(1→O(CH2)5NH2 by C. jejuni CPS Conjugate Antisera

[0188]The synthetic p-methoxyphenyl and aminopentyl glycosides of the MeOPN→6-Gal construct, compounds MeOPN→6-α-D-Gal-(1→OMP and MeOPN→6-β-D-Galp-(1→O(CH2)5NH2, synthesized as described in the above examples, were tested per reactivity with antisera previously raised against C. jejuni CPS conjugates of serotypes HS1, HS3, HS4 and HS23 / 36. Notably, of the listed serotypes, only HS23 / 36 expresses MeOPN-6-Gal.

Materials and Methods

[0189]The synthetic construct MeOPN-6-Gal was adjusted to 1 mg / ml and 2 μl was spotted onto nitrocellulose membranes and allowed to dry. The individual spots were immunodetected with four different polyclonal antisera made against different conventional conjugate vaccines in which different C. jejuni polysaccharide capsules were conjugated to CRM197: (1) rabbit serum against an HS23 / 36 conjugate (final dilution 1:1000 in 20 mM Tris, pH 7.4, 0.425 M...

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Abstract

The invention relates to immunogenic synthetic constructs capable of inducing an immune response against Campylobacter jejuni (C. jejuni) in a subject comprising one or more monosaccharides comprising one or more MeOPN moieties. Specifically, the invention relates to immunogenic synthetic constructs capable of inducing an immune response against C. jejuni in a subject comprising one or more MeOPN-6-Gal monosaccharides, one or more MeOPN-4-Gal monosaccharides, and / or one or more MeOPN-2-Gal monosaccharides. The invention also relates to compositions comprising the immunogenic synthetic constructs, and methods of inducing an immune response against C. jejuni in a subject comprising administering the immunogenic synthetic constructs, and / or compositions comprising the immunogenic synthetic constructs, to the subject. Methods of treating, preventing, or ameliorating a C. jejuni bacterial infection in a subject comprising administering to the subject one or more doses of immunoglobulins directed to one or more of the MeOPN moieties are also contemplated.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]The present application is a Continuation-In-Part of co-pending U.S. Utility patent application Ser. No. 14 / 933,793 filed Nov. 5, 2015, which claims the benefit of U.S. Provisional Patent Application No. 62 / 075,399 filed Nov. 5, 2014, and the benefit of U.S. Provisional Patent Application No. 62 / 127,935 filed Mar. 4, 2015 the entire disclosures of which are incorporated by reference herein.SEQUENCE LISTING[0002]The instant application contains a Sequence Listing which has been submitted in ASCII format via EFS-Web and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 5, 2016 is named “103281CIP_ST25.txt”” and is 4.52 kilobytes in size.FIELD OF THE INVENTION[0003]The inventive subject matter of the instant invention relates to immunogenic synthetic constructs capable of inducing an immune response against Campylobacter jejuni (C. jejuni) in a subject. The inventive subject matter of the instant invention...

Claims

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Application Information

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IPC IPC(8): A61K39/02C07K16/12A61K39/385A61P31/04
CPCA61K39/105C07K16/121A61K39/385A61P31/04A61K2039/545C07K2317/73
Inventor GUERRY, PATRICIAMONTEIRO, MARIO ARTURJIAO, YUENINGPEQUEGNAT, BRITTANY MICHELE
Owner THE UNITED STATES OF AMERICA AS REPRESENTED BY THE SECRETARY OF THE NAVY
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