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Listeria attenuated for entry into non-phagocytic cells, vaccines comprising the listeria, and methods of use thereof

A non-Listeria and Listeria technology, applied in the direction of bacteria, bacterial antigen components, applications, etc., can solve the problems of poor reliability of infectious agents or cancer cells, and inability to respond successfully

Active Publication Date: 2006-04-12
ADURO BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

A particular advantage of xenogeneic antigen delivery is also evidence that administration of attenuated or killed agents or cells has not been successful in eliciting an effective immune response, or that adequate attenuation of infectious agents or cancer cells is less reliable

Method used

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  • Listeria attenuated for entry into non-phagocytic cells, vaccines comprising the listeria, and methods of use thereof
  • Listeria attenuated for entry into non-phagocytic cells, vaccines comprising the listeria, and methods of use thereof
  • Listeria attenuated for entry into non-phagocytic cells, vaccines comprising the listeria, and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0235] Example 1. Construction of Mutant Listeria Strains

[0236] A. Preparation of Mutant Listeria Strains

[0237] The Listeria strain was from 10403S (Bishop et al., J. Immunol. 139:2005 (1987)). The established methods of SOE-PCR and allelic exchange (Camilli et al., Mol. Microbiol. 8: 143 (1993)) were used to generate Lisi with in-frame deletions of the indicated genes. Terrier strains. Mutant strain LLO L461T (DP-L4017) is described in Glomski et al. J. Cell. Biol. 156: 1029 (2002), incorporated herein by reference. The ΔactA mutant (DP-L4029) is the DP-L3078 strain described in Skoble et al., J. of Cell Biology, 150: 527-537 (2000), incorporated herein by reference, which was depleted of prophage. (Prophage curing is described in (Lauer et al., J. Bacteriol. 184:4177 (2002), US Patent Application Publication No. 2003 / 0203472)). LLO has also previously been reported - mutant (DP-L4027) (Lauer et al., J. of Bacteriology, 184:4177-4186 (2002)), and LLOΔ26 (DP-L4042...

Embodiment 2

[0303] Example 2. Pathogenicity study of Listeria

[0304] The median lethal dose (LD) of certain mutant Listeria strains was determined by IV infection of mice 50 ). Three to five female C57BL / 6 mice were infected IV with triplicate 5-fold dilutions of the strain. Mice were observed daily for 10 consecutive days and sacrificed when they showed signs of distress. Calculate the median lethal dose. The data are shown in Table 1 below. The results indicated that mutant Listeria strains deficient in internalin B (ΔinlB, ΔactAΔinlB and ΔactAΔinlAB) were less virulent when combined with actA deletion. Only the ΔinlB strain showed similar virulence to wild Listeria.

[0305] strain

Embodiment 3

[0306] Example 3. Evaluation of in vivo cytotoxic activity in mice inoculated with Listeria monocytogenes

[0307] The ability to lyse antigen-specific target cells in vaccinated mice was evaluated in a series of experiments. In the first experiment, as shown in Table 2, Listeria monocytogenes strains DP-L4029 (ΔactA), DP-L4029ΔinlB (ΔactAΔinlB) and The same strain engineered to express AH1-A5 was inoculated into Balb / c mice. Listeria constructs expressing AH1-A5 also expressed hemolysin-deleted LLO and truncated OVA (see Example 1.C above). The inoculation dose is 0.1LD 50 . The spleens of 10 naive Balb / c mice were harvested in RPMI1640 medium to prepare the target cell population. The cells are isolated and the red blood cells are lysed. White blood cells were counted and divided into two equal portions. Using 0.5 μg / ml of target (AH1, SPSYVYHQF (SEQ ID NO: 8), purchased from SynPep, Dublin, CA) or control (β-gal, TPHPARIGL (SEQ ID NO: 19)) specific peptide at 37°C ...

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Abstract

The present invention provides Listeria that are attenuated for entry into non-phagocytic cells as well as a variety of methods of inducing immune responses involving administering compositions comprising the attenuated Listeria. Some of the attenuated Listeria are mutant Listeria that comprise at least one mutation in a gene encoding an invasin, such as an internalin. Some of the attenuated Listeria are further attenuated for cell-to-cell spread. Pharmaceutical compositions and vaccines useful in the methods of the invention are further provided. Methods of making and improving vaccines are also provided.

Description

[0001] related application [0002] This application claims priority to the following applications: U.S. Provisional Application No. 60 / 446,051, filed February 6, 2003; U.S. Provisional Application No. 60 / 449,153, filed February 21, 2003; Application No. 60 / 490,089, filed July 24, 2003, U.S. Provisional Application No. 60 / 511,719, filed October 15, 2003, U.S. Provisional Application No. 60 / 511,919, filed October 15, 2003 Japan, U.S. provisional application No. 60 / 511,869 patent application, filing date October 15, 2003 and U.S. title "Listeria (Listeria) that enters non-phagocytic cells and is attenuated, containing the Listeria A provisional patent application for vaccines and uses thereof, filed February 2, 2004. The foregoing is incorporated by reference. technical field [0003] In general, the field of the invention relates to attenuated bacteria for use in vaccines. In particular the invention relates to attenuated Listeria monocytogenes for use in vaccines and method...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/02C12N1/21C12N15/00A61P31/00A61P35/00
Inventor T·W·小杜本斯基D·G·布罗克施泰特D·库克
Owner ADURO BIOTECH
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