WO2015076663A1 - Salmonella enterica serovar agona for anti-tumor therapy - Google Patents
Salmonella enterica serovar agona for anti-tumor therapy Download PDFInfo
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- WO2015076663A1 WO2015076663A1 PCT/MY2014/000263 MY2014000263W WO2015076663A1 WO 2015076663 A1 WO2015076663 A1 WO 2015076663A1 MY 2014000263 W MY2014000263 W MY 2014000263W WO 2015076663 A1 WO2015076663 A1 WO 2015076663A1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/66—Microorganisms or materials therefrom
- A61K35/74—Bacteria
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
- C07K14/255—Salmonella (G)
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
- C12N1/20—Bacteria; Culture media therefor
- C12N1/205—Bacterial isolates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K2035/11—Medicinal preparations comprising living procariotic cells
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales
- C12R2001/42—Salmonella
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Definitions
- the present invention relates to Salmonella enterica serovar Agona useful for anti-tumor therapy.
- Salmonella enterica serovar Typhimurium is tested in an anticancer therapy developed recently - the TAPET therapy (Tumor Amplified Protein Expression Therapy) - in which the bacteria are administered to subjects and can act against tumors by targeting them and replicating preferentially in them.
- the Salmonella enterica serovar Typhimurium bacteria have been shown to preferentially replicate and accumulate in tumors, achieving high tumor to normal tissue ratios. They may also carry a gene expressing a protein acting anti-tumorically, such as cytosine deaminase which can convert nontoxic 5-fluorocytosine to an active antitumor agent 5- fluorouracil.
- the Salmonella can either provide direct tumoricidal effects or deliver tumoricidal molecules.
- the preclinical results suggest that the TAPET technology can improve the outcome for solid tumors that are treated primarily by radiation. It was shown that the combination of TAPET and irradiation has a synergic effect.
- Salmonella enterica serovar Typhimurium is a pathogenic strain and poses certain health hazards when used in humans. Therefore, there is a need to look for other serovars which are less virulent but still utilizable as a delivery vector for antitumor therapy. Disclosure of the Invention
- the present invention provides Salmonella enterica serovar Agona (deposited in CCTCC under accession number CCTCC M 2013414) and/or its knockdown strain (deposited in CCTCC under accession number CCTCC M 2013415) for use in anticancer therapy.
- Salmonella enterica serovar Agona can be wild-type or genetically engineered.
- the genetical engineering may include of group II intron to inactivate the virulence genes, knock-down of three genes sopB, sopD and pipD located in the Salmonella Pathogenecity Islands, or any other genetic modification leading to a higher anticancer activity and/or lower pathogenecity of the Salmonella enterica serovar Agona.
- Salmonella enterica serovar Agona is a zoonotic pathogen which is potentially causing infections in humans and animals. Transmission of Salmonella enterica serovar Agona from animals to humans commonly occurs via ingestion of contaminated foods, especially poultry meat.
- Salmonella enterica serovar Agona is the second most prevalent Salmonella isolated from livestock products and raw vegetable since the 1990s. However, up to now there is no report on using Salmonella enterica serovar Agona as anti-tumor vector in cancer therapy.
- this invention provides a knockdown strain of Salmonella enterica serovar Agona, which was originally isolated from indigenous vegetable in Malaysia, and genetically engineered, and which shows very good antitumor activity and low pathogenecity.
- This strain is a strain of Salmonella enterica serovar Agona with knock-down genes of sopB, sopD and pipD or abbreviated to Salmonella enterica serovar Agona AsopBAsopApipD.
- the strain is deposited in China Center for Type Culture Collection (CCTCC) under accession number CCTCC M 2013415.
- CTCC China Center for Type Culture Collection
- Salmonella enterica serovar Agona is capable of providing a system to produce, secrete and deliver peptide antagonists to tumor cells therapy, providing an effective and less expensive way to produce recombinant proteins at the tumor site.
- Figure 1 Means of day of survival on treated tumor-bearing mice. Each bar represents the mean ⁇ SEMfor each group; b d mean with different superscript differ significantly between groups, * Values are significantly different from the negative control group at p ⁇ 0.05.
- Figure 2 Mean of changes in tumour volumes after treatment (mm 3 ). Effects of treatment groups on the changes of tumor volumes; a b mean with different superscript differ significantly between groups; * Values are significantly different from the negative control group at p ⁇ 0.05
- Salmonella enterica serovar Agona was isolated from indigenous vegetables Kesum (Polygonum minus) in Selangor state, Malaysia for the year 2000. Serotyping of the Salmonella enterica serovar Agona was carried out by the Veterinary Research Institute (Ipoh, Malaysia) and forwarded by the Chemistry Department of Malaysia. The Chemistry Department of Malaysia is a national reference laboratory for microbiology food testing in Malaysia.
- Virulotyping of Salmonella enterica serovar Agona was carried out by screened for 20 potential virulence genes hilA, hilC, hilD, orgA, sopE, sifA, ssrB, ttrB, mgtC, misL, rhuM, rmbA, orfL, spi4-F, pipA, pipB, pipD, sopB, sopD and sdiA) using Multiplex Polymerase Chain Reaction approach. Salmonella enterica serovar Agona possesed 95% (19/20) of the virulence associated genes tested.
- a sopE gene was the only virulence gene not present in Salmonella enterica serovar Agona.
- the possesion of 19 of virulence genes from 5 classes of Salmonella pathogenicity Islands and a quorum sensing gene suggest that it may potentially hazard to human health.
- this strain Prior to introducing the Salmonella enterica serovar Agona as anti-tumor vector, this strain was subjected to genetic modification using Targetron technology to knock-down the Salmonella virulence genes of sopB, sopD and pipD located in Salmonella Pathogenicity Island 5 (SPI 5) which are critical for production of disease.
- SPI 5 Salmonella Pathogenicity Island 5
- mice treated with Salmonella entenca serovar Agona showed 100% survival rate throughout the 2 months of experiment duration.
- mice The testing on tumor-bearing mice was carried out to assess the tumoricidal effects of wild and SPIs knockdown of Salmonella enterica serovar Agona and Salmonella enterica serovar Typhimurium.
- LD 50 testing was first conducted, and 10 CFU was selected as the dosage of choice for this study.
- Female and male Balb-C mice at the age of 6 weeks were used in this study.
- a cell density of 3 x 10 6 CT26 cells suspended in PBS were inoculated subcutaneously on the left flank of the mice to induce solid tumor. The tumor was allowed to grow for 3 weeks before treatment were injected into the mice.
- the tumor-bearing mice were then treated with the four bacterial treatments via intraperitoneal and intratumoral route of administration.
- the changes in the sizes of the tumors were observed daily using a calipher.
- the effects of route of administration and genders of the tumor-bearing mice after bacteria treatment were analysed using Two-way ANOVA method.
- the outcome of Two-Way ANOVA, as showed in Table 1 indicates that there was no significant effect observed for the route of administration of treatments and the genders on the survival periods of the tumor-bearing mice and changes in its tumours volumes after treatments, at p ⁇ 0.05.
- Salmonella enterica serovar Typhimurium and Agona exhibited the capacity to inhibit the growth of tumors via intraperitoneal and intratumoral injection of bacteria into tumor-bearing mice.
- Salmonella enterica serovar Agona shows the longest survival after treatment compared to Salmonella enterica serovar Typhimurium. This also reviewed that Salmonella enterica serovar Agona causes milder infections (less pathogenic) when it is compared to Salmonella enterica serovar Typhimurium.
Abstract
The present invention provides Salmonella enterica serovar Agona and/or knockdown strain of Salmonella enterica serovar Agona, optionally genetically engineered, for use in anti-tumor therapy.
Description
SALMONELLA ENTERICA SEROVAR AGONA FOR ANTI-TUMOR
THERAPY
Field of Art
The present invention relates to Salmonella enterica serovar Agona useful for anti-tumor therapy. Background Art
Salmonella enterica serovar Typhimurium is tested in an anticancer therapy developed recently - the TAPET therapy (Tumor Amplified Protein Expression Therapy) - in which the bacteria are administered to subjects and can act against tumors by targeting them and replicating preferentially in them. The Salmonella enterica serovar Typhimurium bacteria have been shown to preferentially replicate and accumulate in tumors, achieving high tumor to normal tissue ratios. They may also carry a gene expressing a protein acting anti-tumorically, such as cytosine deaminase which can convert nontoxic 5-fluorocytosine to an active antitumor agent 5- fluorouracil. Thus, the Salmonella can either provide direct tumoricidal effects or deliver tumoricidal molecules. The preclinical results suggest that the TAPET technology can improve the outcome for solid tumors that are treated primarily by radiation. It was shown that the combination of TAPET and irradiation has a synergic effect.
Salmonella enterica serovar Typhimurium is a pathogenic strain and poses certain health hazards when used in humans. Therefore, there is a need to look for other serovars which are less virulent but still utilizable as a delivery vector for antitumor therapy.
Disclosure of the Invention
The present invention provides Salmonella enterica serovar Agona (deposited in CCTCC under accession number CCTCC M 2013414) and/or its knockdown strain (deposited in CCTCC under accession number CCTCC M 2013415) for use in anticancer therapy.
Salmonella enterica serovar Agona can be wild-type or genetically engineered. The genetical engineering may include of group II intron to inactivate the virulence genes, knock-down of three genes sopB, sopD and pipD located in the Salmonella Pathogenecity Islands, or any other genetic modification leading to a higher anticancer activity and/or lower pathogenecity of the Salmonella enterica serovar Agona. Salmonella enterica serovar Agona is a zoonotic pathogen which is potentially causing infections in humans and animals. Transmission of Salmonella enterica serovar Agona from animals to humans commonly occurs via ingestion of contaminated foods, especially poultry meat. In Malaysia, Salmonella enterica serovar Agona is the second most prevalent Salmonella isolated from livestock products and raw vegetable since the 1990s. However, up to now there is no report on using Salmonella enterica serovar Agona as anti-tumor vector in cancer therapy.
In particular, this invention provides a knockdown strain of Salmonella enterica serovar Agona, which was originally isolated from indigenous vegetable in Malaysia, and genetically engineered, and which shows very good antitumor activity and low pathogenecity. This strain is a strain of Salmonella enterica serovar Agona with knock-down genes of sopB, sopD and pipD or abbreviated to Salmonella enterica serovar Agona AsopBAsopApipD. The strain is deposited in China Center for Type Culture Collection (CCTCC) under accession number CCTCC M 2013415.
Within the framework of the present invention it was shown that the Salmonella enterica serovar Agona is less pathogenic (higher survival rate in model mice) while retaining the antitumor activity corresponding to that of Salmonella enterica serovar Typhimurium.
Thus, Salmonella enterica serovar Agona is capable of providing a system to produce, secrete and deliver peptide antagonists to tumor cells therapy, providing an effective and less expensive way to produce recombinant proteins at the tumor site.
Brief Description of Drawings
Figure 1. Means of day of survival on treated tumor-bearing mice. Each bar represents the mean±SEMfor each group; b d mean with different superscript differ significantly between groups, *Values are significantly different from the negative control group at p<0.05.
Figure 2. Mean of changes in tumour volumes after treatment (mm3). Effects of treatment groups on the changes of tumor volumes; a b mean with different superscript differ significantly between groups; *Values are significantly different from the negative control group at p<0.05
Examples of carrying out the Invention Example 1
Salmonella enterica serovar Agona was isolated from indigenous vegetables Kesum (Polygonum minus) in Selangor state, Malaysia for the year 2000. Serotyping of the Salmonella enterica serovar Agona was carried out by the Veterinary Research Institute (Ipoh, Malaysia) and forwarded by the Chemistry Department of Malaysia. The Chemistry
Department of Malaysia is a national reference laboratory for microbiology food testing in Malaysia.
Virulotyping of Salmonella enterica serovar Agona was carried out by screened for 20 potential virulence genes hilA, hilC, hilD, orgA, sopE, sifA, ssrB, ttrB, mgtC, misL, rhuM, rmbA, orfL, spi4-F, pipA, pipB, pipD, sopB, sopD and sdiA) using Multiplex Polymerase Chain Reaction approach. Salmonella enterica serovar Agona possesed 95% (19/20) of the virulence associated genes tested. A sopE gene was the only virulence gene not present in Salmonella enterica serovar Agona. The possesion of 19 of virulence genes from 5 classes of Salmonella pathogenicity Islands and a quorum sensing gene suggest that it may potentially hazard to human health. Prior to introducing the Salmonella enterica serovar Agona as anti-tumor vector, this strain was subjected to genetic modification using Targetron technology to knock-down the Salmonella virulence genes of sopB, sopD and pipD located in Salmonella Pathogenicity Island 5 (SPI 5) which are critical for production of disease. These three virulence genes are encode Salmonella effector proteins involve in enteropathogenicity in human and animal. Previous studies reported that knockdown of sopB, sopD and pipD genes in Salmonella have been decreased fluid secretion and reduced acute inflammatory cell influx in bovine ligated ileal loops resulting in less virulence towards the calves.
Example 2
A preliminary toxicity study was carried out to compare the pathogenecity within Salmonella entenca serovar Agona and Salmonella enterica serovar Typhimurium. From the study, it was found that mice treated with Salmonella entenca serovar Agona showed 100% survival rate throughout the 2 months of experiment duration. In contrast, Salmonella entenca
serovar Typhimurium killed 50% of the mice population at day 7 (LD50=7). This result indicated that Salmonella enterica serovar Agona showed reduced virulence compared to Salmonella enterica serovar Typhimurium towards mice.
The testing on tumor-bearing mice was carried out to assess the tumoricidal effects of wild and SPIs knockdown of Salmonella enterica serovar Agona and Salmonella enterica serovar Typhimurium. LD50 testing was first conducted, and 10 CFU was selected as the dosage of choice for this study. Female and male Balb-C mice at the age of 6 weeks were used in this study. A cell density of 3 x 106 CT26 cells suspended in PBS were inoculated subcutaneously on the left flank of the mice to induce solid tumor. The tumor was allowed to grow for 3 weeks before treatment were injected into the mice.
The tumor-bearing mice were then treated with the four bacterial treatments via intraperitoneal and intratumoral route of administration. The changes in the sizes of the tumors were observed daily using a calipher. The effects of route of administration and genders of the tumor-bearing mice after bacteria treatment were analysed using Two-way ANOVA method. The outcome of Two-Way ANOVA, as showed in Table 1 , indicates that there was no significant effect observed for the route of administration of treatments and the genders on the survival periods of the tumor-bearing mice and changes in its tumours volumes after treatments, at p<0.05.
000263
Table 1. p values for genders and route of administration
Variables P value
Genders Survival: p = 0.453 Not significant
Female vs Male
Volume: p = 0.179 Not significant
Route of administration Survival: p = 0.071 Not significant
Intraperitoneal vs
Intratumoral
Volume: p = 0.548 Not significant
The effects of bacteria treatments and negative control groups of tumour- bearing mice were analysed using One-way ANOVA. The result indicated that the treatments had significant effects at p < 0.05, on both the survival rate and the changes of the tumor volumes of tumor-bearing mice. For the survival rate of treated tumor-bearing mice, Duncan post-hoc analysis, as showed in Table 2, indicated that knockdown Salmonella entenca serovar Typhimurium showed significance difference at p<0.05 with the mice treated with the control (PBS). Knockdown Salmonella entenca serovar Agona did not show any significance difference with the control group.
Table 2. Duncan post-hoc analysis for the survival rate of treated tumor- bearing mice
Survival period of subject (days)
Duncan
Treatment N Subset for alpha = 0.05
1 2
Control 105 8.39
Knockdown S. Agona 269 8.51
Knockdown S. 42 3.40
Typhimurium
Sig. .868 1.0
Means for group in homogeneous subsets are displayed
Control and knockdown Salmonella enterica serovar Agona treated tumor- bearing mice showed similar survival rate with means days of survival of 8.39 and 8.51 days respectively, followed by knockdown S. Typhimurium, showed the shortest survival rate of tumor-bearing mice which are mean of 3.40 days as showed in Figure 1.
In tumor reduction analysis, as shown in Table 3 and Figure 2, Duncan post-hoc analysis indicates that all 4 different bacterial treatments showed significant difference when it is compared to the control group. However, there were no significant differences between the bacterial treatment itself. The largest reduction of tumour volumes is showed by tumor-bearing mice treated with wild-type Salmonella enterica serovar Typhimurium, with mean reduction of 786.71 mm3 , followed by tumor-bearing mice treated with wild Salmonella enterica serovar Agona (672.00 mm3), knockdown Salmonella enterica serovar Typhimurium (564.42 mm3) and the smallest reduction in tumor volume with mean of 325.44 mm3 showed by tumor-bearing mice treated with knockdown Salmonella enterica serovar Agona.
In overall, The wild type and knocout strains for both Salmonella enterica serovar Typhimurium and Agona exhibited the capacity to inhibit the growth of tumors via intraperitoneal and intratumoral injection of bacteria into tumor-bearing mice. However, Salmonella enterica serovar Agona shows the longest survival after treatment compared to Salmonella enterica serovar Typhimurium. This also reviewed that Salmonella enterica serovar Agona causes milder infections (less pathogenic) when it is compared to Salmonella enterica serovar Typhimurium. As a result, wild type and knocout strains of Salmonella enterica serovar Agona found to be a better candidate as a tumor reduction agent, compared well-documented strain of Salmonella enterica serovar Typhimurium, since it showed longer survival rate after treatment and yet, had similar capacity as a tumor reduction agent.
Table 3. Duncan post-hoc analysis for changes in tumor on treated tumor-bearing mice
Changes in tumor volumes (mm
Duncan
Treatment N Subset for alpha = 0.05
1 2
Wild type S. Agona 10 -671.9970
Knockdown S. Agona 18 -325.4356
Wild type S. Typhimurium 15 -786.7087
Knockdown S. 2 -564.4200
Typhimurium
Control 7 14652.2557
Sig. .872 1.000
Means for group in homogenoues subsets are displayed
Claims
1. Salmonella enterica serovar Agona and/or knockdown strain of Salmonella enterica serovar Agona for use in anti-tumor therapy.
2. Salmonella enterica serovar Agona for use according to claim 1 wherein the Salmonella enterica serovar Agona is wild-type.
3. Knockdown strain of Salmonella enterica serovar Agona for use according to claim 1 wherein the Salmonella enterica serovar Agona knockdown strain is genetically engineered.
4. Knockdown strain of Salmonella enterica serovar Agona for use according to claim 3, wherein the genetical engineering includes insertion of group II intron to inactivate the virulence genes.
5. Knockdown strain of Salmonella enterica serovar Agona for use according to claim 3, wherein the genetical engineering includes knockdown of three genes sopB, sopD and pipD located in the Salmonella Pathogenecity Islands.
6. Knockdown strain of Salmonella enterica serovar Agona (CCTCC M 2013415) showing a low pathogenicity and good antitumor activity.
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| Application Number | Priority Date | Filing Date | Title |
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| MYPI2013702237 | 2013-11-22 | ||
| MYPI2013702237 | 2013-11-22 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000514400A (en) * | 1995-06-07 | 2000-10-31 | エール ユニバーシティー | Vectors for diagnosis and treatment of solid tumors including melanoma |
| WO2010101886A1 (en) * | 2009-03-02 | 2010-09-10 | University Of Rochester | Methods of modifying p53 acetylation and treating cancer using avra |
-
2014
- 2014-11-19 WO PCT/MY2014/000263 patent/WO2015076663A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2000514400A (en) * | 1995-06-07 | 2000-10-31 | エール ユニバーシティー | Vectors for diagnosis and treatment of solid tumors including melanoma |
| WO2010101886A1 (en) * | 2009-03-02 | 2010-09-10 | University Of Rochester | Methods of modifying p53 acetylation and treating cancer using avra |
Non-Patent Citations (3)
| Title |
|---|
| KHOO CH ET AL.: "Pathogenicity and phenotypic analysis of sopB, sopD and pipD virulence factors in Salmonella enterica serovar typhimurium and Salmonella enterica serovar Agona", ANTONIE VAN LEEUWENHOEK, vol. 107, no. 1, January 2015 (2015-01-01), pages 23 - 37 * |
| KHOO CH ET AL.: "Virulotyping of Salmonella enterica subsp. enterica isolated from indigenous vegetables and poultry meat in Malaysia using multiplex-PCR.", ANTONIE VAN LEEUWENHOEK, vol. 96, 2009, pages 441 - 457, XP019745811, DOI: doi:10.1007/s10482-009-9358-z * |
| ZHANG S ET AL.: "The Salmonella enterica serotype typhimurium effector proteins SipA, SopA, SopB, SopD, and SopE2 act in concert to induce diarrhea in calves.", INFECTIONAND IMMUNITY, vol. 70, no. 7, 2002, pages 3843 - 3855 * |
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