OA18794A - Compositions comprising bacterial strains. - Google Patents
Compositions comprising bacterial strains. Download PDFInfo
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- OA18794A OA18794A OA1201800177 OA18794A OA 18794 A OA18794 A OA 18794A OA 1201800177 OA1201800177 OA 1201800177 OA 18794 A OA18794 A OA 18794A
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Abstract
The invention provides compositions comprising bacterial strains for treating and preventing cancer.
Description
COMPOSITIONS COMPRISING BACTERIAL STRAINS
TECHNICAL FIELD
This invention is in the field of compositions comprising bacterial strains isolated from the mammalian digestive tract and the use of such compositions in the treatment of disease.
BACKGROUND TO THE INVENTION
The human intestine is thought to be sterile in utero, but it is exposed to a large variety of maternai and environmental microbes immediately after birth. Thereafter, a dynamic period of microbial colonization and succession occurs, which is influenced by factors such as delivery mode, environment, diet and host génotype, ali of which impact upon the composition of the gut microbiota, particularly during early life. Subsequently, the microbiota stabilizes and becomes adult-like [I], The human gut microbiota contains more than 500-1000 different phylotypes belonging essentially to two major bacterial divisions, the Bacteroidetes and the Firmicutes [2]. The successful symbiotic relationships arising from bacterial colonization of the human gut hâve yielded a wide variety of metabolic, structural, protective and other bénéficiai functions. The enhanced metabolic activities of the colonized gut ensure that otherwise indigestible dietary components are degraded with release of by-products providing an important nutrient source for the host. Similarly, the immunological importance of the gut microbiota is well-recognized and is exemplified in gemifree animais which hâve an impaired immune system that is functionally reconstituted following the introduction of commensal bacteria [3-5].
Dramatic changes in microbiota composition hâve been documented in gastrointestinal disorders such as inflammatory bowel disease (IBD). For example, the levels of Clostridium cluster XlVa bacteria are reduced in IBD patients whilst numbers of E. coli are increased, suggesting a shift in the balance of symbionts and pathobionts within the gut [6-9], Interestingly, this microbial dysbiosis is also associated with imbalances in T effector cell populations.
In récognition of the potential positive effect that certain bacterial strains may hâve on the animal gut, various strains hâve been proposed for use in the treatment of various diseases (see, for example, [10-13]). Also, certain strains, including mostly Lactobacillus and Bifidobacterium strains, hâve been proposed for use in treating various inflammatory and autoimmune diseases that are not directly linked to the intestines (see [14] and [15] for reviews). However, the relationship between different diseases and different bacterial strains, and the précisé effects of particular bacterial strains on the gut and at a systemic level and on any particular types of diseases, are poorly characterised. For example, certain Enterococcus species hâve been implicated in causing cancer [16],
There is a requirement in the art for new methods of treating diseases. There is also a requirement for the potential effects of gut bacteria to be characterised so that new thérapies using gut bacteria can be developed.
SUMMARY OF THE INVENTION
The inventors hâve developed new thérapies for treating and preventing diseases. In particular, the inventors hâve developed new thérapies for treating and preventing cancer. In particular, the inventors hâve identified that bacterial strains of the species Enterococcus gallinarum can be effective for treating and preventing cancer. As described in the examples, oral administration of compositions comprising Enterococcus gallinarum may reduce tumor size in mouse models of cancer.
In preferred embodiments, the invention provides a composition comprising a bacterial strain of the species Enterococcus gallinarum, for use in a method of treating or preventing cancer, such as breast, lung or lîver cancer. The inventors hâve identified that treatment with compositions comprising a bacterial strain of the species Enterococcus gallinarum can reduce tumour growth in mouse models of breast, lung and liver cancer. In certain embodiments, the composition îs for use in a method of reducing tumour size or preventing tumour growth in the treatment of cancer. Compositions using Enterococcus gallinarum may be particularly effective for reducing tumour size or preventing tumour growth in the treatment of cancer.
In preferred embodiments of the invention, the bacterial strain in the composition is of Enterococcus gallinarum. Closely related strains may also be used, such as bacterial strains that hâve a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the I6s rRNA sequence of a bacterial strain of Enterococcus gallinarum. Preferably, the bacterial strain has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to SEQ ID NO:l or 2. Preferably, the sequence identity is to SEQ ID NO:2. Preferably, the bacterial strain for use în the invention has the 16s rRNA sequence represented by SEQ ID NO:2.
Accordingly, the invention also provides a composition comprising a bacterial strain that has a I6s rRNA sequence that is at least 95% identical to the 16s rRNA sequence of a bacterial strain of Enterococcus gallinarum for use in a method of treating or preventing cancer. In particular, the invention provides a composition comprising a bacterial strain that has a 16s rRNA sequence that is at least 95% identical to SEQ ID NO: 2 for use in a method of treating or preventing cancer. In some embodiments, the bacterial strain in the composition is not of Enterococcus gallinarum. In some embodiments, the bacterial strain in the composition is not of Enterococcus gallinarum, but is a closely related strain.
In certain embodiments, the composition of the invention is for oral administration. Oral administration of the strains of the invention can be effective for treating cancer. Also, oral administration is convenient for patients and practitioners and allows delivery to and / or partial or total colonisation of the intestine.
In certain embodiments, the composition of the invention comprises one or more pharmaceutically acceptable excipients or carriers.
In certain embodiments, the composition of the invention comprises a bacterial strain that has been lyophilised. Lyophilisation is an effective and convenient technique for preparing stable compositions that allow delivery of bacteria.
In certain embodiments, the invention provides a food product comprising the composition as described above.
In certain embodiments, the invention provides a vaccine composition comprising the composition as described above.
Additionally, the invention provides a method of treating or preventing cancer, comprising administering a composition comprising a bacterial strain of the species Enterococcus gallinarum.
In developing the above invention, the inventors hâve identified and characterised a bacterial strain that is particulariy useful for therapy. The Enterococcus gallinaruni strain of the invention is shown to be effective for treating cancer. Therefore, in another aspect, the invention provides a cell of the Enterococcus gallinaruni strain deposited under accession number NCIMB 42488, or a dérivative thereof. The invention also provides compositions comprising such cells, or biologically pure cultures of such cells. The invention also provides a cell of the Enterococcus gallinaruni strain deposited under accession number NCIMB 42488, or a dérivative thereof, for use in therapy, in particular for cancer. Similarly, the invention provides a cell of a bacterial strain that has a 16s rRNA sequence that is at least 95% identical to SEQ ID NO: 2, or a dérivative thereof. The invention also provides compositions comprising such cells, or biologically pure cultures of such cells. The invention also provides a cell of a bacterial strain that has a 16s rRNA sequence that is at least 95% identical to SEQ ID NO:2, or a dérivative thereof, for use in therapy, in particular for treating or preventing cancer.
BRIEF DESCRIPTION OF DRAWINGS
Figure 1 : Mouse model of breast cancer - tumor volume.
Figure 2: Mouse model of lung cancer - tumour volume.
Figure 3: Mouse model of liver cancer - liver weight.
Figure 4A: Cytokine levels (pg/ml) in immature dendritic cells (No bacteria).
Figure 4B: Cytokine levels (pg/ml) in immature dendritic cells after the addition of LPS.
Figure 4C: Cytokine levels (pg/ml) in immature dendritic cells after the addition of MRX518.
Figure 4D: Cytokine levels (pg/ml) in immature dendritic cells after the addition of MRX518 and LPS.
Figure 5A: Cytokine levels in THP-l cells (No bacteria).
Figure 5B: Cytokine levels in THP-l cells after addition of bacterial sédiment.
Figure 5C: Cytokine levels in THP-I cells after the addition of MRX518 alone or in combination with LPS.
DISCLOSURE OF THE INVENTION
Bacterial stratus
The compositions of the invention comprise a bacterial strain of the species Enterococcus gallinarum. The examples demonstrate that bacteria of this species are useful for treating or preventing cancer.
The invention also provides compositions comprising a bacterial strain that has a 16s rRNA sequence that is at least 95% identical to the 16s rRNA sequence of a bacterial strain of Enterococcus gallinarum for use in therapy, for example, for use in a method of treating or preventing cancer. In particular, the invention also provides compositions comprising a bacterial strain that has a 16s rRNA sequence that is at least 95% identical to SEQ ID NO: 2 for use in therapy, for example, for use in a method of treating or preventing cancer. In some embodiments, the bacterial strain in the composition is not of Enterococcus gallinarum, but is a closely related strain.
The invention provides an Enterococcus gallinarum for use in therapy, for example, for use in treating or preventing cancer. Similarly, the invention provides a composition comprising a bacterial strain of the species Enterococcus gallinarum, for use in therapy, for example, for use in treating or preventing cancer. In certain embodiments, the compositions of the invention comprise a bacterial strain that has a I6s rRNA sequence that is at least 95% identical to SEQ ID NO: 2, for example which is a Enterococcus gallinarum. and do not contain any other bacterial genus. In certain embodiments, the compositions of the invention comprise a single strain of a bacterial strain that has a I6s rRNA sequence that is at least 95% identical to SEQ ID NO: 2, for example, which is an Enterococcus gallinarum, and do not contain any other bacterial strain or species.
Enterococcus gallinarum forms coccoid cells, mostly in pairs or short chains. It is nonmotile and colonies on blood agar or nutrient agar are circular and smooth. Enterococcus gallinarum reacts with
Lancefïeld group D antisera. The type strain of Enterococcus gallinarum is F87/276 = PB2l = ATCC 49573 = CCUG 18658 = CIP 103013 = JCM 8728 = LMG 13129 = NBRC 100675 = NCIMB 702313 (fbnnerly NCDO 2313) = NCTC 12359 [17], The GenBank accession number for a 16S rRNA gene sequence of Enterococcus gallinarum is AF039900 (disclosed herein as SEQ ID NO:1). An exemplary Enterococcus gallinarum strain is described in [ 17],
The Enterococcus gallinarum bacterium deposited under accession number NCIMB 42488 was tested in the Examples and is also referred to herein as strain MRX518. Référencés to MRX518 and MRx0518 are used interchangeably. A 16S rRNA sequence for the MRX518 strain that was tested is provided in SEQ ID NO:2. Strain MRX518 was deposited with the international depositary authority NCIMB, Ltd. (Ferguson Building, Aberdeen, AB21 9YA, Scotland) by 4D Pharma Research Ltd. (Life Sciences Innovation Building, Aberdeen, AB25 2ZS, Scotland) on 16th November 2015 as “Enterococcus sp and was assigned accession number NCIMB 42488.
The genome of strain MRX518 comprises a chromosome and plasmid. A chromosome sequence for strain MRX518 is provided in SEQ ID NO:3. SEQ ID NO:3 is disclosed in WO 2017/085520. A plasmid sequence for strain MRX518 is provided in SEQ ID NO:4. SEQ ID NO:4 is disclosed in WO 2017/085520. These sequences were generated using the PacBio RS II platform.
Bacterial strains closely related to the strain tested in the examples are also expected to be effective for treating or preventing cancer. In certain embodiments, the bacterial strain for use in the invention has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to the 16s rRNA sequence of a bacterial strain of Enterococcus gallinarum. Preferably, the bacterial strain for use in the invention has a 16s rRNA sequence that is at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% identical to SEQ ID NO: 1 or 2. Preferably, the sequence identity is to SEQ ID NO:2. Preferably, the bacterial strain for use in the invention has the 16s rRNA sequence represented by SEQ ID NO:2.
Bacterial strains that are biotypes of the bacterium deposited under accession number 42488 are also expected to be effective for treating or preventing cancer. A biotype is a closely related strain that has the same or very similar physiological and biochemical characteristics.
Strains that are biotypes of the bacterium deposited under accession number NCIMB 42488 and that are suitable for use in the invention may be identified by sequencing other nucléotide sequences for the bacterium deposited under accession number NCIMB 42488. For example, substantially the whole genome may be sequenced and a biotype strain for use in the invention may hâve at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity across at least 80% of its whole genome (e.g. across at least 85%, 90%, 95% or 99%, or across its whole genome). For example, in some embodiments, a biotype strain has at least 98% sequence identity across at least 98% of its genome or at least 99% sequence identity across 99% of its genome. Other suitable sequences for use in identifying biotype strains may include hsp60 or répétitive sequences such as BOX. ERIC, (GTG)>, or REP or [ 18], Biotype strains may hâve sequences with at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity to the corresponding sequence of the bacterium deposited under accession number NCIMB 42488. In some embodiments, a biotype strain has a sequence with at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identity to the corresponding sequence of strain MRX518 deposited as NCIMB 42488 and comprises a 16S rRNA sequence that is at least 99% identical (e.g. at least 99.5% or at least 99.9% identical) to SEQ ID NO:2. In some embodiments, a biotype strain has a sequence with at least 95%, 96%, 97%, 98%, 99%, 99.5% or 99.9% sequence identify to the corresponding sequence of strain MRX518 deposited as NCIMB 42488 and has the 16S rRNA sequence of SEQ ID NO:2.
In certain embodiments, the bacterial strain for use in the invention has a chromosome with sequence identity to SEQ ID NO:3. In preferred embodiments, the bacterial strain for use in the invention has a chromosome with at least 90% sequence identity (e.g. at least 92%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NO:3 across at least 60% (e.g. at least 65%, 70%, 75%, 80%, 85%, 95%, 96%, 97%, 98%, 99% or 100%) of SEQ ID NO:3. For example, the bacterial strain for use in the invention may hâve a chromosome with at least 90% sequence identity to SEQ ID NO:3 across 70% of SEQ ID NO:3, or at least 90% sequence identity to SEQ ID NO:3 across 80% of SEQ ID NO:3, or at least 90% sequence identity to SEQ ID NO:3 across 90% of SEQ ID NO:3, or at least 90% sequence identity to SEQ ID NO:3 across 100% of SEQ ID NO:3, or at least 95% sequence identity to SEQ ID NO:3 across 70% of SEQ ID NO:3, or at least 95% sequence identity to SEQ ID NO:3 across 80% of SEQ ID NO:3, or at least 95% sequence identity to SEQ ID NO:3 across 90% of SEQ ID NO:3, or at least 95% sequence identity to SEQ ID NO:3 across 100% of SEQ ID NO:3, or at least 98% sequence identity to SEQ ID NO:3 across 70% of SEQ ID NO:3, or at least 98% sequence identity to SEQ ID NO:3 across 80% of SEQ ID NO:3, or at least 98% sequence identity to SEQ ID NO:3 across 90% of SEQ ID NO:3, or at least 98% identity to SEQ ID NO:3 across 95% of SEQ ID NO:3, or at least 98% sequence identify to SEQ ID NO:3 across 100% of SEQ ID NO:3, or at least 99.5% sequence identity to SEQ ID NO:3 across 90% of SEQ ID NO:3, or at least 99.5% identity to SEQ ID NO:3 across 95% of SEQ ID NO:3, or at least 99,5% identity to SEQ ID NO:3 across 98% of SEQ ID NO:3, or at least 99.5% sequence identity to SEQ ID NO:3 across 100% of SEQ ID NO:3.
In certain embodiments, the bacterial strain for use in the invention has a plasmid with sequence identity to SEQ ID NO:4, In preferred embodiments, the bacterial strain for use in the invention has a plasmid with at least 90% sequence identity (e.g. at least 92%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity) to SEQ ID NO:4 across at least 60% (e.g. at least 65%, 70%, 75%, 80%, 85%, 95%, 96%, 97%, 98%, 99% or 100%) of SEQ ID NO:4. For example, the bacterial strain for use in the invention may hâve a plasmid with at least 90% sequence identity to SEQ ID NO:4 across
70% of SEQ ID NO:4, or at least 90% sequence identity to SEQ ID NO:4 across 80% of SEQ ID NO:4, or at least 90% sequence identity to SEQ ID NO:4 across 90% of SEQ ID NO:4, or at least 90% sequence identity to SEQ ID NO:4 across 100% of SEQ ID NO:4, or at least 95% sequence identity to SEQ ID NO:4 across 70% of SEQ ID NO:4, or at least 95% sequence identity to SEQ ID NO:4 across 80% of SEQ ID NO:4, or at least 95% sequence identity to SEQ ID NO:4 across 90% of SEQ ID NO:4, or at least 95% sequence identity to SEQ ID NO:4 across 100% of SEQ ID NO:4, or at least 98% sequence identity to SEQ ID NO:4 across 70% of SEQ ID NO:4, or at least 98% sequence identity to SEQ ID NO:4 across 80% of SEQ ID NO:4, or at least 98% sequence identity to SEQ ID NO:4 across 90% of SEQ ID NO:4, or at least 98% sequence identity to SEQ ID NO:4 across 100% of SEQ ID NO:4.
In certain embodiments, the bacterial strain for use in the invention has a chromosome with sequence identity to SEQ ID NO:3 and a plasmid with sequence identity to SEQ ID NO:4.
In certain embodiments, the bacterial strain for use in the invention has a chromosome with sequence identity to SEQ ID NO:3, for example as described above, and a 16S rRNA sequence with sequence identity to any of SEQ ID NO:1 or 2, for example as described above, preferably with a 16s rRNA sequence that is at least 99% identical to SEQ ID NO: 2, more preferably which comprises the 16S rRNA sequence of SEQ ID NO:2, and optionally comprises a plasmid with sequence identity to SEQ ID NO:4, as described above.
In certain embodiments, the bacterial strain for use in the invention has a chromosome with sequence identity to SEQ ID NO:3, for example as described above, and optionally comprises a plasmid with sequence identity to SEQ ID NO:4, as described above, and is effective for treating or preventing cancer.
In certain embodiments, the bacterial strain for use in the invention has a chromosome with sequence identity to SEQ ID NO:3, for example as described above, and a 16S rRNA sequence with sequence identity to any of SEQ ID NOs: 1 or 2, for example as described above, and optionally comprises a plasmid with sequence identity to SEQ ID NO:4, as described above, and is effective for treating or preventing cancer.
In certain embodiments, the bacterial strain for use in the invention has a 16s rRNA sequence that is at least 99%, 99.5% or 99.9% identical to the 16s rRNA sequence represented by SEQ ID NO: 2 (for example, which comprises the 16S rRNA sequence of SEQ ID NO:2) and a chromosome with at least 95% sequence identity to SEQ ID NO:3 across at least 90% of SEQ ID NO:3, and optionally comprises a plasmid with sequence identity to SEQ ID NO:4, as described above, and which is effective for treating or preventing cancer.
In certain embodiments, the bacterial strain for use in the invention has a I6s rRNA sequence that is at least 99%, 99.5% or 99.9% identical to the 16s rRNA sequence represented by SEQ ID NO: 2 (for example, which comprises the 16S rRNA sequence of SEQ ID NO:2) and a chromosome with at least 98% sequence identity (e.g. at least 99% or at least 99.5% sequence identity) to SEQ ID NO:3 across at least 98% (e.g. across at least 99% or at least 99.5%) of SEQ ID NO:3, and optionally comprises a plasmid with sequence identity to SEQ ID NO:4, as described above, and which is effective for treating or preventing cancer.
In certain embodiments, the bacterial strain for use in the invention is a Enterococcus gallinarum and has a 16s rRNA sequence that is at least 99%, 99.5% or 99.9% identical to the I6s rRNA sequence represented by SEQ ID NO: 2 (for example, which comprises the 16S rRNA sequence of SEQ ID NO:2) and a chromosome with at least 98% sequence identity (e.g. at least 99% or at least 99.5% sequence identity) to SEQ ID NO:3 across at least 98% (e.g. across at least 99% or at least 99.5%) of SEQ ID NO:3, and optionally comprises a plasmid with sequence identity to SEQ ID NO:4, as described above, and which is effective for treating or preventing cancer.
Altematively, strains that are biotypes of the bacterium deposited under accession number NCIMB 42488 and that are suitable for use in the invention may be identified by using the accession number NCIMB 42488 deposit and restriction fragment analysis and/or PCR analysis, for example by using fluorescent amplified fragment length polymorphism (FAFLP) and répétitive DNA element (rep)PCR fmgerprinting, or protein profiling, or partial 16S or 23s rDNA sequencing. In preferred embodiments, such techniques may be used to identify other Enterococcus gallinarum strains.
In certain embodiments, strains that are biotypes of the bacterium deposited under accession number NCIMB 42488 and that are suitable for use in the invention are strains that provide the same pattem as the bacterium deposited under accession number NCIMB 42488 when analysed by amplified ribosomal DNA restriction analysis (ARDRA), for example when using Sau3AI restriction enzyme (for exemplary methods and guidance see, for example,[l9]). Altematively, biotype strains are identified as strains that hâve the same carbohydrate fermentation patterns as the bacterium deposited under accession number NCIMB 42488. In some embodiments, the carbohydrate fermentation pattem is determined using the API 50 CHL panel (bioMérieux). In some embodiments, the bacterial strain used in the invention is:
(i) positive for fermentation of at least one of (e.g. at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 or ail of): L-arabinose, D-ribose, D-xylose, D-galactose, D-glucose, Dfructose, D-mannose, N-acetylglucosamine, amygdalin, arbutin, salicin, D-cellobiose, Dmaltose, sucrose, D-trehalose, gentiobiose, D-tagatose and potassium gluconate; and/or (ii) intermédiare for fermentation of at least one of (e.g. at least 2, 3, 4 or ail of): D-mannitol, Methyl-aD-glycopyranoside, D-lactose, starch, and L-fùcose;
preferably as determined by API 50 CHL analysis (preferably using the API 50 CHL panel from bioMérieux).
Other Enterococcus gallinarum strains that are useful in the compositions and methods of the invention, such as biotypes of the bacterium deposited under accession number NCIMB 42488, may be identified using any appropriate method or strategy, including the assays described in the examples. For instance, strains for use in the invention may be identified by culturing in anaérobie YCFA and/or administering the bacteria to the type II collagen-induced arthritis mouse model and then assessing cytokine levels. In particular, bacterial strains that hâve simîlar growth patterns, metabolic type and/or surface antigens to the bacterium deposited under accession number NCIMB 42488 may be useful in the invention. A useful strain will hâve comparable immune modulatory activity to the NCIMB 42488 strain. In particular, a biotype strain will elicit comparable effects on the cancer disease models to the effects shown in the Examples, which may be identified by using the culturing and administration protocols described in the Examples.
In some embodiments, the bacterial strain used in the invention is:
(i) Positive for at least one of (e.g. at least 2, 3, 4, 5, 6, 7 or ail of): mannose fermentation, glutamic acid decarboxylase, arginine arylamidase, phenylalanine arylamidase, pyroglutamic acid arylamidase, tyrosine arylamidase, histidine arylamidase and serine arylamidase; and/or (ii) Intermediate for at least one of (e.g. at least 2 or ail of): β-galactosidase-ô-phosphate, β-glucosidase and N-acetyl^-glucosaminidase; and/or (ni) Négative for at least one of (e.g. at least 2, 3, 4, 5, 6 or ail of): Raffinose fermentation, Proline arylamidase, Leucyl glycine arylamidase, Leucine arylamidase, Alanine arylamidase, Glycine arylamidase and Glutamyl glutamic acid arylamidase, preferably as determined by an assay of carbohydrate, amino acid and nitrate metabolism, and optionally an assay of alkaline phosphatase activity, more preferably as determined by Rapid ID 32A analysis (preferably using the Rapid ID 32A system from bioMérieux).
In some embodiments, the bacterial strain used in the invention is:
(i) Négative for at least one of (e.g. at least 2, 3, or ail 4 of) glycine arylamidase, raffinose fermentation, proline arylamidase, and leucine arylamidase, for example, as determined by an assay of carbohydrate, amino acid and nitrate metabolism, preferably as determined by Rapid ID 32A analysis (preferably using the Rapid ID 32A System from bioMérieux); and/or (ii) Intermediate positive for fermentation of L-fucose, preferably as determined by API 50 CHL analysis (preferably using the API 50 CHL panel from bioMérieux).
ΙΟ
In some embodiments, the bacterial strain used in the invention is an extracellular ATP producer, for example one which produces 6-6.7 ng/μΐ (for example, 6.1-6.6 ng/μΐ or 6.2-6.5 ng/μΐ or 6.33 ±0.10 ng/μΐ) of ATP as measured using the ATP Assay Kit (Sigma-Aldrich, MAKI90). Bacterial extracellular ATP can hâve pléïotropie effects including activation of T cell-receptor mediated signalling (Schenk et al., 2011), promotion of intestinal Thl7 cell différentiation (Atarashi et al., 2008) and induction of sécrétion of the pro-inflammatory mediator IL-1 β by activating the NLRP3 inflammasome (Karmarkar et al., 2016). Accordingly, a bacterial strain which is an extracellular ATP producer is useful for treating or preventing cancer.
In some embodiments, the bacterial strain for use in the invention comprises one or more of the following three genes: Mobile element protein; Xylose ABC transporter, permease component; and FIG00632333: hypothetical protein. For example, in certain embodiments, the bacterial strain for use in the invention comprises genes encoding Mobile element protein and Xylose ABC transporter, permease component; Mobile element protein and FIG00632333: hypothetical protein; Xylose ABC transporter, permease component and FIG00632333: hypothetical protein; or Mobile element protein, Xylose ABC transporter, permease component, and FIG00632333: hypothetical protein.
A particularly preferred strain of the invention is the Enterococcus gallinarum strain deposîted under accession number NCIMB 42488. This is the exemplary MRX518 strain tested in the examples and shown to be effective for treating disease. Therefore, the invention provides a cell, such as an isolated cell, of the Enterococcus gallinarum strain deposîted under accession number NCIMB 42488, or a dérivative thereof. The invention also provides a composition comprising a cell of the Enterococcus gallinarum strain deposîted under accession number NCIMB 42488, or a dérivative thereof. The invention also provides a biologically pure culture of the Enterococcus gallinarum strain deposîted under accession number NCIMB 42488. The invention also provides a cell of the Enterococcus gallinarum strain deposîted under accession number NCIMB 42488, or a dérivative thereof, for use in therapy, in particular for the diseases described herein. A dérivative of the strain deposîted under accession number NCIMB 42488 may be a daughter strain (progeny) or a strain cultured (subcloned) from the original.
A dérivative of a strain of the invention may be modified, for example at the genetic level, without ablating the biological activity. In particular, a dérivative strain of the invention is therapeutically active. A dérivative strain will hâve comparable immune modulatory activity to the original NCIMB 42488 strain. In particular, a derivatîve strain will elicit comparable effects on the cancer disease models to the effects shown in the Examples, which may be identified by using the culturing and administration protocols described in the Examples. A derivatîve of the NCIMB 42488 strain will generally be a biotype of the NCIMB 42488 strain.
H
Référencés to cells of the Enterococcus gallinarum strain deposited under accession number NCIMB 42488 encompass any cells that hâve the same safety and therapeutic efficacy characteristics as the strains deposited under accession number NCIMB 42488, and such cells are encompassed by the invention. Thus, in some embodiments, reference to cells of the Enterococcus gallinarum strain deposited under accession number NCIMB 42488 refers only to the MRX518 strain deposited under NCIMB 42488 and does not refer to a bacterial strain that was not deposited under NCIMB 42488. In some embodiments, reference to cells of the Enterococcus gallinarum strain deposited under accession number NCIMB 42488 refers to cells that hâve the same safety and therapeutic efficacy characteristics as the strains deposited under accession number NCIMB 42488, but which are not the strain deposited under NCIMB 42488.
In preferred embodiments, the bacterial strains in the compositions of the invention are viable and capable of partially or totaily colonising the intestine.
Treating cancer
In preferred embodiments, the compositions of the invention are for use in treating or preventing cancer. The examples demonstrate that administration ofthe compositions of the invention can lead to a réduction in tumour growth in a number of tumour models.
In certain embodiments, treatment with the compositions of the invention results in a réduction in tumour size or a réduction in tumour growth. In certain embodiments, the compositions of the invention are for use in reducing tumour size or reducing tumour growth. The compositions of the invention may be effective for reducing tumour size or growth. In certain embodiments, the compositions of the invention are for use in patients with solid tumours. In certain embodiments, the compositions of the invention are for use in reducing or preventing angiogenesis in the treatment of cancer. The compositions of the invention may hâve an effect on the immune or inflammatory Systems, which hâve central rôles in angiogenesis. In certain embodiments, the compositions of the invention are for use in preventing metastasis.
In certain embodiments, the compositions of the invention are for use in treating or preventing breast cancer. The examples demonstrate that the compositions of the invention may be effective for treating breast cancer. In certain embodiments, the compositions of the invention are for use in reducing tumour size, reducing tumour growth, or reducing angiogenesis in the treatment of breast cancer. In preferred embodiments the cancer is mammary carcinoma. In preferred embodiments the cancer is stage IV breast cancer.
In certain embodiments, the compositions of the invention are for use in treating or preventing lung cancer. The examples demonstrate that the compositions of the invention may be effective for treating lung cancer. In certain embodiments, the compositions of the invention are for use in reducing tumour size, reducing tumour growth, or reducing angiogenesîs in the treatment of lung cancer. In preferred embodiments the cancer is lung carcinoma.
In certain embodiments, the compositions of the invention are for use in treating or preventing liver cancer. The examples demonstrate that the compositions of the invention may be effective for treating liver cancer. In certain embodiments, the compositions of the invention are for use in reducing tumour size, reducing tumour growth, or reducing angiogenesîs in the treatment of liver cancer. In preferred embodiments the cancer is hepatoma (hepatocellular carcinoma).
In certain embodiments, the compositions of the invention are for use in treating or preventing colon cancer. The examples demonstrate that the compositions of the invention hâve an effect on colon cancer cells and may be effective for treating colon cancer. In certain embodiments, the compositions of the invention are for use in reducing tumour size, reducing tumour growth, or reducing angiogenesîs in the treatment of colon cancer. In preferred embodiments the cancer is colorectal adenocarcinoma.
In some embodiments, the cancer is of the intestine. In some embodiments, the cancer is of a part of the body which is not the intestine. In some embodiments, the cancer is not cancer of the intestine. In some embodiments, the cancer is not colorectal cancer. In some embodiments, the cancer is not cancer ofthe small intestine. In some embodiments, the treating or preventing occurs at a site other than at the intestine. In some embodiments, the treating or preventing occurs at the intestine and also at a site other than at the intestine.
In certain embodiments, the compositions of the invention are for use in treating or preventing carcinoma. The examples demonstrate that the compositions of the invention may be effective for treating numerous types of carcinoma. In certain embodiments, the compositions ofthe invention are for use in treating or preventing non-immunogenic cancer. The examples demonstrate that the compositions of the invention may be effective for treating non-immunogenic cancers.
The therapeutic effects of the compositions of the invention on cancer may be mediated by a proinflammatory mechanism. Examples 2, 4 and 5 demonstrate that the expression of a number of proinflammatory cytokines may be increased following administration of MRX518. Inflammation can hâve a cancer-suppressive effect [20] and pro-inflammatory cytokines such as TNFa are being investigated as cancer thérapies [21 ]. The up-regulation of genes such as TNF shown in the examples may indicate that the compositions of the invention may be useful for treating cancer via a similar mechanism. The up-regulation of CXCR3 ligands (CXCL9, CXCLIO) and IFNy-inducible genes (IL32) may indicate that the compositions of the invention elicit an IFNy-type response. IFNy is a potent macrophage-activating factor that can stimulate tumirocidal activity [22], and CXCL9 and CXCLIO, for example, also hâve anti-cancer effects [23-25]. Therefore, in certain embodiments, the compositions of the invention are for use in promoting inflammation in the treatment of cancer. In
I3 preferred embodiments, the compositions ofthe invention are for use in promoting Thl inflammation in the treatment of cancer. Thl cells produce IFNy and hâve potent anti-cancer effects [20]. In certain embodiments, the compositions of the invention are for use in treating an early-stage cancer, such as a cancer that has not metastasized, or a stage 0 or stage l cancer. Promoting inflammation may be more effective against early-stage cancers [20]. In certain embodiments, the compositions of the invention are for use in promoting inflammation to enhance the effect of a second anti-cancer agent. In certain embodiments, the treatment or prévention of cancer comprises increasing the level of expression of one or more cytokines. For example, in certain embodiments, the treatment or prévention of cancer comprises increasing the level of expression of one or more of IL-Ιβ, IL-6 and TNF-α, for example, IL-1 β and IL-6, IL-1β and TNF-α, IL-6 and TNF-α or ail three of IL-lβ, IL-6 and TNF-α. Increases in levels of expression of any of IL-Ιβ, IL-6 and TNF-α are known to be indicative of efficacy in treatment of cancer.
Examples 4 and 5 demonstrate that when a bacterial strain as described herein is used in combination with lipopolysaccharide (LPS), there is a synergistic increase in IL-Ιβ. LPS is known to elicit a proinflammatory effect. Thus, in certain embodiments, the treatment or prévention comprises using a bacterial strain as described herein in combination with an agent that upregulates IL-Ιβ. In certain embodiments, the treatment or prévention comprises using a bacterial strain as described herein in combination with LPS. Accordingly, a composition of the invention may additionally comprise an agent that upregulates IL-Ιβ. Accordingly, a composition of the invention may additionally comprise LPS.
In certain embodiments, the compositions of the invention are for use in treating a patient that has previously received chemotherapy. In certain embodiments, the compositions of the invention are for use in treating a patient that has not tolerated a chemotherapy treatment. The compositions of the invention may be particularly suitable for such patients.
In certain embodiments, the compositions of the invention are for preventing relapse. The compositions of the invention may be suitable for long-temi administration. In certain embodiments, the compositions of the invention are for use in preventing progression of cancer.
In certain embodiments, the compositions of the invention are for use în treating non-small-cell lung carcinoma. In certain embodiments, the compositions of the invention are for use in treating smallcell lung carcinoma. In certain embodiments, the compositions of the invention are for use in treating squamous-cell carcinoma. In certain embodiments, the compositions of the invention are for use in treating adenocarcinoma. In certain embodiments, the compositions of the invention are for use in treating glandular tumors, carcinoid tumors, or undifferentiated carcinomas.
In certain embodiments, the compositions of the invention are for use in treating hepatoblastoma, cholangiocarcinoma, cholangiocellular cystadenocarcinoma or liver cancer resulting from a viral infection.
In certain embodiments, the compositions of the invention are for use in treating invasive ductal carcinoma, ductal carcinoma in situ or invasive lobular carcinoma.
In further embodiments, the compositions of the invention are for use in treating or preventing acute lymphoblastic leukemia (ALL), acute myeloîd leukemia, adrenocortical carcinoma, basal-cell carcinoma, bile duct cancer, bladder cancer, bone tumor, osteosarcoma/malignant fibrous histiocytoma, brainstem glioma, brain tumor, cerebellar astrocytoma, cérébral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, breast cancer, bronchial adenomas/carcinoids, Burkitt's lymphoma, carcinoid tumor, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, endométrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, întraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), genn cell tumor, glioma, childhood visual pathway and hypothalamic, Hodgkin lymphoma, melanoma, islet cell carcinoma, Kaposi sarcoma, rénal cell cancer, laryngeal cancer, leukaemias, lymphomas, mesothelioma, neuroblastoma, non-Hodgkin lymphoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary adenoma, plasma cell neoplasia, prostate cancer, rénal cell carcinoma, retinoblastoma, sarcoma, testicular cancer, thyroid cancer, or uterine cancer,
The compositions of the invention may be particularly effective when used in combination with further therapeutic agents. The immune-modulatory effects of the compositions of the invention may be effective when combined with more direct anti-cancer agents. Therefore, in certain embodiments, the invention provides a composition comprising a bacterial strain of the species Enterococcus gallinarum and an anticancer agent. In preferred embodiments the anticancer agent is an immune checkpoint inhibitor, a targeted antibody immunotherapy, a CAR-T cell therapy, an oncolytic virus, or a cytostatic drug. In preferred embodiments, the composition comprises an anti-cancer agent selected from the group consisting of: Yervoy (ipilimumab, BMS); Keytruda (pembrolizumab, Merck); Opdivo (nivolumab, BMS); MEDI4736 (AZ/Medlmmune); MPDL3280A (Roche/Genentech); Tremelimumab (AZ/Medlmmune); CT-Oll (pidilizumab, CureTech); BMS986015 (lirilumab, BMS); MEDI0680 (AZ/Medlmmune); MSB-0010718C (Merck); PF-05082566 (Pfizer); MED16469 (AZ/Medlmmune); BMS-986016 (BMS); BMS-663513 (urelumab, BMS); IMP321 (Prima Biomed); LAG525 (Novartis); ARGX-110 (arGEN-X); PF-05082466 (Pfizer); CDX-1127 (varlilumab; CellDex Therapeutics); TRX-518 (GITR Inc.); MK-4166 (Merck); JTX
20ll (Jounce Therapeutics); ARGX-H5 (arGEN-X); NLG-9189 (indoximod, NewLink Genetics); INCB024360 (Incyte); IPH2201 (Innate Immotherapeutics/AZ); NLG-9I9 (NewLink Genetics); antiVISTA (JnJ); Epacadostat (INCB24360, Incyte); F00I287 (Flexus/BMS); CP 870893 (University of Pennsylvania); MGA27I (Macrogenix); Emactuzumab (Roche/Genentech); Galunisertib (Eli Lilly); Ulocuplumab (BMS); BKT140/BL8040 (Biokine Therapeutics); Bavituximab (Peregrine Pharmaceuticals); CC 90002 (Celgene); 852A (Pfizer); VTX-2337 (VentiRx Pharmaceuticals); IMO2055 (Hybridon, Idera Pharmaceuticals); LY2157299 (Eli Lilly); EW-7197 (Ewha Women's University, Korea); Vemurafenib (Plexxikon); Dabrafenib (Genentech/GSK); BMS-777607 (BMS); BLZ945 (Memorial Sloan-Kettering Cancer Centre); Unituxin (dinutuximab, United Therapeutics Corporation); Blincyto (blinatumomab, Amgen); Cyramza (ramucirumab, Eli Lilly); Gazyva (obinutuzumab, Roche/Biogen); Kadcyla (ado-trastuzumab emtansine, Roche/Genentech); Perjeta (pertuzumab, Roche/Genentech); Adcetris (brentuximab vedotin, Takeda/Millennium); Arzerra (ofatumumab, GSK); Vectibix (panîtumumab, Amgen); Avastin (bevacizumab, Roche/Genentech); Erbitux (cetuximab, BMS/Merck); Bexxar (tositumomab-1131, GSK); Zevalin (ibritumomab tiuxetan, Biogen); Campath (alemtuzumab. Bayer); Mylotarg (gemtuzumab ozogamicin, Pfizer); Herceptin (trastuzumab, Roche/Genentech); Rituxan (rituximab, Genentech/Biogen); volociximab (Abbvie); Enavatuzumab (Abbvie); ABT-414 (Abbvie); Elotuzumab (Abbvie/BMS); ALX-0141 (Ablynx); Ozaralizumab (Ablynx); Actimab-C (Actinium); Actimab-P (Actinium); Milatuzumab-dox (Actinium); Emab-SN-38 (Actinium); Naptumonmab estafenatox (Active Biotech); AFM 13 (Affimed); AFM il (Affimed); AGS-16C3F (Agensys); AGS-16M8F (Agensys); AGS-22ME (Agensys); AGS-15ME (Agensys); GS-67E (Agensys); ALXN6000 (samalizumab, Alexion); ALT836 (Altor Bioscience); ALT-801 (Altor Bioscience); ALT-803 (Altor Bioscience); AMG780 (Amgen); AMG 228 (Amgen); AMG820 (Amgen); AMG172 (Amgen); AMG595 (Amgen); AMG110 (Amgen); AMG232 (adecatumumab, Amgen); AMG211 (Amgen/Medlmmune); BAY2010112 (Amgen/Bayer); Rilotumumab (Amgen); Denosumab (Amgen); AMP-514 (Amgen); MEDI575 (AZ/Medlmmune); MEDI3617 (AZ/Med Immune); MEDI6383 (AZ/Medlmmune); MEDI551 (AZ/Medlmmune); Moxetumomab pasudotox (AZ/Medlmmune); MEDI565 (AZ/Medlmmune); MEDI0639 (AZ/Medlmmune); MEDI0680 (AZ/Medlmmune); MEDI562 (AZ/Medlmmune); AV-380 (AVEO); AV203 (AVEO); AV299 (AVEO); BAY79-4620 (Bayer); Anetumab ravtansine (Bayer); vantictumab (Bayer); BAY94-9343 (Bayer); Sibrotuzumab (Boehringer Ingleheim); Bl-836845 (Boehringer Ingleheim); B-701 (BioClin); BI1B015 (Biogen); Obinutuzumab (Biogen/Genentech); BI-505 (Bioinvent); BI-1206 (Bioinvent); TB-403 (Bioinvent); BT-062 (Biotest) BIL-OlOt (Biosceptre); MDX-1203 (BMS); MDX-1204 (BMS); Necituinumab (BMS); CAN-4 (Cantargia AB); CDX-011 (Celldex); CDX1401 (Celldex); CDX301 (Celldex); U31565 (Daiichi Sankyo); patritumab (Daiichi Sankyo); tigatuzumab (Daiichi Sankyo); nimotuzumab (Daiichi Sankyo); DS-8895 (Daiichi Sankyo); DS-8873 (Daiichi Sankyo); DS-5573 (Daiichi Sankyo); MORab-004 (Eisai); MORab-009 (Eisai); MORab-003 (Eisai); MORab-066 (Eisai);
LY3012207 (Eli Lilly); LY2875358 (Eli Lilly); LY2812176 (Eli Lilly); LY30122l7(Eli Lilly); LY2495655 (Eli Lilly); LY3012212 (Eli Lilly); LY30I22II (Eli Lilly); LY3009806 (Eli Lilly); cixutumumab (Eli Lilly); Flanvotumab (Eli Lilly); IMC-TRl (Eli Lilly); Ramucirumab (Eli Lilly); Tabalumab (Eli Lilly); Zanolimumab (Emergent Biosolution); FG-3019 (FibroGen); FPA008 (Five Prime Therapeutics); FP-1039 (Five Prime Therapeutics); FPA144 (Five Prime Therapeutics); catumaxomab (Fresenius Biotech); IMAB362 (Ganymed); IMAB027 (Ganymed); HuMax-CD74 (Genmab); HuMax-TFADC (Genmab); GS-5745 (Gilead); GS-6624 (Gilead); OMP-21M18 (demcizumab, GSK); mapatumumab (GSK); 1MGN289 (ImmunoGen); IMGN901 (ImmunoGen); IMGN853 (ImmunoGen); IMGN529 (ImmunoGen); IMMU-130 (Immunomedics); miiatuzumabdox (Immunomedics); IMMU-115 (Immunomedics); IMMU-132 (Immunomedics); IMMU-106 (Immunomedics); IMMU-102 (Immunomedics); Epratuzumab (Immunomedics); Clivatuzumab (Immunomedics); IPH41 (Innate Immunotherapeutics); Daratumumab (Janssen/Genmab); CNTO-95 (Intetumumab, Janssen); CNTO-328 (siltuximab, Janssen); KB004 (KaloBios); mogamulizumab (Kyowa Hakko Kirrin); KW-287I (ecromeximab, Life Science); Sonepcizumab (Lpath); Margetuximab (Macrogenics); Enoblituzumab (Macrogenics); MGD006 (Macrogenics); MGF007 (Macrogenics); MK-0646 (dalotuzumab, Merck); MK-3475 (Merck); Sym004 (Symphogen/Merck Serono); D117E6 (Merck Serono); MOR208 (Morphosys); MOR202 (Morphosys); Xmab5574 (Morphosys); BPC-1C (ensituximab, Précision Biologics); TAS266 (Novartis); LFA102 (Novartis); BHQ880 (Novartis/Morphosys); QGE031 (Novartis); HCD122 (lucatumumab, Novartis); LJM716 (Novartis); AT355 (Novartis); OMP-21M18 (Demcizumab, OncoMed); OMP52M51 (Oncomed/GSK); OMP-59R5 (Oncomed/GSK); vanlictumab (Oncomed/Bayer); CMC-544 (inotuzumab ozogamicîn, Pfizer); PF-03446962 (Pfizer); PF-04856884 (Pfizer); PSMA-ADC (Progenics); REGN1400 (Regeneron); REGN910 (nesvacumab, Regeneron/Sanofi); REGN421 (enoticumab, Regeneron/Sanofi); RG7221, RG7356, RG7155, RG7444, RG7116, RG7458, RG7598, RG7599, RG7600, RG7636, RG7450, RG7593, RG7596, DCDS3410A, RG7414 (parsatuzumab), RG7160 (imgatuzumab), RG7159 (obintuzumab), RG7686, RG3638 (onartuzumab), RG7597 (Roche/Genentech); SAR307746 (Sanofi); SAR566658 (Sanofi); SAR650984 (Sanofi); SAR153192 (Sanofi); SAR3419 (Sanofi); SAR256212 (Sanofi), SGN-LIV1A (lintuzumab, Seattle Genetics); SGN-CD33A (Seattle Genetics); SGN-75 (vorsetuzumab mafodotin, Seattle Genetics); SGN-19A (Seattle Genetics) SGN-CD70A (Seattle Genetics); SEA-CD40 (Seattle Genetics); ibritumomab tiuxetan (Spectrum); MLN0264 (Takeda); ganitumab (Takeda/Amgen); CEP-37250 (Teva); TB-403 (Thrombogenic); VB4-845 (Viventia); Xmab2512 (Xencor); Xmab5574 (Xencor); nimotuzumab (YM Biosciences); Carlumab (Janssen); NY-ESO TCR (Adaptimmune); MAGE-A-10 TCR (Adaptimmune); CTL019 (Novartis); JCAR015 (Juno Therapeutics); KTE-C19 CAR (Rite Pharma); UCART19 (Cellectis); BPX-401 (Bellicum Pharmaceuticals); BPX-601 (Bellicum Pharmaceuticals); ATTCK20 (Unum Therapeutics); CAR-NKG2D (Celyad); Onyx-015 (Onyx Pharmaceuticals); H101 (Shanghai Sunwaybio); DNX-2401 (DNAtrix); VCN-01 (VCN Biosciences); Colo-Adl (PsiOxus
Therapeutics); ProstAtak (Advantagene); Oncos-102 (Oncos Therapeutics); CG0070 (Cold Genesys); Pexa-vac (JX-594, Jennerex Biotherapeutics); GL-ONCl (Genelux); T-VEC (Amgen); G207 (Medigene); HFIO (Takara Bio); SEPREHVIR (HSV1716, Virttu Biologics); OrienXOlO (OrienGene Biotechnology); Reolysîn (Oncolytics Biotech); SVV-OOl (Neotropix); Cacatak (CVA21, Viralytics); Alimta (Eli Lilly), cisplatin, oxaliplatin, irinotecan, folinic acid, methotrexate, cyclophosphamide, 5-fluorouracil, Zykadîa (Novartis), Tafinlar (GSK), Xalkori (Pfizer), tressa (AZ), Gilotrif (Boehringer Ingelheim), Tarceva (Astellas Pharma), Halaven (Eisai Pharma), Veliparib (Abbvie), AZD9291 (AZ), Alectinib (Chugai), LDK378 (Novartis), Genetespib (Synta Pharma), Tergenpumatucel-L (NewLink Genetics), GVlOOl (Kael-GemVax), Tivantinib (ArQule); Cytoxan (BMS); Oncovîn (Eli Lilly); Adriamycin (Pfizer); Gemzar (Eli Lilly); Xeloda (Roche); Ixempra (BMS); Abraxane (Celgene); Trelstar (Debiophami); Taxotere (Sanofi); Nexavar (Bayer); IMMU-132 (Immunomedics); E7449 (Eisai); Thermodox (Celsion); Cometriq (Exellxis); Lonsurf (Taiho Pharmaceuticals); Camptosar (Pfizer); UFT (Taiho Pharmaceuticals); and TS-1 (Taiho Pharmaceuticals).
In some embodiments, the one or more bacteriai strains having a 16s rRNA sequence that is at least 95% identical to SEQ ID NO:2, for example which is an Entcrococcus gallinarum, is/are the only therapeutically active agent(s) in a composition of the invention. In some embodiments, the bacteriai strain(s) in the composition is/are the only therapeutically active agent(s) in a composition of the invention.
Modes of administration
Preferably, the compositions of the invention are to be administered to the gastrointestinal tract in order to enable delivery to and / or partial or total colonisation of the intestine with the bacteriai strain of the invention. Generally, the compositions of the invention are administered orally, but they may be administered rectally, intranasally, or via buccal or sublingual routes.
In certain embodiments, the compositions of the invention may be administered as a foam, as a spray or a gel.
In certain embodiments, the compositions of the invention may be administered as a suppository, such as a rectal suppository, for example in the form of a theobroma oil (cocoa butter), synthetic hard fat (e.g. suppocire, witepsol), glycero-gelatin, polyethylene glycol, or soap glycerin composition.
In certain embodiments, the composition of the invention is administered to the gastrointestinal tract via a tube, such as a nasogastric tube, orogastric tube, gastric tube, jejunostomy tube (J tube), percutaneous endoscopie gastrostomy (PEG), or a port, such as a chest wall port that provides access to the stomach, jéjunum and other suitable access ports.
is
The compositions of the invention may be administered once, or they may be administered sequentially as part of a treatment regimen. In certain embodiments, the compositions of the invention are to be administered daily.
In certain embodiments of the invention, treatment according to the invention is accompanied by assessment of the patient’s gut microbiota. Treatment may be repeated if delivery of and / or partial or total colonisation with the strain of the invention is not achieved such that efficacy is not observed, or treatment may be ceased if delivery and / or partial or total colonisation is successful and efficacy is observed.
In certain embodiments, the composition of the invention may be administered to a prégnant animal, for example a mammal such as a human în order to reduce the likelihood of cancer developing in her child in utero and ! or after it is bom.
The compositions of the invention may be administered to a patient that has been diagnosed with cancer, or that has been identified as being at risk of a cancer. The compositions may also be administered as a prophylactic measure to prevent the development of cancer in a healthy patient.
The compositions of the invention may be administered to a patient that has been identified as having an abnormal gut microbiota. For example, the patient may hâve reduced or absent colonisation by Enterococcus gallinarum.
The compositions of the invention may be administered as a food product, such as a nutritional supplément.
Generally, the compositions of the invention are for the treatment of humans, although they may be used to treat animais including monogastric mammals such as poultry, pigs, cats, dogs, horses or rabbits. The compositions of the invention may be useful for enhancing the growth and performance of animais. If administered to animais, oral gavage may be used.
Compositions
Generally, the composition of the invention comprises bacteria. In preferred embodiments of the invention, the composition îs formulated in freeze-dried form. For example, the composition of the invention may comprise granules or gelatîn capsules, for example hard gelatin capsules, comprising a bacterial strain of the invention.
Preferably, the composition of the invention comprises lyophilised bacteria. Lyophilisation of bacteria is a well-established procedure and relevant guidance is available in, for example, référencés [26-28],
Altematively, the composition of the invention may comprise a live, active bacterial culture.
In some embodiments, the bacterial strain in the composition of the invention has not been inactivated, for example, has not been heat-inactivated. In some embodiments, the bacterial strain in the composition of the invention has not been killed, for example, has not been heat-killed. In some embodiments, the bacterial strain in the composition of the invention has not been attenuated, for example, has not been heat-attenuated. For example, in some embodiments, the bacterial strain in the composition of the invention has not been killed, inactivated and/or attenuated. For example, in some embodiments, the bacterial strain in the composition of the invention is live. For example, in some embodiments, the bacterial strain in the composition of the invention is viable. For example, in some embodiments, the bacterial strain in the composition of the invention is capable of partially or totally colonising the intestine. For example, in some embodiments, the bacterial strain in the composition of the invention is viable and capable of partially or totally colonising the intestine.
In some embodiments, the composition comprises a mixture of live bacterial strains and bacterial strains that hâve been killed.
In preferred embodiments, the composition of the invention is encapsulated to enable delivery of the bacterial strain to the intestine. Encapsulation protects the composition from dégradation until delivery at the target location through, for example, rupturing with Chemical or physical stimuli such as pressure, enzymatic activity, or physical disintegration, which may be triggered by changes in pH. Any appropriate encapsulation method may be used. Exemplary encapsulation techniques include entrapment within a porous matrix, attachment or adsorption on solid carrier surfaces, selfaggregation by flocculation or with cross-linking agents, and mechanical containment behind a microporous membrane or a microcapsule. Guidance on encapsulation that may be useful for preparing compositions of the invention is available in, for example, reierences [29] and [30].
The composition may be administered orally and may be in the form of a tablet, capsule or powder. Encapsulated products are preferred because Enterococctis gallinaruni are anaerobes. Other ingrédients (such as vitamin C, for example), may be included as oxygen scavengers and prebiotic substrates to improve the delivery and / or partial or total colonisation and survival in vivo. Alternatively, the probiotic composition of the invention may be administered orally as a food or nutritional product, such as milk or whey based fermented dairy product, or as a pharmaceutical product.
The composition may be formulated as a probiotic.
A composition of the invention includes a therapeutically effective amount of a bacterial strain of the invention. A therapeutically effective amount of a bacterial strain is sufficient to exert a bénéficiai effect upon a patient. A therapeutically effective amount of a bacterial strain may be sufficient to resuit in delivery to and / or partial or total colonisation of the patient’s intestine.
A suitable daily dose of the bacteria, for example for an adult human, may be from about l x IO3 to about l x IO colony forming units (CFU); for example, from about l x IO7 to about l x lO10 CFU; in another example from about l x IO6 to about I x IO10 CFU.
In certain embodiments, the composition contains the bacterial strain in an amount of from about 1 x 106 to about 1 x 1011 CFU/g, respect to the weight of the composition; for example, from about 1 x 108 to about 1 x I O10 CFU/g. The dose may be, for example, 1 g, 3g, 5g, and 10g.
Typically, a probiotic, such as the composition of the invention, is optionally combined with at least one suitable prebiotic compound. A prebiotic compound is usually a non-digestible carbohydrate such as an oligo- or polysaccharide, or a sugar alcohol, which is not degraded or absorbed in the upper digestive tract. Known prebiotics include commercial products such as inulin and transgalactooligosaccharides.
In certain embodiments, the probiotic composition of the present invention includes a prebiotic compound in an amount of from about 1 to about 30% by weight, respect to the total weight composition, (e.g. from 5 to 20% by weight). Carbohydrates may be selected from the group consisting of: fructo- oligosaccharides (or FOS), short-chain fructo-oligosaccharides, inulin, isomaltoligosaccharides, pectins, xylo-oligosaccharides (or XOS), chitosan-oligosaccharides (or COS), betaglucans, arable gum modified and résistant starches, polydextrose, D-tagatose, acacia fibers, carob, oats, and citrus fibers. In one aspect, the prebiotics are the short-chain fructo-oligosaccharides (for simplicity shown herein below as FOSs-c.c); said FOSs-c.c. are not digestible carbohydrates, generally obtained by the conversion of the beet sugar and including a saccharose molécule to which three glucose molécules are bonded.
The compositions of the invention may comprise pharmaceutically acceptable excipients or carriers. Examples of such suitable excipients may be found in the reference [31]. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art and are described, for example, in reference [32], Examples of suitable carriers include lactose, starch, glucose, methyl cellulose, magnésium stéarate, mannitol, sorbitol and the like. Examples of suitable diluents include éthanol, glycerol and water. The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice. The pharmaceutical compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), soiubilising agent(s). Examples of suitable binders include starch, gelatin, natural sugars such as glucose, anhydrous lactose, freeflow lactose, beta-lactose, corn sweeteners, natural and synthetic gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol. Examples of suitable lubricants include sodium oleate, sodium stéarate, magnésium stéarate, sodium benzoate, sodium acetate, sodium chloride and the like. Preservatives, stabilîzers, dyes and even flavouring agents may be
2i provided in the pharmaceutical composition. Examples of preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. Antioxidants and suspending agents may be also used.
The compositions of the invention may be formulated as a food product. For example, a food product may provide nutritional benefit in addition to the therapeutic effect of the invention, such as in a nutritional supplément. Similarly, a food product may be formulated to enhance the taste of the composition of the invention or to make the composition more attractive to consume by being more similar to a common food item, rather than to a pharmaceutical composition. In certain embodiments, the composition of the invention is formulated as a milk-based product. The terni milk-based product means any liquid or semi-solid milk- or whey- based product having a varying fat content. The milk-based product can be, e.g., cow's milk, goat's milk, sheep's milk, skimmed milk, whole milk, milk recombined from powdered milk and whey without any processing, or a processed product, such as yoghurt, curdled milk, curd, sour milk, sour whole milk, butter milk and other sour milk products. Another important group includes milk beverages, such as whey beverages, fermented milks, condensed milks, infant or baby milks; flavoured milks, ice cream; milk-containing food such as sweets.
In certain embodiments, the compositions of the invention contain a single bacterial strain or species and do not contain any other bacterial strains or species. Such compositions may comprise only de minimis or bîologically irrelevant amounts of other bacterial strains or species. Such compositions may be a culture that is substantially free from other species of organism. Thus, in some embodiments, the invention provides a composition comprising one or more strains from the species Enterococcus gallinarum. which does not contain bacteria from any other species or which comprises only de minimis or bîologically irrelevant amounts of bacteria from another species for use in therapy.
In some embodiments, the compositions of the invention comprise more than one bacterial strain or species. For example, în some embodiments, the compositions of the invention comprise more than one strain from within the same species (e.g. more than l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40 or 45 strains), and, optionally, do not contain bacteria from any other species. In some embodiments, the compositions of the invention comprise less than 50 strains from within the same species (e.g. less than 45, 40, 35, 30, 25, 20, 15, 12, I0, 9, 8, 7, 6, 5, 4 or 3 strains), and, optionally, do not contain bacteria from any other species. In some embodiments, the compositions of the invention comprise l-40, l-30, l-20, 1-19, 1-18, 1-15, 1-10, l-9, l-8, l-7, l-6, l-5, l-4, l-3, l-2, 250, 2-40, 2-30, 2-20, 2-15, 2-10, 2-5, 6-30, 6-15, 16-25, or 31-50 strains from within the same species and, optionally, do not contain bacteria from any other species. In some embodiments, the compositions of the invention comprise more than one species from within the same genus (e.g. more than l, 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 17, 20, 23, 25, 30, 35 or 40 species), and, optionally, do not contain bacteria from any other genus. In some embodiments, the compositions of the invention comprise less than 50 species from within the same genus (e.g. less than 50, 45, 40, 35, 30, 25, 20, 15, 12, 10, 8, 7, 6, 5, 4 or 3 species), and, optionally, do not contain bacteria from any other genus. In some embodiments, the compositions ofthe invention comprise I-50, l-40, I-30, l-20, 1-15, I-IO, l-9, l-8, l-7, l-6, l-5, l-4, l-3, l-2, 2-50, 2-40,2-30, 2-20, 2-15,2-10,2-5,6-30, 6-15, 16-25, or 3150 species from within the same genus and, optionally, do not contain bacteria from any other genus. The invention comprises any combination ofthe foregoing.
In some embodiments, the composition comprises a microbial consortium. For example, in some embodiments, the composition comprises the bacterial strain having a 16s rRNA sequence that is at least 95% identical to SEQ ID NO:2, for example, which is an Enterococcus gallinarum, as part of a microbial consortium. For example, in some embodiments, the bacterial strain is présent in combination with one or more (e.g. at least 2, 3, 4, 5, 10, 15 or 20) other bacterial strains from other généra with which it can live symbiotically in vivo in the intestine. For example, in some embodiments, the composition comprises a bacterial strain having a 16s rRNA sequence that is at least 95% identical to SEQ ID NO:2, for example, which is an Enterococcus gallinarum, in combination with a bacterial strain from a different genus. In some embodiments, the microbial consortium comprises two or more bacterial strains obtained from a faeces sample of a single organism, e.g. a human. In some embodiments, the microbial consortium is not found together in nature. For example, in some embodiments, the microbial consortium comprises bacterial strains obtained from faeces samples of at least two different organisms. In some embodiments, the two different organisms are from the same species, e.g. two different humans, e.g. two different human infants. In some embodiments, the two different organisms are an infant human and an adult human. In some embodiments, the two different organisms are a human and a non-human mammal.
In some embodiments, the composition of the invention additionally comprises a bacterial strain that has the same safety and therapeutic efficacy characteristics as strain MRX518, but which is not MRX518 deposited as NCIMB 42488, or which is not an Enterococcus gallinarum.
In some embodiments in which the composition of the invention comprises more than one bacterial strain, species or genus, the individual bacterial strains, species or généra may be for separate, simultaneous or sequential administration. For example, the composition may comprise ail of the more than one bacterial strain, species or généra, or the bacterial strains, species or généra may be stored separately and be administered separately, simultaneously or sequentially. In some embodiments, the more than one bacterial strains, species or généra are stored separately but are mixed together prior to use.
In some embodiments, the bacterial strain for use in the invention is obtained from human infant faeces. In some embodiments in which the composition of the invention comprises more than one bacterial strain, ail of the bacterial strains are obtained from human infant faeces or if other bacterial strains are présent they are présent only in de ntinimis amounts. The bacteria may hâve been cultured subséquent to being obtained from the human infant faeces and being used in a composition of the invention.
As mentioned above, in some embodiments, the one or more bacterial strains having a I6s rRNA sequence that is at least 95% identical to SEQ ID NO:2, for example which is an Enterococcus gallinarum, is/are the only therapeutically active agent(s) in a composition of the invention. In some embodiments, the bacterial strain(s) in the composition is/are the only therapeutically active agent(s) in a composition of the invention.
The compositions for use in accordance with the invention may or may not require marketing approval.
In certain embodiments, the invention provides the above pharmaceutical composition, wherein said bacterial strain is lyophilised. In certain embodiments, the invention provides the above pharmaceutical composition, wherein said bacterial strain is spray dried. In certain embodiments, the invention provides the above pharmaceutical composition, wherein the bacterial strain is lyophilised or spray dried and wherein it îs live. In certain embodiments, the invention provides the above pharmaceutical composition, wherein the bacterial strain is lyophilised or spray dried and wherein it is viable. In certain embodiments, the invention provides the above pharmaceutical composition, wherein the bacterial strain is lyophilised or spray dried and wherein it is capable of partially or totally colonising the intestine. In certain embodiments, the invention provides the above pharmaceutical composition, wherein the bacterial strain is lyophilised or spray dried and wherein it is viable and capable of partially or totally colonising the intestine.
In some cases, the lyophilised or spray dried bacterial strain is reconstituted prior to administration. In some cases, the reconstitution is by use of a diluent described herein.
The compositions of the invention can comprise pharmaceutically acceptable excipients, diluents or carriers.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain as used in the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is breast cancer. In preferred embodiments the cancer is mammary carcinoma. In preferred embodiments the cancer is stage IV breast cancer.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain as used in the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is lung cancer. In preferred embodiments the cancer is lung carcinoma.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain as used in the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is liver cancer. In preferred embodiments the cancer is hepatoma (hepatocellular carcinoma).
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is în an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is colon cancer. In preferred embodiments the cancer is colorectal adenocarcinoma.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is carcinoma.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is a non-immunogenic cancer.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is selected from the group consisting of non-smali-cell lung carcinoma, small-cell lung carcinoma, squamous-cell carcinoma, adenocarcinoma, glandular tumors, carcinoid tumors undifferentiated carcînomas.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder îs selected from the group consisting of hepatoblastoma, cholangiocarcînoma. cholangiocellular cystadenocarcinoma or liver cancer resulting from a viral infection.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is selected from the group consisting of invasive ductal carcinoma, ductal carcinoma in situ or invasive lobular carcinoma.
In certain embodiments, the invention provides a pharmaceutical composition comprising: a bacterial strain of the invention; and a pharmaceutically acceptable excipient, carrier or diluent; wherein the bacterial strain is in an amount sufficient to treat a disorder when administered to a subject in need thereof; and wherein the disorder is selected from the group consisting of acute lymphoblastic leukemia (ALL), acute myeloid leukemia. adrenocortical carcinoma, basal-cell carcinoma, bile duct cancer, bladder cancer, bone tumor, osteosarcoma/malignant fibrous histiocytoma, brainstem glioma, brain tumor, cerebellar astrocytoma, cérébral astrocytoma/malignant glioma, ependymoma, medulloblastoma, supratentorial primitive neuroectodermal tumors, breast cancer, bronchial adenomas/carcinoids, Burkitt's lymphoma, carcinoid tumor, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, chronic myeloproliferative disorders, colon cancer, cutaneous T-cell lymphoma, endométrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, intraocular melanoma, retinoblastoma, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), germ cell tumor, glioma, childhood visual pathway and hypothalamic, Hodgkin lymphoma, melanoma, islet cell carcinoma, Kaposi sarcoma, rénal cell cancer, laryngeal cancer, leukaemias, lymphomas, mesothelioma, neuroblastoma, non-Hodgkin lymphoma, oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic cancer, parathyroid cancer, pharyngeal cancer, pituitary adenoma, plasma cell neoplasia, prostate cancer, rénal cell carcinoma, retinoblastoma, sarcoma, testicular cancer, thyroîd cancer, or uterine cancer.
In certain embodiments, the invention provides the above pharmaceutical composition, wherein the amount of the bacterial strain is from about l χ 103 to about l χ 1011 colony forming units per grain with respect to a weight of the composition.
In certain embodiments, the invention provides the above pharmaceutical composition, wherein the composition is administered at a dose of l g, 3 g, 5 g or 10 g.
In certain embodiments, the invention provides the above pharmaceutical composition, wherein the composition is administered by a method selected from the group consisting of oral, rectal, subcutaneous, nasal, buccal, and sublingual.
In certain embodiments, the invention provides the above pharmaceutical composition, comprising a carrier selected from the group consisting of lactose, starch, glucose, methyl cellulose, magnésium stéarate, mannitol and sorbitol.
In certain embodiments, the invention provides the above pharmaceutical composition, comprising a diluent selected from the group consisting of éthanol, glycerol and water.
In certain embodiments, the invention provides the above pharmaceutical composition, comprising an excipient selected from the group consisting of starch, gelatin, glucose, anhydrous lactose, freeflow lactose, beta-lactose, corn sweetener, acacia, tragacanth, sodium alginate, carboxymethyl cellulose, polyethylene glycol, sodium oleate, sodium stéarate, magnésium stéarate, sodium benzoate, sodium acetate and sodium chloride.
In certain embodiments, the invention provides the above pharmaceutical composition, further comprising at least one of a preservative, an antioxidant and a stabilizer.
In certain embodiments, the invention provides the above pharmaceutical composition, comprising a preservative selected from the group consisting of sodium benzoate, sorbic acid and esters of phydroxybenzoic acid.
In certain embodiments, the invention provides the above pharmaceutical composition, wherein when the composition is stored in a sealed container at about 4°C or about 25°C and the container is placed in an atmosphère having 50% relative humidity, at least 80% of the bacterial strain as measured in colony forming units, remains after a period of at least about: l month, 3 months, 6 months, I year, l .5 years, 2 years. 2.5 years or 3 years.
In some embodiments, the composition of the invention is provided in a sealed container comprising a composition as described herein. In some embodiments, the sealed container is a sachet or boule. In some embodiments, the composition of the invention is provided in a syringe comprising a composition as described herein.
The composition of the present invention may, in some embodiments, be provided as a pharmaceutical formulation. For example, the composition may be provided as a tablet or capsule. In some embodiments, the capsule is a gélatine capsule (“gel-cap”).
In some embodiments, the compositions of the invention are administered orally. Oral administration may învolve swallowing, so that the compound enters the gastrointestinal tract, and/or buccal, lingual, or sublingual administration by which the compound enters the blood stream directly from the mouth.
Pharmaceutical formulations suitable for oral administration include solid plugs, solid microparticulates, semi-solid and liquid (including multiple phases or dispersed Systems) such as tablets; soft or hard capsules containing multi- or nano-particulates, liquîds (e.g. aqueous solutions), émulsions or powders; lozenges (including liquid-filled); chews; gels; fast dîspersing dosage forms; films; ovules; sprays; and buccal/mucoadhesive patches.
In some embodiments the pharmaceutical formulation is an enteric formulation, i.e. a gastro-résistant formulation (for exampie, résistant to gastric pH) that is suitable for delivery of the composition of the invention to the intestine by oral administration. Enteric formulations may be particularly useful when the bacteria or another component of the composition is acid-sensitive, e.g. prone to dégradation under gastric conditions.
In some embodiments, the enteric formulation comprises an enteric coating. In some embodiments, the formulation is an enteric-coated dosage form. For example, the formulation may be an entericcoated tablet or an enteric-coated capsule, or the like. The enteric coating may be a conventional enteric coating, for example, a conventional coating for a tablet, capsule, or the like for oral delivery. The formulation may comprise a film coating, for example, a thin film layer of an enteric polymer, e.g. an acid-insoluble polymer.
In some embodiments, the enteric formulation is intrinsically enteric, for example, gastro-résistant without the need for an enteric coating. Thus, în some embodiments, the formulation is an enteric formulation that does not comprise an enteric coating. In some embodiments, the formulation is a capsule made from a thermogelling material. In some embodiments, the thermogelling material is a cellulosic material, such as methylcellulose, hydroxymethylcellulose or hydroxypropylmethylcellulose (HPMC). In some embodiments, the capsule comprises a shell that does not contain any film forming polymer. In some embodiments, the capsule comprises a shell and the shell comprises hydroxypropylmethylcellulose and does not comprise any film forming polymer (e.g. see [33 ]). In some embodiments, the formulation is an intrinsically enteric capsule (for example, Vcaps® from Capsugel).
In some embodiments, the formulation is a soft capsule. Soft capsules are capsules which may, owing to additions of softeners, such as, for example, glycerol, sorbitol, maltitol and polyethylene glycols, présent in the capsule shell, hâve a certain elasticity and softness. Soft capsules can be produced, for example, on the basîs of gélatine or starch. Gelatine-based soft capsules are commercially available from various suppliers. Depending on the method of administration, such as, for example, orally or rectally, soft capsules can hâve various shapes, they can be, for example, round, oval, oblong or torpedo-shaped. Soft capsules can be produced by conventional processes, such as, for example, by the Scherer process, the Accogel process or the droplet or blowing process.
Culturing methods
The bacterial strains for use in the present invention can be cultured using standard microbiology techniques as detailed in, for example, references [34-36],
The solid or liquid medium used for culture may be YCFA agar or YCFA medium. YCFA medium may include (per 100ml, approximate values): Casîtone (l.O g), yeast extract (0.25 g), NaHCO3 (0.4 g), cysteine (0.1 g), K2HPO4 (0.045 g), KH2PO4 (0.045 g), NaCl (0.09 g), (NH4)2SO4 (0.09 g), MgSO4 7H2O (0.009 g), CaCl2 (0.009 g), resazurin (0.1 mg), hemin (l mg), biotîn (l pg), cobalamin (l pg),p-aminobenzoic acid (3 pg), folie acid (5 pg), and pyridoxamine (15 pg).
Bacterial strains for use in vaccine compositions
The inventors hâve identified that the bacterial strains of the invention are useful for treating or preventing cancer. This is likely to be a resuit of the effect that the bacterial strains of the invention hâve on the host immune system. Therefore, the compositions of the invention may also be useful for preventing cancer, when administered as vaccine compositions. In certain such embodiments, the bacterial strains ofthe invention are viable. In certain such embodiments, the bacterial strains of the invention are capable of partially or totally colonising the intestine. In certain such embodiments, the bacterial strains of the invention are viable and capable of partially or totally colonising the intestine. In other certain such embodiments, the bacterial strains of the invention may be killed, inactivated or attenuated. In certain such embodiments, the compositions may comprise a vaccine adjuvant. In certain embodiments, the compositions are for administration via injection, such as via subeutaneous injection.
General
The practice of the present invention will employ, unless otherwise indicated, conventional methods of chemistry, biochemistry, molecular biology, immunology and pharmacology, within the skill of the art. Such techniques are explained fully in the literature. See, e.g., references [37] and [38-44], etc.
The term “comprising” encompasses “including” as well as “consisting” e.g. a composition “comprising” X may consist exclusively of X or may include something additional e.g. X + Y.
The term “about” in relation to a numerical value is optional and means, for example, .r+10%,
The word “substantially” does not exclude “completely” e.g. a composition which is “substantially free” from Y may be completely free from Y. Where necessary, the word “substantially” may be omitted from the définition of the invention.
References to a percentage sequence identity between two nucieotide sequences means that, when aligned, that percentage of nucléotides are the same in comparing the two sequences. This alignment and the percent homology or sequence identity can be determined using software programs known in the art, for example those described in section 77.18 of ref. [45], A preferred alignment is determined by the Smith-Waterman homology search algorithm using an affine gap search with a gap open penalty of 12 and a gap extension penalty of 2, BLOSUM matrix of 62. The SmithWaterman homology search algorithm is disclosed in ref. [46].
Unless specifically stated, a process or method comprising numerous steps may comprise additional steps at the beginning or end of the method, or may comprise additional intervening steps. Also, steps may be combined, omitted or performed in an alternative order, if appropriate.
Various embodiments of the invention are described herein. It will be appreciated that the features specified in each embodiment may be combined with other specified features, to provide further embodiments. In particular, embodiments highlighted herein as being suitable, typical or preferred may be combined with each other (except when they are mutually exclusive).
MODES FOR CARRYING OUT THE INVENTION
Example 1 - Efficacy of bacterial inocula in mouse models of cancer
Summary
This study tested the efficacy of compositions comprising bacterial strains according to the invention in four tumor models.
Materials
Test substance - Bacterial strain #MRX518.
Reference substance - Anti-CTLA-4 antibody (clone: 9H10, catalog: BE0131, isotype: Syrian Hamster IgGl, Bioxcell).
Test and reference substances vehicles - Bacterial culture medium (Yeast extract, Casitone, Fatty Acid medium (YCFA)). Each day of injection to mice, antibody was diluted with PBS (ref: BE14516F, Lonza, France).
Treatment doses - Bacteria: 2xl08 in 200 pL The a-CTLA-4 was înjected at 10 mg/kg/inj. AntiCTLA-4 was administered at a dose volume of 10 mL/kg/adm (i.e. for one mouse weighing 20 g, 200 pL of test substance will be administered) according to the most recent body weight of mice.
Routes of administration - Bacterial inoculum was administered by oral gavage (per os, PO) via a cannula. Cannulas were decontaminated every day. Anti-CTLA-4 was înjected into the peritoneal cavity of mice (Intraperitoneally, IP).
Culture conditions of bacterial strain - The culture conditions for the bacterial strain were as follows:
• Pipette 10 mL of YCFA (from the prepared 10 mL E&O lab bottles) into Hungate tubes • Seal the tubes and flush with CO? using a syringe input and exhaust system • Autoclave the Hungate tubes • When cooled, inoculate the Hungate tubes with l mL of the glycerol stocks • Place the tubes in a static 37°C incubator for about 16 hours.
• The following day, take 1 mL of this subculture and inoculate 10 mL of YCFA (pre-warmed flushed Hungate tubes again, ail in duplicate) • Place them in a static 37°C incubator for 5 to 6h
Cancer cell line and culture conditions The cell lines that were used are detailed in the table below:
Cell line | Type | Mouse strain | Origin |
EMT-6 | Breast carcinoma | BALB/c | ATCC |
LL/2(LLC1) | Lung carcinoma | C57BL/6 | ATCCCRL1642 |
Hepa 1-6 | Hepatocellular carcinoma | C57BL/6 | IPSEN INNOVATION |
The EMT-6 cell line was established from a transplantable murine mammary carcinoma that arose in a BALB/cCRGL mouse after implantation of a hyperplastic mammary alveolar nodule [47],
The LL/2 (LLC1) cell line was established from the lung of a C57BL mouse bearing a tumor resulting from an implantation of primary Lewis lung carcinoma [48],
The Hepa 1-6 cell line is a derivatîve of the BW7756 mouse hepatoma that arose in a C57/L mouse [49],
Cell culture conditions - Ail cell lines were grown as monolayer at 37°C in a humidified atmosphère (5% CO?, 95% air). The culture medium and supplément are indicated in the table below:
3l
Cell line | Culture medium | Supplément |
EMT6 | RPM1 1640 containing 2mM L-glutamine (ref: BE12-702F, Lonza) | 10% fêtai bovine sérum (ref: #3302, Lonza) |
LL/2 (LLCl) | RPMI 1640 containing 2mM L-glutamine (ref: BE12-702F, Lonza) | 10% fêtai bovine sérum (ref: #3302, Lonza) |
Hepa 1 -6 | DMEM (ref: 11960-044, Gibco) | 10% fêtai bovine sérum (ref: #3302, Lonza) 2mM L-Glutamine penicillin-streptomycin (Sigma G-6784) |
For experimental use, adhèrent tumor cells were detached from the culture flask by a 5 minute treatment with trypsin-versene (ref: BE17-161E, Lonza), in Hanks' medium without calcium or magnésium (ref: BEI0-543F, Lonza) and neutralized by addition of complété culture medium. The cells were counted in a hemocytometer and their viability will be assessed by 0.25% trypan blue exclusion assay.
Use of animais Healthy female Balb/C (BALB/cByJ) mice, of matching weight and âge, were obtained from CHARLES RIVER (L'Arbresles) for the EMT6 model experiments.
Healthy female C57BL/6 (C57BL16J) mice, of matching weight and âge, were obtained from CHARLES RIVER (L'Arbresles) for the LL/2(LLCl) and the Hepa l-6 model experiments.
Animais were maintained in SPF health status according to the FELASA guidelines, and animal housing and experimental procedures according to the French and European Régulations and NRC Guide for the Care and Use of Laboratory Animais were followed [50,51], Animais were maintained in housing rooms under controlled environmental conditions: Température: 22 ± 2°C, Humidity 55 ± 10%, Photoperiod ( 12h light/12h dark), HEPA filtered air, 15 air exchanges per hour with no recirculation. Animal enclosures were provided with stérile and adéquate space with bedding material, food and water, environmental and social enrichment (group housing) as described: 900 cm2 cages (ref: green, Tecniplast) in ventilated racks, Epicéa bedding (SAFE), 10 kGy Irradiated diet (A04-10, SAFE), Complété food for immuno-competent rodents - R/M-H Extrudate, water from water bottles.
Experimental design and treatments
Antitunior activity, EMT6 model
Treatment schedule - The start of first dosing was considered as DO. On DO, non-engrafted mice were randomized according to their individual body weîght into groups of 9/8 using Vivo manager® software (Biosystemes, Coutemon, France). On DO, the mice received vehicle (culture medium) or bacterial strain. On Dl4, ail mice were engrafted with EMT-6 tumor cells as described below. On 5 D24, mice from the positive control group received anti-CTLA-4 antibody treatments.
The treatment schedule is summarized in the table below:
Group | No. Animais | Treatment | Dose | Route | Treatment Schedule |
l | 8 | Untreated | - | - | - |
2 | 8 | Vehicle (media) | - | PO | QlDx42 |
3 | 9 | Bacterial strain #l (MRX518) | 2xl08 bacteria | PO | QlDx42 |
4 | 8 | Anti-CTLA4 | 10 mg'kg | IP | TWx2 |
The monitoring of animais was performed as described below.
Induction of EMT6 tumors in animais - On Dl4, tumors were induced by subcutaneous injection of IxIO6 EMT-6 cells in 200 pL R.PMI 1640 into the right flank ofmice.
Euthanasia - Each mouse was euthanized when it reached a humane endpoint as described below, or after a maximum of 6 weeks post start of dosing.
Antitumor activity, LL/2 (LLCl) model
Treatment schedule - The start of first dosing was considered as DO. On DO, non-engrafted mice were randomized according to their individual body weight into 7 groups of 9/8 using Vivo I5 manager® software (Biosystemes, Coutemon, France). On DO, the mice will received vehicle (culture medium) or bacterial strain. On Dl4, ail mice were engrafted with LL/2 tumor cells as described below. On D27, mice from the positive control group received anti-CTLA-4 antibody treatments.
The treatment schedule is summarized in the table below:
Group | No. Animais | Treatment | Dose | Route | Treatment Schedule |
l | 8 | Untreated | - | - | |
2 | 9 | Vehicle (media) | - | PO | QlDx42 |
3 | 9 | Bacterial strain #l (MRX518) | 2xlOs bacteria | PO | QlDx42 |
4 | 8 | Anti-CTLA4 | 10 mg/kg | IP | TWx2 |
The monitoring of animais was performed as described below.
Induction of LL/2 (LLCl) tumors in animais - On Dl 4, tumors were induced by subcutaneous injection ofIxlO6 LL/2 (LLCl ) cells in 200 pL RPMl 1640 into the right flank of mice.
Euthanasia - Each mouse was euthanized when it reached a humane endpoint as described below, or after a maximum of 6 weeks post start of dosing.
Antitumor activity, Hepal-6 mode!
Treatment schedule - The start of first dosing was considered as DO. On DO, non-engrafted mice I0 were randomized according to their individual body weight into 7 groups of 9 using Vivo manager® software (Biosystemes, Coutemon, France). On DO, the mice received vehicle (culture medium) or bacterial strain. On Dl4, ail mice were engrafted with Hepa l-6 tumor cells as described below. On Dl6, mice from the positive control group received anti-CTLA-4 antibody treatments.
The treatment schedule is summarized in the table below:
Group | No. Animais | Treatment | Dose | Route | Treatment Schedule |
l | 9 | Untreated | - | - | - |
2 | 9 | Vehicle (media) | - | PO | QlDx42 |
6 | 9 | Bacterial strain #4 (MRX518) | 2xl08 bacteria | PO | QlDx42 |
7 | 9 | Anti-CTLA4 | 10 mg/kg | IP | TWx2 |
The monitoring of animais was performed as described below.
Orthotopic induction of Hepa l-6 tumor cells in animais by intrasplenic injection - On Dl4, one million (IxlO6) Hepa l-6 tumor cells in 50 pL RPMI 1640 medium were transplanted via intrasplenic injection into mice. Briefly, a small left subcostal flank incision was made and the spleen was exteriorized. The spleen was exposed on a stérile gauze pad, and injected under visual control with the cell suspension with a 27-gauge needle. After the cell inoculation, the spleen was excised.
Euthanasia - Each mouse was euthanized when it reached a humane endpoint as described in section below, or after a maximum of 6 weeks post start of dosing.
Evaluation of tumor burden at euthanasia - At the time of termination, livers were collected and weighed.
Animal monitoring
Clinical monitoring - The length and width of the tumor was measured twice a week with callipers and the volume of the tumor was estimated by this formula [52]:
_ . width 2 x length
Tumor volu me =-----------2
Humane endpoints [53]: Signs of pain, sufifering or distress: pain posture, pain face mask, behaviour; Tumor exceeding 10% of normal body weight, but non-exceeding 2000 mm3; Tumors interfering with ambulation or nutrition; Ulcerated tumor or tissue érosion; 20% body weight loss remaining for 3 consecutive days; Poor body condition, émaciation, cachexia, déhydration; Prolonged absence of voluntary responses to extemal stimuli; Rapid laboured breathing, anaemia, significant bleeding; Neurologie signs: circling, convulsion, paralysis; Sustained decrease in body température; Abdominal distension.
Anaesthesia - Isoflurane gas anesthésia were used for ail procedures: surgery or tumor inoculation,
i.v. injections, blood collection. Ketamine and Xylazine anesthésia were used for stereotaxia surgical procedure.
Analgesia - Carprofen or multimodal carprofen/buprenorphine analgesia protocol were adapted to the severity of surgical procedure. Non-pharmacological care was provided for ail painful procedures. Additîonally, phannacological care not interfering with studies (topic treatment) were provided at the recommendation of the attending veterinarian.
Euthanasia - Euthanasia of animais was performed by gas anesthésia over-dosage (Isoflurane) followed by cervical dislocation or exsanguination.
Results
Antitumor activity, EMT6 model
The results are shown in Figure l. Treatment with the bacterial strain of the invention led to a clear réduction in tumour volume relative to both the négative Controls. The positive control also led to a réduction in tumour volume, as would be expected.
Antitumor activity, LL/2 (LLC1) model
The results are shown in Figure 2. Treatment with the bacterial strain of the invention led to a clear réduction in tumour volume relative to both the négative Controls.
Antitumor activity', Hepal-6 model
The results are shown in Figure 3. The untreated négative control does not appear as would be expected, because liver weight was lower in this group than the other groups. However, the vehicle négative control and the positive control groups both appear as would be expected, because mice treated with vehicle alone had larger livers than mice treated with anti-CTLA4 antibodies, reflecting a greater tumour burden in the vehicle négative control group. Treatment with the bacterial strain of the invention led to a clear réduction in liver weight (and therefore tumour burden) relative to the mice in the vehicle négative control group.
These data indicate that strain MRX518 may be useful for treating or preventing cancer, and in particular for reducing tumour volume in breast, lung and liver cancers.
Example 2 - PCR gene analysis
A pure culture of bacteria MRX518 was studied in a PCR gene analysis. There were two arms to the experiment: l) MRX518 was co-cultured with human colonie cells (CaCo2) to investigate the effects of the bacteria on the host, and 2) MRX518 was co-cultured on CaCo2 cells that were stimulated with ILl to mimic the effect of the bacteria in an inflammatory environment. The effects in both scénarios were evaluated through gene expression analysis. The results are shown below:
Gene | Fold change | Function |
CXCL3 | 28412.73 | CXCR2 ligand, |
CXCL2 | 135.42 | CXCR2 ligand, 90% homology with CXCLl. |
CXCL9 | 34.76 | CXCR3 ligand, primarily thought of as Thl cell chemoattractant (inducible by IFN-g) |
IL8 | 3l.8l | Cytokine, chemoattractant (especially neutrophils), many |
receptors including CXCRl and CXCR2/ | ||
CXCLl | 16.48 | CXCR2 ligand, stimulâtes cell prolifération as well as migration, overexpression is neuroprotective in EAE. |
CD40 | 14.33 | Co-stimulatory molécule, route of T cell dépendent DC activation. |
TNF | 13.50 | Major proinflammatory cytokine |
IL17C | 12.18 | Promûtes antibacterial response from epthielium, synergistic with IL-22, |
CXCLl 0 | 10.66 | Close homology with CXCL9, think also CXCR3 ligand? |
HSPAIB | 10.19 | Heat shock protein |
NFKB IA | 8.87 | NFkB signalling; PI3K |
JUN | 7.61 | Antibacterial response; GPCR signalling. |
TNFAIP3 | 6.63 | TNF signalling |
DUSPl | 6.36 | Anti-inflammatory phosphatase, inactivâtes MAPKs |
JUNB | 5.36 | Transcription factor, JAK-STAT signalling |
BIRC3 | 4.86 | Adherens junctions, tight junctions |
DUSP2 | 4.59 | Anti-inflammatory, inactivâtes MAPK. |
1L32 | 4.29 | Proinflammatory cytokine, induced by IFN-g, IL-18 |
DUSP5 | 3.12 | Anti-inflammatory, inactivâtes MAPK |
FOS | 3.03 | Transcription factors, TLR signalling, forms part of AP-l |
GADD45B | 2.89 | Cell growth and prolifération |
CLDN4 | 2.61 | Tight junctions |
ADM | 2.57 | NFkB signalling |
KLFIO | 2.49 | Cell arrest, TGF-b singllaing. |
DEFB4A | -2.34 | Antimicrobial peptide |
APBAl | -2.53 | Signalling |
IGFBPl | -2.72 | Signalling pathway |
IL28B | -2.73 | IFN-lambda, antiviral immune defence, |
ILIO | -3.38 | Anti-inflammatory cytokine |
NR4A1 | -5.57 | Nuclear receptor, anti-inflammatory, regulator of T cell prolifération. T helper cell différentiation |
NOD2 | -14.98 | PRR, inflammasome activator, promûtes autophagy |
INOS | -26.88 | Proinflammatory, generator of nitric oxide |
These data appear to show two gene expression signatures - CXCRl/2 ligands (CXCL3, CXCL2, CXCLl, IL-8), which is associated with pro-inflammatory cell migration, and CXCR3 ligands (CXCL9,CXCLlO), which is more specifically indicative of IFN-y-type responses, also supported by 5 IL-32, which is IFN-y-inducible.
Exatnple 3 - Stability testing
A composition described herein containing at least one bacterial strain described herein is stored in a sealed container at 25 C or 4 C and the container is placed in an atmosphère having 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90% or 95% relative humidity. After l month, 2 months, 3 months, 6 months, I0 l year, l .5 years, 2 years, 2.5 years or 3 years, at least 50%, 60%, 70%, 80% or 90% of the bacterial strain shall remain as measured in colony forming units determined by standard protocols.
Example 4 - cytokine production in immature dendritic cells induced by MRX518 compared to MRX518 + LPS
Summary
This study tested the effect of the bacterial strain MRX518 alone and in combination with 5 lipopolysaccharide (LPS) on cytokine production in immature dendritic cells.
A monocyte population was isolated from peripheral blood mononuclear cells (PBMCs). The monocyte cells were subsequently differentiated into immature dendritic cells. The immature dendritic cells were plated out at 200,000 cells/well and incubated with MRX518 at a final concentration of l07/ml, with the optional addition of LPS at a final concentration of lOOng/ml. The 10 négative control involved incubating the cells with RPM1 media alone and positive Controls incubated the cells with LPS at a final concentration of lOOng/ml. The cytokine content of the cells was then analysed.
Results
The results of these experiments can be seen in Figures 4a-d. The addition of MRX518 alone leads to 15 a substantial increase in the level of cytokines IL-6 and TNF-α compared to the négative control (Figure 4a and c). The addition of LPS (positive control) leads to an increase in the level of IL-6 and TNF-α compared to the négative control but not IL-l β (Figure 4b). A combination of MRX518 and LPS led to a synergistîc increase in the level of IL-1 β produced (Figure 4d).
Conclusion
MRX518 has the ability to induce higher IL-6 and TNF-α cytokine production in immature dendritic cells. The combination LPS and MRX518 can increase the levels of cytokines IL-Ιβ in immature dendritic cells. These data indicate that MRX518 alone or in combination with LPS can increase inflammatory cytokines IL-Ιβ, IL-6 and TNF-α, which promûtes inflammation that can suppress cancer. Treatment with MRX518 alone or in combination with can induce cytokines that can limit 25 tumour growth.
Example 5 - cytokine production in ΊΉΡ-1 cells induced by MRX518 compared to MRX518 + LPS
Summary
This study tested the effect of bacterial strain MRX518 alone and in combination with LPS on 30 cytokine production in THP-l cells, a model cell line for monocytes and macrophages.
THF-l cells were differentiated into MO medium for 48h with 5ng/mL phorbol-l2-myristate-l3acetate (PMA). These cells were subsequently incubated with MRX518 at a final concentration of l08/ml, with or without the addition of LPS at a final concentration of lOOng/ml. The bacteria were then washed off and the cells allowed to incubate under normal growing conditions for 24 h. The 5 cells were then spun down and the resulting supematant was analysed for cytokine content.
Results
The results of these experiments can be seen in Figures 5a-c. The addition of MRX518 without LPS leads to an increase in the cytokine levels of IL-1 β, IL-6 and TNF-α compared to the no bacterial and the bacterial sédiment Controls. The addition of LPS and MRX518 leads to a synergistic increase in the production of cytokines.
Conclusion
MRX518 has the ability to induce cytokine production in THP-I cells, which can be synergistically increased with the addition of LPS. These data indicate that MRX518 alone or in combination with LPS can increase inflammatory cytokines IL-1 β, IL-6 and TNF-α, which promotes inflammation that can suppress cancer. Treatment wîth MRX518 alone or in combination with can induce cytokines that can limit tumour growth.
Sequences
SEQ ID NO:l (Enterococcus gallinat um 16S rRNA gene - AF039900)
1 | taatacatgc | aagtcgaacg | ctttttcttt | caccggagct | tgctccaccg | aaagaaaaag |
61 | agtggcgaac | gggtgagtaa | cacgtgggta | acctgcccat | cagaagggga | taacacttgg |
121 | aaacaggtgc | taataccgta | taacactatt | ttccgcatgg | aagaaagttg | aaaggcgctt |
181 | ttgcgtcact | gatggatgga | cccgcggtgc | attagctagt | tggtgaggta | acggctcacc |
241 | aaggccacga | tgcatagccg | acctgagagg | gtgatcggcc | acactgggac | tgagacacgg |
301 | cccagactcc | tacgggaggc | agcagtaggg | aatcttcggc | aatggacgaa | agCctgaccg |
361 | agcaacgccg | cgtgagtgaa | gaaggttttc | ggatcgtaaa | actctgttgt | tagagaagaa |
421 | caaggatgag | agtagaacgt | tcatcccttg | acggtatcta | accagaaagc | cacggctaac |
481 | tacgtgccag | cagccgcggt | aatacgtagg | tggcaagcgt | tgtccggatt | tattgggcgt |
541 | aaagcgagcg | caggcggttt | cttaagtctg | atgtgaaagc | ccccggctca | accggggagg |
601 | gtcattggaa | actgggagac | t Cgagtgcag | aagaggagag | tggaattcca | tgtgtagcgg |
661 | tgaaatgcgt | agatatatgg | aggaacacca | gtggcgaagg | cggctctctg | gtctgtaact |
721 | gacgctgagg | ctcgaaagcg | tggggagcga | acaggattag | atacccrggt | agtccacgcc |
781 | gtaaacgatg | agtgctaagt | gttggagggr | t tccgccctt | cagtgctgca | gcaaacgcat |
841 | taagcactcc | gcctggggag | tacgaccgca | aggttgaaac | tcaaaggaat | tgacgggggc |
901 | ccgcacaagc | ggtggagcat | gtggtttaat | tcgaagcaac | gcgaagaacc | ttaccaggtc |
961 | ttgacatcct | ttgaccactc | tagagataga | gcttcccctt | cgggggcaaa | gtgacaggtg |
1021 | gtgcatggtt | gtcgtcagct | cgtgtcgtga | gatgttgggt | taagtcccgc | aacgagcgca |
1081 | acccttattg | ttagttgcca | tcatttagtt | gggcactcta | gcgagactgc | cggtgacaaa |
1141 | ccggaggaag | gtggggatga | cgtcaaatca | tcatgcccct | tatgacctgg | gctacacacg |
4l
1201 tgctacaatg ggaagtacaa cgagttgcga agtcgcgagg ctaagctaat ctcttaaagc 1261 ttctctcagt tcggattgta ggctgcaact cgcctacatg aagccggaat cgctagtaat 1321 cgcggatcag cacgccgcgg tgaatacgtt cccgggcctt gtacacaccg cccgtcacac 1381 cacgagagtt tgcaacaccc gaagtcggtg aggtaacctt tttggagcca gccgcctaag 1441 gtgggataga tgattggggt gaagtcgtaa caaggtagcc gtaCcggaag gtgcggctgg 1501 atcacc
SEQ ID NO:2 (consensus 16S rRNA sequence for Enterococcus gallinatum strain MRX518)
TGCTATACATGCAGTCGAACGCTTTTTCTTTCACCGGAGCTTGCTCCACCGAAAGAAAAAGAGTGGCGAACGGGTGA
GTAACACGTGGGTAACCTGCCCATCAGAAGGGGATAACACTTGGAAACAGGTGCTAATACCGTATAACACTATTTTC
CGCATGGAAGAAAGTTGAAAGGCGCTTTTGCGTCACTGATGGATGGACCCGCGGTGCATTAGCTAGTTGGTGAGGTA
ACGGCTCACCAAGGCCACGATGCATAGCCGACCTGAGAGGGTGATCGGCCACACTGGGACTGAGACACGGCCCAGAC
TCCTACGGGAGGCAGCAGTAGGGAATCTTCGGCAATGGACGAAAGTCTGACCGAGCAACGCCGCGTGAGTGAAGAAG
GTTTTCGGATCGTAAAACTCTGTTGTTAGAGAAGAACAAGGATGAGAGTAGAACGTTCATCCCTTGACGGTATCTAA
CCAGAAAGCCACGGCTAACTACGTGCCAGCAGCCGCGGTAATACGTAGGTGGCAAGCGTTGTCCGGATTTATTGGGC
GTAAAGCGAGCGCAGGCGGTTTCTTAAGTCTGATGTGAAAGCCCCCGGCTCAACCGGGGAGGGTCATTGGAAACTGG
GAGACTTGAGTGCAGAAGAGGAGAGTGGAATTCCATGTGTAGCGGTGAAATGCGTAGATATATGGAGGAACACCAGT
GGCGAAGGCGGCTCTCTGGTCTGTAACTGACGCTGAGGCTCGAAAGCGTGGGGAGCGAACAGGATTAGATACCCTGG
TAGTCCACGCCGTAAACGATGAGTGCTAAGTGTTGGAGGGTTTCCGCCCTTCAGTGCTGCAGCAAACGCATTAAGCA
CTCCGCCTGGGGAGTACGACCGCAAGGTTGAAACTCAAAGGAATTGACGGGGGCCCGCACAAGCGGTGGAGCATGTG
GTTTAATTCGAAGCAACGCGAAGAACCTTACCAGGTCTTGACATCCTTTGACCACTCTAGAGATAGAGCTTCCCCTT
CGGGGGCAAAGTGACAGGTGGTGCATGGTTGTCGTCAGCTCGTGTCGTGAGATGTTGGGTTAAGTCCCGCAACGAGC
GCAACCCTTATTGTTAGTTGCCATCATTTAGTTGGGCACTCTAGCGAGACTGCCGGTGACAAACCGGAGGAAGGTGG
GGATGACGTCAAATCATCATGCCCCTTATGACCTGGGCTACACACGTGCTACAATGGGAAGTACAACGAGTTGCGAA
GTCGCGAGGCTAAGCTAATCTCTTAAAGCTTCTCTCAGTTCGGATTGTAGGCTGCAACTCGCCTACATGAAGCCGGA
ATCGCTAGTAATCGCGGATCAGCACGCCGCGGTGAATACGTTCCCGGGCCTTGTACACACCGCCCGTCACACCACGA
GAGTTTGTAACACCCGAAGTCGGTGAGGTAACCTTTTTGGAGCCAGCCGCCTAAGGTG
SEQ ID NO:3 (strain MRX518 chromosome sequence) - see electronic sequence listing.
SEQ ID NO:4 (strain MRX518 plasmid sequence) - see electronic sequence listing.
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Claims (17)
1. A composition comprising a bacterial strain of the species Enterococcus gallinarum for use in therapy.
2. The composition of claim l for use in a method of treating or preventing cancer.
3. The composition for use of claim l or claim 2 which does not contain bacteria from any other species, or which comprises only de minimis or biologically irrelevant amounts of bacteria from another species.
4. The composition of any one of the preceding daims, wherein the composition is for use in a method of treating or preventing lung cancer, breast cancer, liver cancer or colon cancer.
5. The composition of any one of the preceding daims, wherein the composition is for use in a method of reducing tumour size, reducing tumour growth, preventing metastasis or preventing angiogenesis.
6. The composition for use of any one of daims l-5, wherein the bacterial strain has the I6s rRNA sequence represented by SEQ ID NO:2.
7. The composition for use of any one of the preceding daims, wherein the bacterial strain is lyophilised.
8. The composition for use of any one of the preceding daims, wherein the bacterial strain is viable and capable of partially or totally colonising the intestine.
9. The composition for use of any one of the preceding daims, wherein the composition comprises a single strain of Enterococcus gallinarum.
10. The composition for use of any one of the preceding daims, which comprises the Enterococcus gallinarum bacterial strain as part of a microbial consortium.
11. A food product or vaccine composition comprising the composition of any one of the preceding daims, for the use of any one of the preceding daims.
12. A cell of the Enterococcus gallinarum strain deposited under accession number NCIMB 42488, or a dérivative thereof.
13. A composition comprising the cell of daim 12.
14. The composition ofclaim 13, comprising a pharmaceutically acceptable carrier or excipient.
15. A biologically pure culture of the Enterococcus gallinarum strain deposited under accession number NCIMB 42488, or a dérivative thereof.
16. A cell of the Enterococcus gallinarum strain deposited under accession number NCIMB 42488, or a dérivative thereof, for use in therapy.
17. The cell ofclaim 16, wherein the cell is for use in a method defined in any one ofdaims 2, 4 or 5.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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GB1520502.4 | 2015-11-20 | ||
GB1604924.9 | 2016-03-23 |
Publications (1)
Publication Number | Publication Date |
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OA18794A true OA18794A (en) | 2019-06-28 |
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