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Engineered immunostimulatory bacterial strains and uses thereof

An immunostimulatory, immune cell technology, applied in the direction of blood/immune system cells, bacteria, anti-animal/human immunoglobulin, etc.

Pending Publication Date: 2021-04-16
阿克蒂姆治疗有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Designing immunotherapies that overcome immune tolerance and escape while limiting autoimmune-related toxicities of current immunotherapies challenges the field of immuno-oncology

Method used

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  • Engineered immunostimulatory bacterial strains and uses thereof
  • Engineered immunostimulatory bacterial strains and uses thereof
  • Engineered immunostimulatory bacterial strains and uses thereof

Examples

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[0217] A. Definition

[0218]Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents, patent applications, published applications and publications, GenBank sequences, databases, websites, and other published materials referred to throughout the disclosure herein are incorporated by reference in their entirety unless otherwise indicated. To the extent a term herein has multiple definitions, the definition in this section shall prevail. Where reference is made to URLs or other such identifiers or addresses, it should be understood that such identifiers can change and specific information on the Internet can come and go, but equivalent information can be found by searching the Internet. References thereto demonstrate the availability and public dissemination of such information.

[0219] As used herein, a therapeutic bacterium is a bacte...

Embodiment 1

[0754] Embodiment 1 Salmonella asd gene knockout strain engineering

[0755] Strain AST-101 was prepared. It is an attenuated Salmonella typhimurium strain derived from strain YS1646 (available from ATCC, catalog number 202165 ) that has been engineered asd - (asd knockout). In this example, the Salmonella typhimurium strain YS1646 asd - Gene deletion is achieved by e.g. figure 1 Engineering was performed as shown and as a modification of the Datsenko and Wanner method (Proc. Natl. Acad. Sci. USA 97:6640-6645 (2000)) as described below. The methods and resulting products in this and all of the following examples can be used with other starting bacteria, such as wild-type Salmonella typhimurium, such as the strain deposited under ATCC deposit number #14028.

[0756] Introduction of λ-Red helper plasmid into YS1646

[0757] As previously described (Sambrook J., (1998) Molecular Cloning, A Laboratory Manual, 2nd Ed. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory) by g...

Embodiment 2

[0770] Example 2 Generation of modified Salmonella typhimurium strains from wild type Salmonella typhimurium

[0771] Separate deletion of purI from the genome of wild-type Salmonella typhimurium strain ATCC 14028 using the lambda-derived Red recombination system as described in Datsenko and Wanner (Proc. Natl. Acad. Sci. USA 97:6640-6645 (2000)) , msbB and asd genes to generate a base strain named 14028:ΔpurI / ΔmsbB / Δasd. The flagellin genes fljB and fliC were subsequently deleted to generate strain 14028: ΔpurI / ΔmsbB / Δasd / ΔfljB / Δflic, and then the pagP gene was deleted to generate strain 14028: ΔpurI / ΔmsbB / Δasd / ΔfljB / Δflicl / ΔpagP. Strains 14028:ΔpurI / ΔmsbB / Δasd / ΔfljB / Δflic and 14028:ΔpurI / ΔmsbB / Δasd / ΔfljB / Δflicl / ΔpagP were electroporated with plasmids containing functional asd genes to complement the chromosomal deletion of asd and ensure plasmid maintenance in vivo , and the eukaryotic expression cassette encodes the red fluorescent protein mCherry under the control of the ...

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Abstract

Provided are delivery immunostimulatory bacteria that have enhanced colonization of tumors, the tumor microenvironment and / or tumor-resident immune cells, and enhanced anti-tumor activity. The immunostimulatory bacteria are modified by deletion of genes encoding the flagella or modification of the genes so that functional flagella are not produced, and / or are modified by deletion of pagP or modification of pagP to produce inactive PagP product. As a result, the immunostimulatory bacteria are flagellin- and / or pagP -. The immunostimulatory bacteria optionally have additional genomic modifications so that the bacteria are adenosine or purine auxotrophs. The bacteria optionally are one or more of asd -, purI - and msbB -. The immunostimulatory bacteria, such as Salmonella species, are modified to encode immunostimulatory proteins that confer anti-tumor activity in the tumor microenvironment, and / or are modified so that the bacteria preferentially infect immune cells in the tumor microenvironment or tumor-resident immune cells and / or induce less cell death in immune cells than in other cells. Also provided are methods of inhibiting the growth or reducing the volume of a solid tumor by administering the immunostimulatory bacteria.

Description

[0001] Related applications [0002] This application claims International Patent Application No. PCT / US2018 / 041713 filed on July 11, 2018 and published as WO 2019 / 014398 on January 17, 2019 and filed on July 11, 2018 and published on January 2019 The benefit of priority to co-pending US Patent Application Serial No. 16 / 033,187, published on the 17th as US Publication No. U.S. 2019 / 0017050 Al, each by applicant Actym Therapeutics, Inc., inventors Christopher D. Thanos, LauraHix Glickman and Justin Skoble; and each titled "ENGINEERED IMMUNO STIMULATORY BACTERIAL STRAINS AND USES THEREOF". [0003] Also claims the benefit of priority to U.S. Provisional Application Serial No. 62 / 789,983, filed January 08, 2019, applicant Actym Therapeutics, Inc., inventors Christopher D. Thanos, Laura Hix Glickman, Justin Skoble, and Alexandre Charles Michel Iannello and entitled "ENGINEERED IMMUNO STIMULATORY BACTERIAL STRAINS AND USESTHEREOF". Also claims priority of U.S. Provisional Applicatio...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N1/21C12N15/74C12N5/0783C12N5/0789A61K35/74A61K39/395A61K38/19A61K38/20A61K39/112A61K35/17A61K35/28A61K45/06A61P35/00A61P35/02A61P35/04C12R1/42
CPCC07K14/55C12N1/36C12N15/113C12N2320/32A61K35/74A61P35/00A61K2035/11A61K35/28A61K38/19Y02A50/30A61K39/464832A61K39/4644A61K2239/50A61K39/4622A61K39/4611A61K39/4614A61K39/0275A61K45/06C07K14/521C07K16/248C07K16/2818C07K16/2827C12N15/74C12R2001/42C12N1/205C07K16/22C07K2319/02C12N2310/141C07K2317/622C07K2319/095
Inventor C·D·萨诺斯L·H·格利克曼J·斯科博A·C·M·扬内洛
Owner 阿克蒂姆治疗有限公司
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