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Biofusion proteins as Anti-malaria vaccines

A fusion protein and protein technology, which can be used in drug combinations, fusion polypeptides, antibody mimics/scaffolds, etc., and can solve problems such as high cost, high technical requirements, and difficulty in reproduction.

Active Publication Date: 2019-07-02
VAC4ALL PTE LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, chemical coupling has several disadvantages
It is technically demanding, difficult to reproduce and quite expensive

Method used

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  • Biofusion proteins as Anti-malaria vaccines
  • Biofusion proteins as Anti-malaria vaccines
  • Biofusion proteins as Anti-malaria vaccines

Examples

Experimental program
Comparison scheme
Effect test

Embodiment

[0116] Previous studies have shown that frequent malaria exposure confers immunity in adults, which prevents or alleviates the disease. This immunity can be passively transferred by administration of immunoglobulin (IgG) from malaria-immunized adults.

[0117] A parasite killing mechanism, termed antibody-dependent cell-mediated inhibition (ADCI), was identified. Screening of broad genomic DNA libraries by ADCI led to the identification of merozoite-surface protein 3 (MSP3) and subsequently several other antigens, including PEBS.

[0118] Identification of cytotropic antibodies as a surrogate for protection: ADCI-mediating cytotropic (leukocyte-binding) anti-MSP3 antibodies IgG1 and IgG3 were found to be consistently associated with a reduced risk of malaria in epidemiological studies in many different settings. The antibodies also mediate protection against P. falciparum in infected animals.

[0119] Such studies indicate the properties of an effective immune response and g...

Embodiment 4

[0124] Example 4 provides the results using the LSA5-CRM construct.

[0125] Materials and methods

[0126] Generation of expression constructs and production of biofusion proteins in E. coli

[0127] The gene sequence encoding a chimeric immunogen consisting of detoxified diphtheria toxin CRM197 covalently linked at the N-terminus and C-terminus to the malaria peptide antigen was chemically synthesized (GenScript) ( figure 1 ) and codon-optimized for production in E. coli. Restriction sites for Nco I and Xho I were added at the 5' and 3' ends, respectively, for cloning in the expression plasmid pET-26a (Novagen). The sequence inserted into the shuttle plasmid pUC57 was checked by sequencing and accelerated lyophilized (4 μg).

[0128] The MSP3-1 peptide in PP21 (plasmodB acc. Nbr PF3D7_1035400) corresponds to amino acids (AA) 155 to 249 in MSP3-1.

[0129] Other hybrid immunogens have been designed against CRM197 (Table 3). In PP22, the MSP3-1 peptide was replaced by t...

Embodiment 1

[0209] Example 1: Immunogenicity of PP21, the CRMP97-MS3 fusion construct

[0210] The immune response induced by PP21 was evaluated in the following animal models:

[0211] · BALB-C mice

[0212] · C57BL mice

[0213] ·Squirrel Monkey

[0214] • Human immunogenic mouse model (HIMM) in which cells from human spleen tissue transplanted into immunocompromised NSG mice were immunized in vivo and sera and cells from the immunized animals were used for immune analysis.

[0215] All experiments were performed in a comparative manner using the benchmark antigen MSP3-LSP (a long synthetic peptide covering the region 186-271 of MSP3-1) used in clinical trials and using Montanide ISA 720, since laboratory mice are usually sensitive to hydrogen oxidized Aluminum reacts poorly and the route of injection in HIMM does not allow the use of aluminum hydroxide, and mainly due to the aim of comparing constructs rather than adjuvants, it is known that in humans, aluminum hydroxide adjuvanted ...

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Abstract

The invention relates to fusion proteins which comprise at least one antigenic amino acid sequence fused to a carrier heterologous protein sequence, wherein the antigenic sequence comprises an epitopic sequence of a Plasmodium protein and the carrier heterologous protein sequence is a sequence that is immunogenic in humans. The proteins are useful as anti-malaria vaccines.

Description

[0001] The present invention relates to protection against malaria, and more particularly to malaria vaccines comprising fusion proteins. Background technique [0002] The parasites responsible for malaria in humans, including Plasmodium falciparum in particular, exhibit different morphologies in human hosts and express different antigens depending on their localization in the organism of the infected host. The morphological and antigenic differences of these parasites in humans during their life cycle enable at least 4 distinct developmental stages. The initial developmental stage of the parasite in humans corresponds to the sporozoite form introduced into the blood of the host by the bite of the parasite's insect vector. The second stage corresponds to the passage of the parasite through the liver and infection of hepatocytes, where the parasite develops to form a hepatic schizont which, after its maturation (e.g., in the case of P. 6 days) to release hepatic merozoites by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/015A61K39/385A61K39/00
CPCA61K39/015A61K2039/54A61K2039/545A61K2039/6037A61P33/06Y02A50/30A61K39/385C07K14/34C07K14/445A61K2039/6031C07K2319/00C12N15/62C12N15/64
Inventor 皮埃尔·德吕耶
Owner VAC4ALL PTE LTD
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