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Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment

A stimulant and active technology, applied in the direction of blood/immune system cells, bacteria, anti-tumor drugs, etc.

Pending Publication Date: 2021-12-03
阿克蒂姆治疗有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Designing immunotherapeutic approaches to 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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  • Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment
  • Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment
  • Immunostimulatory bacteria engineered to colonize tumors, tumor-resident immune cells, and the tumor microenvironment

Examples

Experimental program
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preparation example Construction

[0806] The prepared product provided herein includes packaging materials. Packaging materials for packaging pharmaceutical products are well known to those skilled in the art. See, eg, US Patent Nos. 5,323,907, 5,052,558, and 5,033,252, each of which is incorporated herein by reference in its entirety. Examples of pharmaceutical packaging materials include, but are not limited to, blister packs, bottles, tubes, inhalers, pumps, bags, vials, containers, syringes, bottles, and any packaging material suitable for the formulation of choice and the intended mode of administration and treatment. Examples of manufactured products are containers including single and dual chamber containers. Such containers include, but are not limited to, tubes, bottles, and syringes. The container may further comprise a needle for intravenous administration.

[0807] The choice of packaging depends on the reagents, and whether the compositions are packaged together or separately. Typically, the p...

Embodiment 1

[0854] Auxotrophic strain of Salmonella typhimurium

[0855] Salmonella strain YS1646 is auxotrophic for adenosine

[0856] The strains provided herein are engineered to be auxotrophic for adenosine. As a result, it is attenuated in vivo because it cannot replicate in the low adenosine concentrations of normal tissues, and colonization occurs mainly in the solid tumor microenvironment (TME) where adenosine levels are high. Salmonella strain YS1646 is a derivative of wild-type strain ATCC #14028, engineered to be auxotrophic for purines due to disruption of the purI gene (synonymous with purM) (Low et al. (2004) Methods Mol. Med 90:47 -60). Subsequent analysis of the entire genome of YS1646 showed that the purI gene was actually not deleted, but was destroyed by chromosomal inversion (Broadway et al. (2014) 1Biotechnol.192:177-178), and the entire gene was still contained on both chromosomes of YS1646. section, flanked by intervening sequences, one of which has an active tra...

Embodiment 2

[0862] Intracellular replication defect attributed to msbB mutation

[0863] The YS1646 strain contains mutations in purI, which restrict replication to sites containing high concentrations of purines, adenosine, or ATP, and in msbB, which alter lipopolysaccharide (LPS) surface coating to reduce TLR4-mediated pro-inflammatory signaling . It has also been established that, unlike wild-type Salmonella, strain YS1646 cannot replicate in macrophages. Experiments were performed to determine which of these gene mutations conferred this phenotype in the wild type strain ATCC 14028.

[0864] In this assay, mouse RAW macrophages (InvivoGen, San Diego, Ca.) were infected with a wild-type Salmonella strain containing purI, msbB, or both deletions at a multiplicity of infection (MOI) of approximately 30 min per cell. 5 bacteria, then wash the cells with PBS, and add medium containing gentamicin to kill extracellular bacteria. Gentamicin does not kill intracellular bacteria because it c...

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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 by 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 and / or purine auxotrophs. The bacteria optionally are one or more of asct, purl' and msbB'. The immunostimulatory bacteria, such as Salmonella species, are modified to encode proteins that induce type I interferon (IFN) expression, or that are variants thereof that have increased activity to induce type I IFN expression, or that are variants thereof that result in constitutive expression of type I IFN. The bacteria can encode a modified Stimulator of Interferon Genes (STING) protein from a non-human species, that has lower NF-kappaB signaling activity, and, optionally, higher type I IFN pathway signaling activity, compared to human STING. 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 application [0002] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 962,140, ​​filed January 16, 2020, entitled "Immunostimulatory Bacteria Engineered To Colonize Tumors, Tumor-Resident Immune Cells, And The Tumor Microenvironment," Applicant is Actym Therapeutics, Inc., and the inventors are Christopher D. Thanos, Laura Hix Glickman, Justin Skoble, Alexandre Charles Michel Iannello, and Haixing Kehoe. [0003] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 934,478, filed November 12, 2019, entitled "Immunostimulatory Bacteria Engineered To Colonize Tumors And TheTumor Microenvironment," filed by Actym Therapeutics, Inc., and The inventors are Christopher D. Thanos, Laura Hix Glickman, Justin Skoble and Alexandre Charles Michel Iannello. [0004] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 828,990, filed April 3, 2019, en...

Claims

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Application Information

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IPC IPC(8): C07K14/47C07K19/00C12N15/74C12N1/21C12N5/10A61K38/17A61K35/74A61K48/00A61K45/06A61K9/00A61K9/12A61K39/395A61K35/768A61P35/00A61P35/02A61P35/04C12R1/42
CPCC07K14/47C12N15/74C12N5/0636C12N5/0634A61K35/74A61K48/0058A61K48/0008A61K38/1709A61K45/06A61K9/0053A61K9/0031A61K9/12A61K9/0019A61K39/3955A61K35/768A61P35/00A61P35/02A61P35/04C07K2319/00C12N2510/00A61K38/00A61K2300/00C07K14/461C07K14/465C07K14/4705C12N1/36A61K38/19C12N15/1135C12N2310/141C12N2310/17C12N2310/531
Inventor C·D·萨诺斯L·H·格利克曼J·斯科博A·C·M·扬内洛H·基欧
Owner 阿克蒂姆治疗有限公司
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