Tumor modulation via injection of non-infectious microorganisms

Abstract

The application relates to methods for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor, as well as bacteria strain compositions of same.

Description

Attorney Docket No. 243735.000480TUMOR MODULATION VTA INJECTION OF NON-TNFECTTOUS MICROORGANISMSSEQUENCE LISTING

[0001] The instant application contains a Sequence Listing which has been submitted electronically in XML format and is hereby incorporated by reference in its entirety. Said XML copy, created on December 30, 2025, is named 243735_000480_SL.xml and is 6,708,870 bytes in size.CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 741,528, filed January 3, 2025, the disclosure of which is herein incorporated by reference in its entirety.FIELD

[0003] The application relates to methods for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient to elicit and / or augment an antitumor response, as well as bacteria strain compositions comprising bacteria from one or more bacterial strains useful for eliciting and / or augmenting an anti-tumor response in a patient as determined by the methods as described herein or a closely related OTU.BACKGROUND

[0004] The gastrointestinal tract harbors a diverse and dense population of commensal microbes that have coevolved with the host (Foster, et al., 2017; Hooper, et al., 2001). The microbes have been selected for traits that allow them to thrive amidst intense interbacterial competition (there are as many as 1012bacterial cells per gram of stool (Schluter, et al., 2023)), to utilize host factors (Kashyap, et al., 2013; Sonnenburg, et al., 2005), and against traits that would destroy the host (Foster, et al., 2017). These properties enable the microbes to efficiently colonize the gastrointestinal lumen and epithelium without causing invasive infections under homeostatic conditions. Key features that mediate this phenotype include metabolic enzymes that enable growth in the anaerobic environment of the gastrointestinal tract, mucinases that enable harvesting 1323665488vlAttorney Docket No. 243735.000480of carbohydrate and amino acid from epithelial mucins, and digestive enzymes that enable consumption of nutrients, including those that cannot be used by the host or arise as intermediate products from fermentative metabolism such as lactate (Winter, et al., 2014; Rakoff-Nahoum, et al., 2016; Park, et al., 2022; Stahl, et al. 2011; Kim, et al., 2021; Louis, et al., 2022).

[0005] Bacteria that have been studied for tumor control have historically been selected based on the ease of genetic manipulation and growth in laboratory environment (i.e., environments rich in nutrients and exposed to open air). Typically, these bacteria are strains of facultative aerobes such as Escherichia coli (Redenti, et al., 2024; Canale, et al., 2021) and Salmonella (Nguyen, et al., 2024) species, which despite attenuation of virulence factors, retain the ability to cause lethal infection at high doses. Nonetheless, existing technologies comprise intravenous (IV) injection of genetically engineered E. coli to target tumors. Thus, there remains a need for methods for identifying a bacterial strain or consortium of bacterial strains capable of being detected in a tumor in a patient to elicit an anti-tumor response, as well as bacteria strain compositions useful for eliciting an anti-tumor response.SUMMARY OF THE INVENTION

[0006] As specified in the Background section above, there is a great need in the art for methods for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient to elicit and / or augment an anti-tumor response, as well as bacteria strain compositions useful for eliciting and / or augmenting an anti-tumor response.

[0007] In one aspect, provided herein is a method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient, said method comprising:(a) determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins;(b) determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model;(c) determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site; and / or2323665488vlAttorney Docket No. 243735.000480(d) determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0008] In some embodiments, step (a) comprises determining whether a gene encoding an enzyme that degrades glycoproteins can be activated in the bacterial strain or consortium of bacterial strains.

[0009] In some embodiments, the at least one enzyme is a protease, glycosidase, or glycopeptidase.

[0010] In some embodiments, the protease is a mucin-degrading protease.

[0011] In some embodiments, the glycosidase is a mucinase, sialidase, galactosidase, and / or fucosidase.

[0012] In some embodiments, step (a) comprises determining whether a gene encoding an enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis is active in the bacterial strain or consortium of bacterial strains.

[0013] In some embodiments, the immune cytotoxic cells are T cells and / or NK cells.

[0014] In some embodiments, step (a) comprises determining tumor-specific glycoproteins and determining whether the bacterial strain or consortium of bacterial strains can digest the tumorspecific glycoproteins.

[0015] In some embodiments, step (b) comprises determining whether the high doses of the bacterial strain or consortium of bacterial strains are non-lethal in an in vivo animal model.

[0016] In some embodiments, step (b) comprises determining whether the high doses of the bacterial strain or consortium of bacterial strains do not cause acute lung injury, kidney injury, or liver injury in an in vivo animal model.

[0017] In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1011colony forming units (CFU) / kg.

[0018] In some embodiments, the administration of the high doses of the bacterial strain or consortium of bacterial strains in step (b) comprises at least one of oral, intravenous, intraperitoneal, intratumoral, intravesical, dermal, intrathecal, intranasal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).3323665488vlAttorney Docket No. 243735.000480

[0019] In some embodiments, step (c) comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to utilize non-caloric sugars in the absence of glucose in vitro.

[0020] In some embodiments, the non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, or N-acetylglucosamine.

[0021] In some embodiments, step (d) comprises administering the bacterial strain or consortium of bacterial strains in an in vivo model system of the tumor type expressed in the patient and testing a tumor expressed in the in vivo model system for detection of the bacterial strain or consortium of bacterial strains in the tumor.

[0022] In some embodiments, detection is tested within 24 hours to 10 days post administration.

[0023] In some embodiments, step (d) comprises injecting the bacterial strain or consortium of bacterial strains in an isolated tumor and determining whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 10 days.

[0024] In some embodiments, the isolated tumor is the same type of tumor expressed in the patient.

[0025] In some embodiments, the isolated tumor is obtained from the patient.

[0026] In some embodiments, detection of the bacterial strain or consortium of bacterial strains in the tumor includes measuring by qPCR, measuring growth of the bacterial strain or consortium of bacterial strains on agar plates from tumor homogenates, or using high-throughput sequencing methods.

[0027] In some embodiments, the high-throughput sequencing methods are selected from the group consisting of using an amplicon sequencing approach, a 454 machine, miSeq, Pacbio, or other related devices, profiling of microbial 16S ribosomal RNA genes (16S rDNA), and next generation sequencing (NGS).

[0028] In some embodiments, the method further comprises determining whether the bacterial strain or consortium of bacterial strains does not express a catalase.

[0029] In some embodiments, the method further comprises determining whether the bacterial strain or consortium of bacterial strains expresses a catalase.4323665488vlAttorney Docket No. 243735.000480

[0030] In some embodiments, the bacterial strain or consortium of bacterial strains elicit an antitumor response.

[0031] In some embodiments, the bacterial strain or consortium of bacterial strains augment an anti -tumor response.

[0032] In some embodiments, the anti-tumor response is i) reduced tumor growth, ii) tumor reduction, iii), tumor eradication, iv) enhanced anti-tumor immune response, v) tumor genomic composition alteration, and / or vi) tumor phenotype alteration.

[0033] In some embodiments, the altered tumor phenotype is characterized by i) altered gene expression in a bulk of the tumor, ii) altered gene expression in a tumor single cell subset, iii) altered tumor cell composition, and / or iv) altered tumor response to an anti-tumor therapy.

[0034] In some embodiments, the altered gene expression is characterized by increased gene signatures associated with anti-tumor immunity.

[0035] In some embodiments, the increased gene signatures associated with anti-tumor immunity comprise increased expression of PDL1, CXCL9, CXCL10, and / or CXCL11.

[0036] In some embodiments, the altered tumor cell composition is characterized by increased density and / or proportion of tumor infiltrating leukocytes, increased density and / or proportion of tumor infiltrating lymphocytes, and / or reduced density and / or proportion of tumor suppressive myeloid cells.

[0037] In some embodiments, the altered tumor cell composition is measured by cytometry, by single-cell, by deconvoluted bulk RNA sequencing, by microscopy imaging, by immunohistology, by tumor growth kinetics, by tumor reduction, and / or by altered activity of infiltrating immune cells.

[0038] In some embodiments, the altered activity of infiltrating immune cells comprises increased density and / or proportion of tumor infiltrating leukocytes, increased density and / or proportion of tumor infiltrating lymphocytes, and / or increased anti-tumor phenotypes of infiltrating leukocytes.

[0039] In some embodiments, the method further comprises administering one or more treatments to the subject.

[0040] In some embodiments, the one or more treatments comprises administering the bacterial strain or consortium of bacterial strains.5323665488vlAttorney Docket No. 243735.000480

[0041] In some embodiments, the one or more treatments comprises administering an effective amount of a composition that stimulates growth and / or activity of the bacterial strain or consortium of bacterial strains.

[0042] In some embodiments, the one or more treatments further comprises administering an antitumor therapy.

[0043] In some embodiments, the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.

[0044] In some embodiments, the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infiltrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

[0045] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

[0046] In some embodiments, the route of administration for said one or more treatments comprises at least one of intratumoral, intravenous, intravesical, dermal, transdermal, subcutaneous, intrathecal, intranasal, intraperitoneal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

[0047] In some embodiments, the one or more treatment comprises administering nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site.

[0048] In some embodiments, the nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or the nutrients that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site comprise at least one non-caloric sugar.6323665488vlAttorney Docket No. 243735.000480

[0049] In some embodiments, the non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.

[0050] In a further aspect, provided herein is a bacteria strain composition comprising (i) bacteria from one or more bacterial strains as determined by the methods as described herein or a closely related OTU which has at least 90% (or at least 95%, or at least 97%, or at least 99%) sequence identity to the 16S rRNA gene over its entire length or has at least 90% (or at least 95%, or at least 99%) sequence identity to any single V region of the 16S rRNA gene and (ii) a carrier and / or an excipient and / or one or more additional composition which stimulate growth and / or activity and / or preserve viability of one or more bacteria present in the composition.

[0051] In some embodiments, the bacteria strain composition elicits an anti-tumor response in a patient.

[0052] In some embodiments, the bacteria strain composition augments an anti-tumor response in a patient.

[0053] In some embodiments, the bacteria strain composition comprises (i) gene products as determined by the methods herein or a closely related OTU which has at least 90% (or at least 95%, or at least 97%, or at least 99%) sequence identity to sialidase of Akkermansia muciniphila (gene name HXS70 08015), glycopeptidase of Bacteroides thetaiotaomicron (gene name BT4244-M60L or metalloprotease of Escherichia coli (gene name stcE) and (ii) a carrier and / or an excipient and / or one or more additional composition which stimulate growth and / or activity and / or preserve viability of one or more bacteria present in the composition.

[0054] In some embodiments, the additional composition is at least one nutrient that is metabolically inaccessible to the patient and / or the tumor, and / or at least one nutrient that is shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site.

[0055] In some embodiments, the nutrient that is metabolically inaccessible to the patient and / or the tumor, and / or the nutrient that is shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site comprises at least one non-caloric sugar.7323665488vlAttorney Docket No. 243735.000480

[0056] In some embodiments, the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.

[0057] In some embodiments, the composition further comprises or is administered with one or more anti-tumor therapy.

[0058] In some embodiments, the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.

[0059] In some embodiments, the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infdtrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

[0060] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

[0061] In some embodiments, the one or more bacterial strain is selected from the phylum of: Bacillota (Firmicutes), Bacteroidota (Bacteroidetes), Pseudomonadota (Proteobacteria), Actinomycetota (Actinobacteria), Fusobacteriota (Fusobacteria), Verrucomicrobiota (Verrucomicrobia), Cyanobacteriota (Cyanobacteria), Spirochaetota (Spirochaetes), and My coplasm ota (Teneri cutes), and combinations thereof.

[0062] In some embodiments, the one or more bacterial strain is selected from the genus of Mediterraneibacter, Lactobacillus, Bacteroides, Prevotella, Clostridium, Streptococcus, Escherichia, Enterococcus, Fusobacterium, Ruminococcus, Faecalibacterium, Veillonella, Staphylococcus, Propionibacterium, Peptostreptococcus, Eubacterium, Roseburia, Blautia, Sutterella, Helicobacter, Campylobacter, Haemophilus, Rothia, Akkermansia, Pseudomonas,8323665488vlAttorney Docket No. 243735.000480Neisseria, Porphyromonas, Moraxella, Corynebacterium, Methanobrevibacter, Klebsiella, Proteus, Actinomyces, Bifidobacterium, Dorea, Selenomonas, Tannerella, Treponema, Alistipes, Parabacteroides, Megasphaera, Odoribacter, Mogibacterium, Desulfovibrio, Gemella, Dialister, Lachnospira, Collinsella, Butyrivibrio, Leptotrichia, Capnocytophaga, Bilophila, Vibrio, Slackia, Burkholderia, Rhodobacter, Aeromonas, Alcaligenes, Acidaminococcus, Cloacibacterium, Eggerthella, Coprococcus, Anaerostipes, Oscillospira, Fecalibacterium, Syntrophomonas, Turicibacter, Bamesiella, Victivallis, Tissierella, Veillonellaceae, Sporosarcina, Veillonella, Oribacterium, Desulfitobacterium, Shigella, Gordonibacter, Citrobacter, Anaerostipes, Solobacterium, Flavonifractor, Prevotella, Holdemania, Adlercreutzia, Lactonifactor, Methanosphaera, Phascolarctobacterium, Paraprevotella, Sarcina, Lactococcus, Weissella, Variovorax, Sphingobacterium, Enterobacter, Citrobacter, Klebsiella, Acinetobacter, Janthinobacterium, Providencia, and Stenotrophomonas, and combinations thereof.

[0063] In some embodiments, the one or more bacterial strain is selected from the species of Akkermansia muciniphila, Mediterraneibacter gnavus, Roseburia intestinalis, Streptococcus salivarius, Bacteroides thetaiotaomicron, Bifidobacterium dentium, Bifidobacterium longum, Veillonella parvula, Ruminococcus gnavus, Ruminococcus intestinalis, and Bacillus subtillis, and combinations thereof.

[0064] In another aspect, provided herein is a method for modulating a tumor microenvironment in a patient, said method comprising administering to the patient the bacteria from one or more bacterial strains as determined by the methods as described herein or the bacteria strain composition as described herein.

[0065] In some embodiments, the bacteria elicits an anti-tumor response in a patient.

[0066] In some embodiments, the bacteria augments an anti-tumor response in a patient.

[0067] In some embodiments, the tumor microenvironment is the tumor mucin microenvironment.

[0068] In some embodiments, the tumor microenvironment is the tumor immune microenvironment.

[0069] In some embodiments, the modulation of the tumor microenvironment increases susceptibility of the tumor to immune cytotoxic cell-mediated killing or phagocytosis.

[0070] In a further aspect, provided herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the bacteria9323665488vlAttorney Docket No. 243735.000480from one or more bacterial strains as determined by the methods as described herein or the bacteria strain composition as described herein.

[0071] In some embodiments, the bacteria elicits an anti -turn or response in a patient.

[0072] In some embodiments, the bacteria augments an anti-tumor response in a patient.

[0073] In a further aspect, provided herein is a method of reducing a size and / or volume of a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the bacteria from one or more bacterial strains as determined by the methods described herein or the bacteria strain composition as described herein.

[0074] In some embodiments, the tumor size and / or volume is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0075] In some embodiments, the cancer is breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, bladder cancer, skin cancer, central nervous system cancer, nasal cancer, stomach cancer, peritoneal cancer, pancreatic cancer, kidney cancer, liver cancer, esophageal cancer, squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma, basal cell carcinoma, neuroendocrine cancer, bile duct cancer, thyroid cancer, adrenal cancer, soft tissue sarcoma, bone cancer, testicular cancer, nasal cancer, oropharyngeal cancer, anal cancer, penile cancer, vaginal cancer, cervical cancer, thymus cancer, or uveal melanoma.

[0076] In some embodiments, the cancer is characterized by the presence of a tumor. In some embodiments, administration of the bacteria results in a reduction in size and / or volume of the tumor in the subject. In some embodiments, the tumor size and / or volume is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0077] In some embodiments, the administration to the patient comprises at least one of oral, intravenous, intraperitoneal, intratumoral, intravesical, dermal, transdermal, subcutaneous, intrathecal, intranasal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

[0078] In some embodiments, the method further comprises administering one or more additional treatments to the patient.10323665488vlAttorney Docket No. 243735.000480

[0079] In some embodiments, the one or more additional treatments comprises an effective amount of a composition that stimulates growth and / or activity of the bacteria from one or more bacterial strains.

[0080] In some embodiments, the one or more additional treatments comprises an anti-tumor therapy.

[0081] In some embodiments, the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.

[0082] In some embodiments, the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infiltrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

[0083] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

[0084] In some embodiments, the one or more additional treatments comprises nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site.

[0085] In some embodiments, the nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site comprise at least one non-caloric sugar.

[0086] In some embodiments, the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.11323665488vlAttorney Docket No. 243735.000480

[0087] These and other aspects of the present invention will be apparent to those of ordinary skill in the art in the following description, claims, and drawings.BRIEF DESCRIPTION OF THE DRAWINGS

[0088] Figure 1 shows survival of mice injected intravenously with gut bacteria. The survival curve of mice shows that while E. coll led to rapid death among all mice (n=6) within the first day, Akkermansia muciniphila did not lead to any observable detrimental effects and all mice were alive until the end of the experiment (day 12, n=6); similar results were obtained for other candidate taxa including / ?, gnavus, R. intestinalis, B. thetaiotaomicron, S. salivarius, and B. dentium.

[0089] Figures 2A-2F show private nutrient mediated enrichment of bacteria in coculture with tumor cells augments bacteria-mediated tumor cell viability reduction. Figure 2A shows 24 hour growth with “non-caloric” sugars. A screen using 2’-fucosyllactose (2FL), trehalose (Tre), alpha-methylglucoside (AMG), isomalt (IsoM), N-acetyl glucosamine (GlcNAc), psicose (Psi), arabinose (Ara), and glucose (Glu) provided a map of non-caloric sugar utilization of selected bacterial strains. Numbers were calculated as the optical density (ODeoo) upon treatment with sugar minus the ODeoo upon treatment without sugar. Non-caloric sugars promoted growth of several candidate therapeutic bacteria. Figure 2B shows the growth curve of S. salivarius in minimal sugar cell culture medium with various added sugars. Figure 2C shows total counts of MC38 cells after 24 hours incubation with and without sucrose. Figure 2D shows viability of MC38 cells after 24 hours incubation with and without sucrose. Figure 2E shows Colony -Forming Units (CFU) of live S. salivarius after 24 hours co-culturing with MC38 with and without sucrose. Figure 2F shows viability of MC38 cells after 24 hours co-culturing with S. salivarius with and without sucrose.

[0090] Figure 3 shows anaerobe gut bacteria persist in the tumor. Bacterial load was measured via qPCR and confirmed positive detection of five gut commensal anaerobes, A. muciniphila (Am), R. gnavus (Rg), R. intestinalis (Ri), .S', salivarius (Ss), and B. thetaiotaomicron (Btheta), 96 hours post intratumoral injection. Viability of detected bacteria was confirmed via plate assays.

[0091] Figures 4A-4C show tumor-induced mice after injection with bacteria. Fig. 4A shows the experimental scheme. On Day -9, C57BL / 6 mice maintained in a specific pathogen-free facility were injected subcutaneously with cancer cells (250,000 MC38) to induce a tumor. On Day 0, a 12323665488vlAttorney Docket No. 243735.000480consortium of IO10colony forming units of anaerobically grown Bifidobacterium denlium, Bacteroides thetaiotaomicron, Streptococcus salivarius, and Veillonella parvuta were injected intravenously, i.e., into the blood stream. Six days later (Day 6), tumors were extracted to quantify presence of injected bacteria. Fig. 4B shows the survival of mice post intravenous injection of the bacterial consortium (n=8). All mice survived this high load of bacteria injected intravenously. Fig.4C shows persistent colonization of tumors by injected bacteria. Tumors harvested on Day 6 were homogenized and incubated anaerobically on agar medium for 3 days. Bacterial growths were lysed and subjected to quantitative PCR using genome-specific primers for each bacteria, with Akkermansia muciniphila genomic DNA serving as a negative control. Each of the injected bacteria was detectable in the tumor homogenates (n=3).

[0092] Figures 5A-5B show private nutrient supplementation enhances intratumoral bacterial abundance and is associated with reduced tumor growth. Figure 5A shows quantitative PCR analysis of B. thetaiotaomicron in subcutaneous KPC tumors 48 h after inj ection, normalized to tumor cell content using a mutant TP53 genomic marker (mean values shown along x-axis in parentheses; p = 0.07, one-sided t-test). Figure 5B shows tumor volume change in sucrose-supplemented, bacteria-treated mice over 48 hours following bacterial administration (p < 0.05).DETAILED DESCRIPTION

[0093] It was hypothesized that features of the gut commensal microbes comprising gastrointestinal colonization abilities could be leveraged to augment cancer treatments, specifically for epithelial cancers. Cancers of epithelial origin, such as those of gastrointestinal, pulmonary, and urogenital organs, develop in part by generating a formidable microenvironment that is prohibitive for immunologic tumor clearance. Voracious nutritional and oxygen consumption by growing tumor cells generates a nutrient poor, hypoxic, acidic environment that hampers the growth and function of antitumor immune cells. Heavily glycosylated glycoproteins that provide barrier functions on healthy epithelial cells, known as mucins, are hijacked by epithelial cancers as shields against antitumor immunity. Many solid tumors are recalcitrant to immunotherapies. This is often attributed to an immunosuppressive tumor microenvironment.

[0094] While these microenvironmental factors are unfavorable to antitumor immune cells, they are precisely the conditions in which commensal microbes have evolved to thrive, especially gut 13323665488vlAttorney Docket No. 243735.000480commensals. Commensal microbes, therefore, may be preadapted to colonizing the tumor microenvironment and may do so preferentially over healthy tissues owing to the relative intratumoral immune suppression and negative selection in blood or well-oxygenated healthy tissues. The colonizing commensal bacteria may even facilitate tumor control by introducing growth competition against tumor cells while simultaneously degrading cancer-expressed mucins to expose tumor cells for immune clearance. Bacterial products that accumulate in colonized tumors may also fuel inflammation, rendering immunologically “cold” tumors “hot.”

[0095] The present disclosure concerns the reversion of the immunosuppressive tumor microenvironment and / or the tumor mucin environment by leveraging the evolved response of the body to danger signals arising at the gut-microbiome interface, as well as physical modulation of the tumor by the activity of tumor-resident microbes. Gut commensal microbes harbor genetic features that enable selective tumor colonization and facilitate tumor clearance. The invention concerns first, the identification of safe microorganisms, or a consortium of safe microorganisms, to colonize a recalcitrant tumor as current approaches are often limited to genetically engineered but potentially harmful species. Repurposing of gut commensal microbes is expected to be safer than the use of aerobes such as Escherichia coli and Salmonella species. Second, administering the microorganisms or consortium of microorganisms to a patient with a tumor, optionally with “private” nutrients that are indigestible to the host and tumor but support growth of the administered bacteria, augments the microorganisms’ ability to colonize the tumor as colonization of tumors can be challenging with all existing approaches. Third, immunotherapy can be combined with the adjuvant administration of bacteria.Definitions

[0096] As used herein, the terms “microbe” or “microorganism” are interchangeable and encompass both prokaryotic organisms including bacteria and archaea, and eukaryotic organisms, including fungi, present as components of the mammalian microbiota, and viruses.

[0097] The terms “gut microbe” and “gut bacteria” are used interchangeably and refer to the microorganisms that colonize the digestive tract. The term “gut microbiota” refers to a community of gut microbes.

[0098] Specific taxa and changes in gut bacteria discussed herein can be detected using various methods, including without limitation, quantitative PCR or high-throughput sequencing methods14323665488vlAttorney Docket No. 243735.000480which detect over- and under-represented genes in the total bacterial population (e.g., sequencing for microbial community analysis e.g., using an amplicon sequencing approach, a 454 machine, miSeq, Pacbio, or other related devices); profding of microbial 16S ribosomal RNA genes (16S rDNA), next generation sequencing (NGS) etc.), or transcriptomic or proteomic studies that identify lost (or under-represented) or gained microbial transcripts or proteins within total bacterial populations. See, e.g., U.S. Patent Publication No. 2010 / 0074872; Eckburg et al., Science, 2005, 308:1635-8; Costello et al., Science, 2009, 326:1694-7; Grice et al., Science, 2009, 324:1190-2; Li et al., Nature, 2010, 464: 59-65; Bjursell et al., Journal of Biological Chemistry, 2006, 281:36269-36279; Mahowald et al., PNAS, 2009, 14:5859-5864; Wikoff et al., PNAS, 2009, 10:3698-3703.

[0099] As used herein, the term “16S rDNA sequencing” refers to the sequencing of 16S ribosomal DNA (rDNA) or 16S ribosomal RNA (rRNA) gene sequences by using primers such as universal primers and / or species-specific primers to identify the bacteria present in a sample. rDNA and rRNA genes contain both highly conserved sites and hypervariable regions that can provide family, genus, and / or species-specific signature sequences useful for identification of bacteria. Such universal primers are well known in the art.

[0100] As used herein, the term “operational taxonomic unit” or “OTU” refers to group of bacterial sequences that share >90% sequence identity. A “type” or a plurality of “types” of bacteria includes an OTU or a plurality of different OTUs, and also encompasses differences in species, genus, family or order of bacteria. The specific genetic sequence may be the 16S rDNA or rRNA gene sequence or a portion of the 16S rDNA or rRNA gene sequence or it may be a functionally conserved housekeeping gene found broadly across the eubacterial kingdom. Alternatively, assignments are based on the related method, amplicon sequence variants, ASV, which reduces the noise associated with sequencing errors.

[0101] A “consortium” of bacterial strains is defined herein as a preparation of live, viable bacteria belonging to more than one strain. The consortium of bacterial strains may comprise a combination of more than one species of genetically defined bacterial isolates from the human commensal gut microbiota.15323665488vlAttorney Docket No. 243735.000480

[0102] The term "metabolically inaccessible" refers to substances that do not facilitate the growth of human cancer cell lines. Metabolically inaccessible substances may facilitate the growth of bacteria in carbohydrate-deficient medium.

[0103] The terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing, delaying, or reducing the incidence and / or likelihood of the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0104] As used herein, the term “therapeutically effective amount” or “effective amount” refers to the amount of a bacterial inoculant, a compound, or a composition, that when administered to a subject for treating (e.g., preventing or ameliorating) a state, disorder or condition, is sufficient to effect such treatment. The “effective amount” will vary depending, e.g., on the compound, composition, bacteria or analogues administered as well as the disease, its severity, and physical conditions and responsiveness of the subject to be treated.

[0105] As used herein, the term “combination” of a compound, composition, or bacterial inoculant and at least a second pharmaceutically active ingredient means at least two, but any desired combination of compound, composition, or bacterial inoculant can be delivered simultaneously or sequentially (e.g., within a 24 hour period).

[0106] The terms “patient”, “individual”, “subject”, and “animal” are used interchangeably herein and refer to mammals, including, without limitation, human and veterinary animals (e.g., cats, dogs, cows, horses, goats, sheep, pigs, rabbits, mice, etc.) and experimental animal models. In a preferred embodiment, the subject is a human.

[0107] The term “animal model” may include refer to mammals, including, without limitation, cats, dogs, cows, horses, goats, sheep, pigs, rabbits, mice, etc. In a preferred embodiment, the animal model is mice. In another preferred embodiment, the animal model is16323665488vlAttorney Docket No. 243735.000480rabbits. Rabbits may display higher endotoxin sensitivity (e.g., a feature of human innate immunity) than mice.

[0108] As used herein, the term “stimulate” when used in connection with growth and / or activity of bacteria encompasses the term “enhance”.

[0109] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Alternatively, the carrier can be a solid dosage form carrier, including but not limited to one or more of a binder (for compressed pills), a glidant, an encapsulating agent, a flavorant, and a colorant. Suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin.

[0110] The term “about” or “approximately” means within a statistically meaningful range of a value. Such a range can be within an order of magnitude, preferably within 50%, more preferably within 20%, still more preferably within 10%, and even more preferably within 5% of a given value or range. The allowable variation encompassed by the term “about” or “approximately” depends on the particular system under study, and can be readily appreciated by one of ordinary skill in the art.

[0111] The terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denote the presence of “at least one” of the referenced item.

[0112] The practice of the present invention employs, unless otherwise indicated, conventional techniques of statistical analysis, molecular biology (including recombinant techniques), microbiology, cell biology, and biochemistry, which are within the skill of the art. Such tools and techniques are described in detail in e.g., Sambrook et al. (2001) Molecular Cloning: A Laboratory Manual. 3rd ed. Cold Spring Harbor Laboratory Press: Cold Spring Harbor, New York; Ausubel et al. eds. (2005) Current Protocols in Molecular Biology. John Wiley and Sons, Inc.: Hoboken, NJ; Bonifacino et al. eds. (2005) Current Protocols in Cell Biology. John Wiley and Sons, Inc.: Hoboken, NJ; Coligan et al. eds. (2005) Current Protocols in Immunology, John Wiley and Sons, Inc.: Hoboken, NJ; Coico et al. eds. (2005) Current Protocols in17323665488vlAttorney Docket No. 243735.000480Microbiology, John Wiley and Sons, Inc.: Hoboken, NJ; Coligan et al. eds. (2005) Current Protocols in Protein Science, John Wiley and Sons, Inc.: Hoboken, NJ; and Enna et al. eds. (2005) Current Protocols in Pharmacology, John Wiley and Sons, Inc.: Hoboken, NJ. Additional techniques are explained, e.g., in U.S. Patent No. 7,912,698 and U.S. Patent Appl. Pub. Nos.2011 / 0202322 and 2011 / 0307437.Methods and Compositions of the Invention

[0113] As specified in the Background section above, there is a great need in the art for methods for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient to elicit or augment an anti-tumor response, as well as bacteria strain compositions useful for eliciting or augmenting an anti-tumor response.Methods for identifying a bacterial strain or consortium of bacterial strains

[0114] In one aspect, provided herein is a method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient, said method comprising:(a) determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins;(b) determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model; (c) determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site; and / or (d) determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0115] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins.

[0116] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether18323665488vlAttorney Docket No. 243735.000480administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model.

[0117] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site.

[0118] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0119] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins and determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model.

[0120] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins and determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site.

[0121] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins and determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0122] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether19323665488vlAttorney Docket No. 243735.000480administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model and determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site.

[0123] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model and determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0124] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site and determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0125] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model, determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site, and determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0126] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins, determining whether the bacterial strain or consortium of bacterial20323665488vlAttorney Docket No. 243735.000480strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site, and determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0127] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins, determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model, and determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

[0128] In one instance, the method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins, determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model, and determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site.

[0129] The number of bacterial strains in the consortium of bacterial strains may range from 2 bacterial strains to 12 bacterial strains or more, or may be preferably less than 12 bacterial strains. The number of bacterial strains in the consortium may be comprised of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or more bacterial strains. The consortium of bacterial strains may be tested together, as if the consortium were comprised of only one bacterial strain.

[0130] Determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor can be determined by computational prediction and / or in vitro assay of cancer cell lines (e.g., HeLa cells) on minimal or complex media.21323665488vlAttorney Docket No. 243735.000480

[0131] The bacterial strain or consortium of bacterial strains are capable of being detectable in a tumor. The bacterial strain or consortium of bacterial strains may be capable of colonizing a tumor. The colonization of the tumor may mean colonization of the tumor selectively over colonization of other tissues. The colonization of the tumor may drive the tumor-selective effect of the anti-tumor response. Colonization of the tumor may mean being detectable in the tumor.

[0132] Glycoproteins are proteins that contain (e.g., are linked to) carbohydrate chains (i.e., oligosaccharide chains). Many proteins expressed by cancer cells may be glycoproteins. Glycoproteins comprise many different protein classes. Mucins are glycoproteins that are a major component of the physical barrier of epithelial cells, e.g., to lubricate the epithelial cells, protect the epithelial cells from damage, and engage in signal transduction. Glycoproteins can advance cancer in multiple ways, e.g., glycoproteins can serve as physical barriers protecting the cancer cells from attack by immune cells, induce and / or propagate signaling promoting cancer growth, inactivate immune cells and / or recruit immune suppressor cells inhibiting attack of cancer cells by immune cells, elicit angiogenesis providing blood supply to tumors, and promote motility and / or invasiveness allowing cancer cells to spread and metastasize.

[0133] The bacterial strain or consortium of bacterial strains can be detected in a tumor, such as, e.g., a tumor or a part thereof grown in vitro or a tumor isolated from a subject. The tumor may be a solid tumor, a primary tumor, an orthotopic tumor, a heterotopic tumor (i.e., a tumor under the skin), a metastatic tumor, an experimental tumor (e.g., a tumor created in vivo), a tumor of any of the cell lines listed herein, and / or a tumor in a patient-derived xenograft. The bacterial strain or consortium of bacterial strains may be detected in cancer cell lines in vitro. The cancer cell lines may include HeLa, OVCAR3, Caco2, HCT116, Capanl, Panel, MDAMB468, MCF7, A549, Calu3, Dul45, RCC4, HepG2, HuCCTl, Raji, Daudi, Ramos (RA 1), and T98G. The cancer cell lines may be human cancer cell lines. The cancer cell lines may comprise cancer cell lines from multiple organs. The cancer cell lines may express mucins.

[0134] In some embodiments, step (a) comprises determining whether a gene encoding an enzyme that degrades glycoproteins can be activated in the bacterial strain or consortium of bacterial strains.22323665488vlAttorney Docket No. 243735.000480

[0135] In some embodiments, step (a) comprises determining whether a gene encoding an enzyme that degrades glycoproteins is expressed in the bacterial strain or consortium of bacterial strains. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains expresses at least one enzyme that degrades glycoproteins. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains comprises at least one gene that encodes at least one enzyme that degrades glycoproteins. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains expresses at least one gene that encodes at least one enzyme that degrades glycoproteins. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains comprises at least one active gene that encodes at least one enzyme that degrades glycoproteins. In some embodiments, step (a) comprises determining whether at least one gene that encodes at least one enzyme that degrades glycoproteins is active in the bacterial strain or consortium of strains.

[0136] In some embodiments, the at least one enzyme is a protease, glycosidase, or glycopeptidase.

[0137] In some embodiments, the protease is a mucin-degrading protease.

[0138] Proteases are enzymes that can break down the protein component of glycoproteins (i.e., enzymes that cleave peptide bonds within proteins). The mucin-degrading protease may comprise a matrix metalloproteinase (MMP), a cysteine protease, a serine protease, an endopeptidase, or an exopeptidase.

[0139] In some embodiments, the glycosidase is a mucinase, sialidase, galactosidase, and / or fucosidase.

[0140] Glycosidases are enzymes that can cleave the carbohydrate portions of glycoproteins (i.e., enzymes that cleave sugar-sugar bonds within sugar chains attached to glycoproteins). Sialidases are enzymes that can remove sialic acids, galactosidases are enzymes that can remove galactose, and fucosidases are enzymes that can remove fructose.

[0141] Glycopeptidases are enzymes that can cleave amino acid-sugar bonds.

[0142] In some embodiments, step (a) comprises determining whether a gene encoding an enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis is active in the bacterial strain or consortium of bacterial strains.23323665488vlAttorney Docket No. 243735.000480

[0143] In some embodiments, step (a) comprises determining whether a gene encoding an enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis is expressed in the bacterial strain or consortium of bacterial strains. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains expresses at least one enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains comprises at least one gene that encodes at least one enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains expresses at least one gene that encodes at least one enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis. In some embodiments, step (a) comprises determining whether the bacterial strain or consortium of bacterial strains comprises at least one active gene that encodes at least one enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis. In some embodiments, step (a) comprises determining whether at least one gene that encodes at least one enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis is active in the bacterial strain or consortium of strains.

[0144] In some embodiments, the immune cytotoxic cells are T cells and / or NK cells.

[0145] In some embodiments, step (a) comprises determining tumor-specific glycoproteins and determining whether the bacterial strain or consortium of bacterial strains can digest the tumorspecific glycoproteins.

[0146] In some embodiments, step (b) comprises determining whether the high doses of the bacterial strain or consortium of bacterial strains are non-lethal in an in vivo animal model.

[0147] In some embodiments, step (b) comprises determining whether the high doses of the bacterial strain or consortium of bacterial strains do not cause acute lung injury, kidney injury, or liver injury in an in vivo animal model.

[0148] In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1011colony forming units (CFU) / kg.24323665488vlAttorney Docket No. 243735.000480

[0149] In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 1015colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 106colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 107colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 108colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 109colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1 C and IO10colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 1011colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 1012colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 105and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 107colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 108colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 109colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and IO10colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 1011colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 1012colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 106and 1014colony forming units (CFU) / kg.25323665488vlAttorney Docket No. 243735.000480In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 108colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 109colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and IO10colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1011colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1012colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 108and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 108and 109colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 108and IO10colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 108and 1011colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 108and 1012colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 108and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 108and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 109and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 109and IO10colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 109and 1011colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 109and 1012colony forming units (CFU) / kg. In some26323665488vlAttorney Docket No. 243735.000480embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 109and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 109and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between IO10and 1015colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between IO10and 1011colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between IO10and 1012colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between IO10and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between IO10and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1011and 1015colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1011and 1012colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1011and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1011and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1012and 1015colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1012and 1013colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1012and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1013and 1015colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1013and 1014colony forming units (CFU) / kg. In some embodiments, the high doses of the bacterial strain or consortium of bacterial strains are between 1014and 1015colony forming units (CFU) / kg.

[0150] In some embodiments, the administration of the high doses of the bacterial strain or consortium of bacterial strains in step (b) comprises at least one of oral, intravenous, intraperitoneal, intratumoral, intravesical, dermal, transdermal, subcutaneous, intrathecal,27323665488vlAttorney Docket No. 243735.000480intranasal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

[0151] In some embodiments, step (c) comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to utilize non-caloric sugars in the absence of glucose in vitro.

[0152] In some embodiments, the non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, or N-acetylglucosamine.

[0153] In some embodiments, step (d) comprises administering the bacterial strain or consortium of bacterial strains in an in vivo model system of the tumor type expressed in the patient and testing a tumor expressed in the in vivo model system for detection of the bacterial strain or consortium of bacterial strains in the tumor.

[0154] In some embodiments, detection is tested within 24 hours to 10 days post administration.

[0155] In some embodiments, detection is tested within 12 hours to 20 days post administration. In some embodiments, detection is tested within 24 hours to 20 days post administration. In some embodiments, detection is tested within 36 hours to 20 days post administration. In some embodiments, detection is tested within 48 hours to 20 days post administration. In some embodiments, detection is tested within 72 hours to 20 days post administration. In some embodiments, detection is tested within 4 days to 20 days post administration. In some embodiments, detection is tested within 5 days to 20 days post administration. In some embodiments, detection is tested within 6 days to 20 days post administration. In some embodiments, detection is tested within 7 days to 20 days post administration. In some embodiments, detection is tested within 8 days to 20 days post administration. In some embodiments, detection is tested within 9 days to 20 days post administration. In some embodiments, detection is tested within 10 days to 20 days post administration. In some embodiments, detection is tested within 11 days to 20 days post28323665488vlAttorney Docket No. 243735.000480administration. In some embodiments, detection is tested within 12 days to 20 days post administration. In some embodiments, detection is tested within 13 days to 20 days post administration. In some embodiments, detection is tested within 14 days to 20 days post administration. In some embodiments, detection is tested within 16 days to 20 days post administration. In some embodiments, detection is tested within 18 days to 20 days post administration. In some embodiments, detection is tested within 12 hours to 18 days post administration. In some embodiments, detection is tested within 24 hours to 18 days post administration. In some embodiments, detection is tested within 36 hours to 18 days post administration. In some embodiments, detection is tested within 48 hours to 18 days post administration. In some embodiments, detection is tested within 72 hours to 18 days post administration. In some embodiments, detection is tested within 4 days to 18 days post administration. In some embodiments, detection is tested within 5 days to 18 days post administration. In some embodiments, detection is tested within 6 days to 18 days post administration. In some embodiments, detection is tested within 7 days to 18 days post administration. In some embodiments, detection is tested within 8 days to 18 days post administration. In some embodiments, detection is tested within 9 days to 18 days post administration. In some embodiments, detection is tested within 10 days to 18 days post administration. In some embodiments, detection is tested within 11 days to 18 days post administration. In some embodiments, detection is tested within 12 days to 18 days post administration. In some embodiments, detection is tested within 13 days to 18 days post administration. In some embodiments, detection is tested within 14 days to 18 days post administration. In some embodiments, detection is tested within 16 days to 18 days post administration. In some embodiments, detection is tested within 12 hours to 16 days post administration. In some embodiments, detection is tested within 24 hours to 16 days post administration. In some embodiments, detection is tested within 36 hours to 16 days post administration. In some embodiments, detection is tested within 48 hours to 16 days post administration. In some embodiments, detection is tested within 72 hours to 16 days post administration. In some embodiments, detection is tested within 4 days to 16 days post administration. In some embodiments, detection is tested within 5 days to 16 days post administration. In some embodiments, detection is tested within 6 days to 16 days post29323665488vlAttorney Docket No. 243735.000480administration. In some embodiments, detection is tested within 7 days to 16 days post administration. In some embodiments, detection is tested within 8 days to 16 days post administration. In some embodiments, detection is tested within 9 days to 16 days post administration. In some embodiments, detection is tested within 10 days to 16 days post administration. In some embodiments, detection is tested within 11 days to 16 days post administration. In some embodiments, detection is tested within 12 days to 16 days post administration. In some embodiments, detection is tested within 13 days to 16 days post administration. In some embodiments, detection is tested within 14 days to 16 days post administration. In some embodiments, detection is tested within 12 hours to 14 days post administration. In some embodiments, detection is tested within 24 hours to 14 days post administration. In some embodiments, detection is tested within 36 hours to 14 days post administration. In some embodiments, detection is tested within 48 hours to 14 days post administration. In some embodiments, detection is tested within 72 hours to 14 days post administration. In some embodiments, detection is tested within 4 days to 14 days post administration. In some embodiments, detection is tested within 5 days to 14 days post administration. In some embodiments, detection is tested within 6 days to 14 days post administration. In some embodiments, detection is tested within 7 days to 14 days post administration. In some embodiments, detection is tested within 8 days to 14 days post administration. In some embodiments, detection is tested within 9 days to 14 days post administration. In some embodiments, detection is tested within 10 days to 14 days post administration. In some embodiments, detection is tested within 11 days to 14 days post administration. In some embodiments, detection is tested within 12 days to 14 days post administration. In some embodiments, detection is tested within 13 days to 14 days post administration. In some embodiments, detection is tested within 12 hours to 13 days post administration. In some embodiments, detection is tested within 24 hours to 13 days post administration. In some embodiments, detection is tested within 36 hours to 13 days post administration. In some embodiments, detection is tested within 48 hours to 13 days post administration. In some embodiments, detection is tested within 72 hours to 13 days post administration. In some embodiments, detection is tested within 4 days to 13 days post administration. In some embodiments, detection is tested within 5 days to 13 days post30323665488vlAttorney Docket No. 243735.000480administration. In some embodiments, detection is tested within 6 days to 13 days post administration. In some embodiments, detection is tested within 7 days to 13 days post administration. In some embodiments, detection is tested within 8 days to 13 days post administration. In some embodiments, detection is tested within 9 days to 13 days post administration. In some embodiments, detection is tested within 10 days to 13 days post administration. In some embodiments, detection is tested within 11 days to 13 days post administration. In some embodiments, detection is tested within 12 days to 13 days post administration. In some embodiments, detection is tested within 12 hours to 12 days post administration. In some embodiments, detection is tested within 24 hours to 12 days post administration. In some embodiments, detection is tested within 36 hours to 12 days post administration. In some embodiments, detection is tested within 48 hours to 12 days post administration. In some embodiments, detection is tested within 72 hours to 12 days post administration. In some embodiments, detection is tested within 4 days to 12 days post administration. In some embodiments, detection is tested within 5 days to 12 days post administration. In some embodiments, detection is tested within 6 days to 12 days post administration. In some embodiments, detection is tested within 7 days to 12 days post administration. In some embodiments, detection is tested within 8 days to 12 days post administration. In some embodiments, detection is tested within 9 days to 12 days post administration. In some embodiments, detection is tested within 10 days to 12 days post administration. In some embodiments, detection is tested within 11 days to 12 days post administration. In some embodiments, detection is tested within 12 hours to 11 days post administration. In some embodiments, detection is tested within 24 hours to 11 days post administration. In some embodiments, detection is tested within 36 hours to 11 days post administration. In some embodiments, detection is tested within 48 hours to 11 days post administration. In some embodiments, detection is tested within 72 hours to 11 days post administration. In some embodiments, detection is tested within 4 days to 11 days post administration. In some embodiments, detection is tested within 5 days to 11 days post administration. In some embodiments, detection is tested within 6 days to 11 days post administration. In some embodiments, detection is tested within 7 days to 11 days post administration. In some embodiments, detection is tested within 8 days to 11 days post31323665488vlAttorney Docket No. 243735.000480administration. In some embodiments, detection is tested within 9 days to 11 days post administration. In some embodiments, detection is tested within 10 days to 11 days post administration. In some embodiments, detection is tested within 12 hours to 10 days post administration. In some embodiments, detection is tested within 24 hours to 10 days post administration. In some embodiments, detection is tested within 36 hours to 10 days post administration. In some embodiments, detection is tested within 48 hours to 10 days post administration. In some embodiments, detection is tested within 72 hours to 10 days post administration. In some embodiments, detection is tested within 4 days to 10 days post administration. In some embodiments, detection is tested within 5 days to 10 days post administration. In some embodiments, detection is tested within 6 days to 10 days post administration. In some embodiments, detection is tested within 7 days to 10 days post administration. In some embodiments, detection is tested within 8 days to 10 days post administration. In some embodiments, detection is tested within 9 days to 10 days post administration. In some embodiments, detection is tested within 12 hours to 9 days post administration. In some embodiments, detection is tested within 24 hours to 9 days post administration. In some embodiments, detection is tested withinhours to 9 days post administration. In some embodiments, detection is tested within 48 hours to 9 days post administration. In some embodiments, detection is tested within 72 hours to 9 days post administration. In some embodiments, detection is tested within 4 days to 9 days post administration. In some embodiments, detection is tested within 5 days to 9 days post administration. In some embodiments, detection is tested within 6 days to 9 days post administration. In some embodiments, detection is tested within 7 days to 9 days post administration. In some embodiments, detection is tested within 8 days to 9 days post administration. In some embodiments, detection is tested within 12 hours to 8 days post administration. In some embodiments, detection is tested within 24 hours to 8 days post administration. In some embodiments, detection is tested within 36 hours to 8 days post administration. In some embodiments, detection is tested within 48 hours to 8 days post administration. In some embodiments, detection is tested within 72 hours to 8 days post administration. In some embodiments, detection is tested within 4 days to 8 days post administration. In some embodiments, detection is tested within 5 days to 8 days post32323665488vlAttorney Docket No. 243735.000480administration. In some embodiments, detection is tested within 6 days to 8 days post administration. In some embodiments, detection is tested within 7 days to 8 days post administration. In some embodiments, detection is tested within 12 hours to 7 days post administration. In some embodiments, detection is tested within 24 hours to 7 days post administration. In some embodiments, detection is tested within 36 hours to 7 days post administration. In some embodiments, detection is tested within 48 hours to 7 days post administration. In some embodiments, detection is tested within 72 hours to 7 days post administration. In some embodiments, detection is tested within 4 days to 7 days post administration. In some embodiments, detection is tested within 5 days to 7 days post administration. In some embodiments, detection is tested within 6 days to 7 days post administration. In some embodiments, detection is tested within 12 hours to 6 days post administration. In some embodiments, detection is tested within 24 hours to 6 days post administration. In some embodiments, detection is tested within 36 hours to 6 days post administration. In some embodiments, detection is tested within 48 hours to 6 days post administration. In some embodiments, detection is tested within 72 hours to 6 days post administration. In some embodiments, detection is tested within 4 days to 6 days post administration. In some embodiments, detection is tested within 5 days to 6 days post administration. In some embodiments, detection is tested within 12 hours to 5 days post administration. In some embodiments, detection is tested within 24 hours to 5 days post administration. In some embodiments, detection is tested within 36 hours to 5 days post administration. In some embodiments, detection is tested within 48 hours to 5 days post administration. In some embodiments, detection is tested within 72 hours to 5 days post administration. In some embodiments, detection is tested within 4 days to 5 days post administration. In some embodiments, detection is tested within 12 hours to 4 days post administration. In some embodiments, detection is tested within 24 hours to 4 days post administration. In some embodiments, detection is tested within 36 hours to 4 days post administration. In some embodiments, detection is tested within 48 hours to 4 days post administration. In some embodiments, detection is tested within 72 hours to 4 days post administration. In some embodiments, detection i s tested within 12 hours to 72 hours post administration. In some embodiments, detection i s tested within 24 hours to 72 hours post323665488vlAttorney Docket No. 243735.000480administration. In some embodiments, detection is tested within 36 hours to 72 hours post administration. In some embodiments, detection is tested within 48 hours to 72 hours post administration. In some embodiments, detection is tested within 12 hours to 48 hours post administration. In some embodiments, detection is tested within 24 hours to 48 hours post administration. In some embodiments, detection is tested within 36 hours to 48 hours post administration. In some embodiments, detection is tested within 12 hours to 36 hours post administration. In some embodiments, detection is tested within 24 hours to 36 hours post administration. In some embodiments, detection is tested within 12 hours to 24 hours post administration.

[0156] In some embodiments, step (d) comprises injecting the bacterial strain or consortium of bacterial strains in an isolated tumor and determining whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 10 days.

[0157] In some embodiments, step (d) comprises injecting the bacterial strain or consortium of bacterial strains in an isolated tumor and determining whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about34323665488vlAttorney Docket No. 243735.00048020 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 10 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 11 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 13 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 14 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 16 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 18 days to at least about 20 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 10 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for35323665488vlAttorney Docket No. 243735.000480at least about 11 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 13 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 14 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 16 days to at least about 18 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 10 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 11 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 13 days to at least about 16 days. In some embodiments, it is determined whether the36323665488vlAttorney Docket No. 243735.000480bacterial strain remains persistent and viable for at least about 14 days to at least about 16 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 10 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 11 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 13 days to at least about 14 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 1337323665488vlAttorney Docket No. 243735.000480days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 10 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 11 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 days to at least about 13 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least38323665488vlAttorney Docket No. 243735.000480about 8 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 10 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 11 days to at least about 12 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 10 days to at least about 11 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 10 days. In some embodiments, it is determined whether the39323665488vlAttorney Docket No. 243735.000480bacterial strain remains persistent and viable for at least about 72 hours to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 9 days to at least about 10 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 8 days to at least about 9 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 8 days. In some embodiments, it is determined whether40323665488vlAttorney Docket No. 243735.000480the bacterial strain remains persistent and viable for at least about 48 hours to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 7 days to at least about 8 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 5 days to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 6 days to at least about 7 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 6 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 6 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 6 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 6 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 6 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 6 days. In some embodiments, it is determined whether41323665488vlAttorney Docket No. 243735.000480the bacterial strain remains persistent and viable for at least about 5 days to at least about 6 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 5 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 5 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 5 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 5 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 5 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 4 days to at least about 5 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 4 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 4 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 4 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 4 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 72 hours to at least about 4 days. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 72 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 72 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 72 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 48 hours to at least about 72 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 48 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 48 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 36 hours to at least about 48 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 36 hours.42323665488vlAttorney Docket No. 243735.000480In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 36 hours. In some embodiments, it is determined whether the bacterial strain remains persistent and viable for at least about 12 hours to at least about 24 hours.

[0158] In some embodiments, the isolated tumor is the same type of tumor expressed in the patient.

[0159] In some embodiments, the isolated tumor is obtained from the patient.

[0160] The isolated tumor may be obtained post-surgery. The bacterial strain or consortium of bacterial strains from said isolated tumor may be characterized, i.e., the strain or consortium of strains that comprise the bacterial strain or consortium of bacterial strains may be determined. The characterized bacterial strain or consortium of bacterial strains may be used to derive a patient-specific composition of a bacterial strain or consortium of bacterial strains. The patient-specific composition of a bacterial strain or consortium of bacterial strains may be used to treat metastasis, i.e., by the tumor.

[0161] In some embodiments, detection of the bacterial strain or consortium of bacterial strains in the tumor includes measuring by qPCR, measuring growth of the bacterial strain or consortium of bacterial strains on agar plates from tumor homogenates, or using high-throughput sequencing methods.

[0162] In some embodiments, the high-throughput sequencing methods are selected from the group consisting of using an amplicon sequencing approach, a 454 machine, miSeq, Pacbio, or other related devices, profiling of microbial 16S ribosomal RNA genes (16S rDNA), and next generation sequencing (NGS).

[0163] In some embodiments, the method further comprises determining whether the bacterial strain or consortium of bacterial strains does not express a catalase.

[0164] In some embodiments, the method further comprises determining whether the bacterial strain or consortium of bacterial strains expresses a catalase.

[0165] Catalase expression may be functionally tested by using hydrogen peroxide as a substrate, e.g., the hydrogen peroxide reacts with the catalase enzyme to produce oxygen. The oxygen production can confirm the presence of catalase and can comparatively quantify the amount of catalase enzyme.43323665488vlAttorney Docket No. 243735.000480

[0166] The catalase expressed in the bacterial strain or consortium of bacterial strains may be from one of three main classes of catalases that are present in bacteria: 1) monofunctional catalases (e.g., comprising three subclades each with a specific active site heme orientation), 2) bifunctional catalase-peroxidases, and 3) manganese-containing catalases. Conserved motifs of the three main classes of catalases that are present in bacteria include: 1) RERIPERXVHAKG (SEQ ID NO: 1) and RLFXYXD (SEQ ID NO: 2) heme-ligand binding domains for monofunctional catalases, 2) a MGLIYVNPEG (SEQ ID NO: 3) motif around the catalytic tyrosine in bifunctional catalase-peroxidases, and 3) a Glu4His2Mn2 (SEQ ID NO: 2816) active site geometry for the manganese-containing catalases.

[0167] In some embodiments, the catalase gene and / or protein comprises one of the following accession numbers: XM 069354561.1 (SEQ ID NO: 4), XM_069439244.1 (SEQ ID NO: 5), XM_003071809.2 (SEQ ID NO: 6), XM_066124241.1 (SEQ ID NO: 7), XM_067649124.1 (SEQ ID NO: 8), XM_067651490.1 (SEQ ID NO: 9), XM_067653012.1 (SEQ ID NO: 10), XM_067653050.1 (SEQ ID NO: 11), XM_067664389.1 (SEQ ID NO: 12), XM_067676644.1 (SEQ ID NO: 13), XM_067682195.1 (SEQ ID NO: 14), NM_001022677.3 (SEQ ID NO: 15), PQ097011.1 (SEQ ID NO: 16), XM_066763643.1 (SEQ ID NO: 17), XM_066771233.1 (SEQ ID NO: 18), XM_066771932.1 (SEQ ID NO: 19), XM_066801617.1 (SEQ ID NO: 20), XM_066829952.1 (SEQ ID NO: 21), XM_066833933.1 (SEQ ID NO: 22), XM_066835778.1 (SEQ ID NO: 23), XM_066840224.1 (SEQ ID NO: 24), XM_066849499.1 (SEQ ID NO: 25), XM_066863095.1 (SEQ ID NO: 26), XM_066871987.1 (SEQ ID NO: 27), XM_066874376.1 (SEQ ID NO: 28), XM_066880488.1 (SEQ ID NO: 29), XM_066892018.1 (SEQ ID NO: 30), XM 066953121.1 (SEQ ID NO: 31), XM 066954653.1 (SEQ ID NO: 32), XM_066959505.1 (SEQ ID NO: 33), XM_066961121.1 (SEQ ID NO: 34), XM_066963137.1 (SEQ ID NO: 35), XM_066965393.1 (SEQ ID NO: 36), PP998215.1 (SEQ ID NO: 37), PP998216.1 (SEQ ID NO: 38), PP998217.1 (SEQ ID NO: 39), PP998218.1 (SEQ ID NO: 40), PP998219.1 (SEQ ID NO: 41), PP998220.1 (SEQ ID NO: 42), PP998221.1 (SEQ ID NO: 43), PP998222.1 (SEQ ID NO: 44), NM_001180564.1 (SEQ ID NO: 45), NM_001181217.1 (SEQ ID NO: 46), XM_001933648.2 (SEQ ID NO: 47), XM_001934461.2 (SEQ ID NO: 48), XM_001935042.1 (SEQ ID NO: 49), XM_001939640.2 (SEQ ID NO: 50), XM_002614233.2 (SEQ ID NO: 51), XM_002616785.2 (SEQ ID NO: 52), XM_003841381.2 (SEQ ID NO: 53),44323665488vlAttorney Docket No. 243735.000480XM_006684265.2 (SEQ ID NO: 54), XM_006689714.2 (SEQ ID NO: 55), XM_007809343.2 (SEQ ID NO: 56), XM_007811266.2 (SEQ ID NO: 57), XM_007813538.2 (SEQ ID NO: 58), XM 007815133.2 (SEQ ID NO: 59), XM 014675429.1 (SEQ ID NO: 60), XM 014678114.1 (SEQ ID NO: 61), XM_014682224.1 (SEQ ID NO: 62), XM_014683121.1 (SEQ ID NO: 63), XM_014683848.1 (SEQ ID NO: 64), XM_014685468.1 (SEQ ID NO: 65), XM_014693716.1 (SEQ ID NO: 66), XM_014693970.1 (SEQ ID NO: 67), XM_024905210.2 (SEQ ID NO: 68), XM_032022286.1 (SEQ ID NO: 69), XM_032034412.2 (SEQ ID NO: 70), XM_066103629.1 (SEQ ID NO: 71), XM_066103732.1 (SEQ ID NO: 72), XM_066104430.1 (SEQ ID NO: 73), XM_066119285.1 (SEQ ID NO: 74), XM_066127189.1 (SEQ ID NO: 75), XM_066150824.1 (SEQ ID NO: 76), XM_053190148.2 (SEQ ID NO: 77), XM_O53192630.2 (SEQ ID NO: 78), XM_053194547.2 (SEQ ID NO: 79), XM_018317211.2 (SEQ ID NO: 80), XM_018322520.1 (SEQ ID NO: 81), XM_018322662.2 (SEQ ID NO: 82), XM_023600510.2 (SEQ ID NO: 83), XM_025726427.1 (SEQ ID NO: 84), XM_064993934.1 (SEQ ID NO: 85), XM_064996338.1 (SEQ ID NO: 86), XM_064801381.1 (SEQ ID NO: 87), XM_064816966.1 (SEQ ID NO: 88), XM_064818406.1 (SEQ ID NO: 89), XM_064822868.1 (SEQ ID NO: 90), XM_064827609.1 (SEQ ID NO: 91), XM_064830351.1 (SEQ ID NO: 92), XM_064838655.1 (SEQ ID NO: 93), XM_064838656.1 (SEQ ID NO: 94), XM_064872735.1 (SEQ ID NO: 95), XM_064877697.1 (SEQ ID NO: 96), XM_064885458.1 (SEQ ID NO: 97), XM_064905050.1 (SEQ ID NO: 98), XM_064912848.1 (SEQ ID NO: 99), XM_064919807.1 (SEQ ID NO: 100), AB092339.1 (SEQ ID NO: 101), XM_020190108.1 (SEQ ID NO: 102), PP438775.1 (SEQ ID NO: 103), PP438776.1 (SEQ ID NO: 104), PP438777.1 (SEQ ID NO: 105), PP261184.1 (SEQ ID NO: 106), XM 063028593.1 (SEQ ID NO: 107), XM 063028620.1 (SEQ ID NO: 108), XM 063029638.1 (SEQ ID NO: 109), XM_062880027.1 (SEQ ID NO: 110), XM_062881749.1 (SEQ ID NO: 111), XM_062881999.1 (SEQ ID NO: 112), XM_062891229.1 (SEQ ID NO: 113), XM_062893023.1 (SEQ ID NO: 114), XM_062893275.1 (SEQ ID NO: 115), XM_062913405.1 (SEQ ID NO: 116), XM_062915178.1 (SEQ ID NO: 117), XM_062915422.1 (SEQ ID NO: 118), XM_062916826.1 (SEQ ID NO: 119), XM_062916827.1 (SEQ ID NO: 120), XM_062917531.1 (SEQ ID NO: 121), XM_062917865.1 (SEQ ID NO: 122), XM_062927097.1 (SEQ ID NO: 123), XM_062948072.1 (SEQ ID NO: 124), XM_062949825.1 (SEQ ID NO: 125), XM_062950081.1 (SEQ ID NO: 126), XM_013473344.1 (SEQ ID NO: 127), XM_013474959.1 (SEQ ID NO: 128), XM_013475732.145323665488vlAttorney Docket No. 243735.000480(SEQ ID NO: 129), XM_013476522.1 (SEQ ID NO: 130), XM_01347665 .1 (SEQ ID NO: 131), XM_062772868.1 (SEQ ID NO: 132), XM_062773172.1 (SEQ ID NO: 133), XM_062776448.1 (SEQ ID NO: 134), XM 062785942.1 (SEQ ID NO: 135), XM 062794640.1 (SEQ ID NO: 136), XM_062797295.1 (SEQ ID NO: 137), XM_062812878.1 (SEQ ID NO: 138), XM_062814318.1 (SEQ ID NO: 139), XM_062815982.1 (SEQ ID NO: 140), XM_062816402.1 (SEQ ID NO: 141), XM_062822732. 1 (SEQ ID NO: 142), XM_062827614.1 (SEQ ID NO: 143), XM_062832050.1 (SEQ ID NO: 144), XM_062832193.1 (SEQ ID NO: 145), XM_062865581.1 (SEQ ID NO: 146), OQ605106.1 (SEQ ID NO: 147), OQ605108.1 (SEQ ID NO: 148), OQ605109.1 (SEQ ID NO: 149), XM_018174055.1 (SEQ ID NO: 150), XM_018174832.1 (SEQ ID NO: 151), XM_018184728.1 (SEQ ID NO: 152), XM_018185099.1 (SEQ ID NO: 153), XM_018879549.1 (SEQ ID NO: 154), XM_007723261.1 (SEQ ID NO: 155), XM_007726380.1 (SEQ ID NO: 156), XM_007729746.1 (SEQ ID NO: 157), XM_007729892.1 (SEQ ID NO: 158), XM_007730979.1 (SEQ ID NO: 159), XM_007735023.1 (SEQ ID NO: 160), XM_007736409.1 (SEQ ID NO: 161), XM_007737286. 1 (SEQ ID NO: 162), XM_007743991.1 (SEQ ID NO: 163), XM_007745166.1 (SEQ ID NO: 164), XM_007745819.1 (SEQ ID NO: 165), XM_007747608.1 (SEQ ID NO: 166), XM_007751368.1 (SEQ ID NO: 167), XM_007751526.1 (SEQ ID NO: 168), XM_007752089.1 (SEQ ID NO: 169), XM_007756615.1 (SEQ ID NO: 170), XM_007757200.1 (SEQ ID NO: 171), XM_007758553.1 (SEQ ID NO: 172), XM_007759022.1 (SEQ ID NO: 173), XM_007761834.1 (SEQ ID NO: 174), XM_007762840.1 (SEQ ID NO: 175), XM_007762888.1 (SEQ ID NO: 176), XM_013400367.1 (SEQ ID NO: 177), XM_013400537.1 (SEQ ID NO: 178), XM_013401103.1 (SEQ ID NO: 179), XM_013405948.1 (SEQ ID NO: 180), XM_013409523.1 (SEQ ID NO: 181), XM 013410724.1 (SEQ ID NO: 182), XM 013569353.1 (SEQ ID NO: 183), XM 013570609.1 (SEQ ID NO: 184), XM_013570618.1 (SEQ ID NO: 185), XM_013576454.1 (SEQ ID NO: 186), XM_013576735.1 (SEQ ID NO: 187), XM_013576912.1 (SEQ ID NO: 188), XM_019153708.1 (SEQ ID NO: 189), XM_019154874.1 (SEQ ID NO: 190), XM_007788332. 1 (SEQ ID NO: 191), XM_007806658.1 (SEQ ID NO: 192), XM_006667658.1 (SEQ ID NO: 193), XM_006672872.1 (SEQ ID NO: 194), XM_007306965.1 (SEQ ID NO: 195), XM_007307522.1 (SEQ ID NO: 196), XM_007378497. 1 (SEQ ID NO: 197), XM_007380414.1 (SEQ ID NO: 198), XM_007772434.1 (SEQ ID NO: 199), XM_007775848.1 (SEQ ID NO: 200), XM_007777993.1 (SEQ ID NO: 201), XM_007778542.1 (SEQ ID NO: 202), XM_007780247.1 (SEQ ID NO: 203), XM_007782800.146323665488vlAttorney Docket No. 243735.000480(SEQ ID NO: 204), XM_007863074.1 (SEQ ID NO: 205), XM_007869059.1 (SEQ ID NO: 206), XM_007870761.1 (SEQ ID NO: 207), XM_007871823.1 (SEQ ID NO: 208), XM_009155327.1 (SEQ ID NO: 209), XM 009156345.1 (SEQ ID NO: 210), XM 009161943.1 (SEQ ID NO: 211), XM_009542036.1 (SEQ ID NO: 212), XM_009550530.1 (SEQ ID NO: 213), XM_009554551.1 (SEQ ID NO: 214), XM_011275140.1 (SEQ ID NO: 215), XM_011275452.1 (SEQ ID NO: 216), XM_011324622.1 (SEQ ID NO: 217), XM_011327863.1 (SEQ ID NO: 218), XM_011328072.1 (SEQ ID NO: 219), XM_016415052.1 (SEQ ID NO: 220), XM_016416601.1 (SEQ ID NO: 221), XM_033567965.1 (SEQ ID NO: 222), XM_003014257.1 (SEQ ID NO: 223), XM_007372466.1 (SEQ ID NO: 224), XM_007819259.1 (SEQ ID NO: 225), XM_007821201.1 (SEQ ID NO: 226), XM_007823783.1 (SEQ ID NO: 227), XM_007823877.1 (SEQ ID NO: 228), XM_007824738.1 (SEQ ID NO: 229), XM_007828325.2 (SEQ ID NO: 230), XM_007828434.2 (SEQ ID NO: 231), XM_009852821.1 (SEQ ID NO: 232), XM_009853185.1 (SEQ ID NO: 233), XM_013165370.1 ( SEQ ID NO : 234), XM_013165377.1 (SEQ ID NO : 235), XM_013167513.1 (SEQ ID NO : 236), XM_013167521.1 (SEQ ID NO: 237), XM_013387174.1 (SEQ ID NO: 238), XM_013388071.1 (SEQ ID NO: 239), XM_014080964.1 (SEQ ID NO: 240), XM_014312661.1 (SEQ ID NO: 241), XM_014315762.1 (SEQ ID NO: 242), XM_014318248.1 (SEQ ID NO: 243), XM_014800859.1 (SEQ ID NO: 244), XM_014803416.1 (SEQ ID NO: 245), XM_024463979.1 (SEQ ID NO: 246), XM_024465027.1 (SEQ ID NO: 247), XM_025526551.1 (SEQ ID NO: 248), XM_025529249.1 (SEQ ID NO: 249), XM_025530145.1 (SEQ ID NO: 250), XM_025530149.1 (SEQ ID NO: 251), XM_025530398.1 (SEQ ID NO: 252), XM_025531405.1 (SEQ ID NO: 253), XM_025537084.1 (SEQ ID NO: 254), XM_025537550.1 (SEQ ID NO: 255), XM_028636925.1 (SEQ ID NO: 256), XM 028641417.1 (SEQ ID NO: 257), XM 036677444.1 (SEQ ID NO: 258), XM 036680117.1 (SEQ ID NO: 259), XM_036681750.1 (SEQ ID NO: 260), XM_036685176.1 (SEQ ID NO: 261), XM_036685949.1 (SEQ ID NO: 262), XM_036775286.1 (SEQ ID NO: 263), XM_041822840.1 (SEQ ID NO: 264), XM_041824324.1 (SEQ ID NO: 265), XM_041825292.1 (SEQ ID NO: 266), XM_041826927.1 (SEQ ID NO: 267), XM_041832803.1 (SEQ ID NO: 268), XM_051478651.1 (SEQ ID NO: 269), XM_013383516.1 (SEQ ID NO: 270), XM_016732933.1 (SEQ ID NO: 271), XM_016733806.1 (SEQ ID NO: 272), XM_016734431.1 (SEQ ID NO: 273), XM_016735711.1 (SEQ ID NO: 274), XM_018139352.1 (SEQ ID NO: 275), XM_018140504.1 (SEQ ID NO: 276), XM_018141189.1 (SEQ ID NO: 277), XM_020270787.1 (SEQ ID NO: 278), XM_020270921.147323665488vlAttorney Docket No. 243735.000480(SEQ ID NO: 279), XM_020271194.1 (SEQ ID NO: 280), XM_020271910.1 (SEQ ID NO: 281), XM_020273825.1 (SEQ ID NO: 282), XM_020276438.1 (SEQ ID NO: 283), XM_031218972.1 (SEQ ID NO: 284), XM 031220264.1 (SEQ ID NO: 285), XM 031220534.1 (SEQ ID NO: 286), XM_031220571.1 (SEQ ID NO: 287), XM_031223918.1 (SEQ ID NO: 288), XM_031228457.1 (SEQ ID NO: 289), XM_049365528.1 (SEQ ID NO: 290), OR885514.1 (SEQ ID NO: 291), XM_001528347.1 (SEQ ID NO: 292), XM_001208852.1 (SEQ ID NO: 293), XM_001210880.1 (SEQ ID NO: 294), XM_001216081.1 (SEQ ID NO: 295), XM_001216098.1 (SEQ ID NO: 296), XM_001270163.1 (SEQ ID NO: 297), XM_001270391.1 (SEQ ID NO: 298), XM_001270473.1 (SEQ ID NO: 299), XM_001273664.1 (SEQ ID NO: 300), XM_001274803.1 (SEQ ID NO: 301), XM_001486129.1 (SEQ ID NO: 302), XM_001486130.1 (SEQ ID NO: 303), XM_001889460.1 (SEQ ID NO: 304), XM_002479644.1 (SEQ ID NO: 305), XM_002480185.1 (SEQ ID NO: 306), XM_002480924.1 (SEQ ID NO: 307), XM_002484086.1 (SEQ ID NO: 308), XM_002487780.1 (SEQ ID NO: 309), XM_002542024.1 (SEQ ID NO: 310), XM_002543996.1 (SEQ ID NO: 311), XM 003018921.1 (SEQ ID NO: 312), XM_003320261.2 (SEQ ID NO: 313), XM_003333415.2 (SEQ ID NO: 314), XM_003889540.1 (SEQ ID NO: 315), XM_060422076.1 (SEQ ID NO: 316), XM_060431978.1 (SEQ ID NO: 317), XM_060433843.1 (SEQ ID NO: 318), XM_060443758.1 (SEQ ID NO: 319), XM_060450499.1 (SEQ ID NO: 320), XM_060454595.1 (SEQ ID NO: 321), XM_060460736.1 (SEQ ID NO: 322), XM_060461078.1 (SEQ ID NO: 323), XM_060463395.1 (SEQ ID NO: 324), XM_060465855.1 (SEQ ID NO: 325), XM_060475718.1 (SEQ ID NO: 326), XM_060475735.1 (SEQ ID NO: 327), XM_060476175.1 (SEQ ID NO: 328), XM_060479542.1 (SEQ ID NO: 329), XM_060484762.1 (SEQ ID NO: 330), XM_060485936.1 (SEQ ID NO: 331), XM 060487449.1 (SEQ ID NO: 332), XM 060487812.1 (SEQ ID NO: 333), XM 060493288.1 (SEQ ID NO: 334), XM_060503717.1 (SEQ ID NO: 335), XM_060511306.1 (SEQ ID NO: 336), XM_060517947.1 (SEQ ID NO: 337), XM_060525179.1 (SEQ ID NO: 338), XM_060526107.1 (SEQ ID NO: 339), XM_060528171.1 (SEQ ID NO: 340), XM_060529272.1 (SEQ ID NO: 341), XM_060533703.1 (SEQ ID NO: 342), XM_060540482.1 (SEQ ID NO: 343), XM_060541483.1 (SEQ ID NO: 344), XM_060541677.1 (SEQ ID NO: 345), XM_060544634.1 (SEQ ID NO: 346), XM_060557332.1 (SEQ ID NO: 347), XM_060559332.1 (SEQ ID NO: 348), XM_060561375.1 (SEQ ID NO: 349), XM_060561421.1 (SEQ ID NO: 350), XM_060564084.1 (SEQ ID NO: 351), XM_060568992.1 (SEQ ID NO: 352), XM_060575768.1 (SEQ ID NO: 353), XM_060585049.148323665488vlAttorney Docket No. 243735.000480(SEQ TD NO: 354), XM_060592382.1 (SEQ ID NO: 355), OQ944104.1 (SEQ ID NO: 356), XM_001388584.3 (SEQ ID NO: 357), OR475421.1 (SEQ ID NO: 358), OR475422.1 (SEQ ID NO: 359), OR475423.1 (SEQ ID NO: 360), OR483870.1 (SEQ ID NO: 361), OR483871.1 (SEQ ID NO: 362), OR483872.1 (SEQ ID NO: 363), OR453983.1 (SEQ ID NO: 364), OR566917.1 (SEQ ID NO: 365), XM_038936519.1 (SEQ ID NO: 366), XM_038936955.2 (SEQ ID NO: 367), XM_038937175.1 (SEQ ID NO: 368), XM_038938647.1 (SEQ ID NO: 369), XM_038940155.2 (SEQ ID NO: 370), XM_038943957.1 (SEQ ID NO: 371), XM_059637989.1 (SEQ ID NO: 372), XM_059637990.1 (SEQ ID NO: 373), XM_018379773.1 (SEQ ID NO: 374), XM_018381787.1 (SEQ ID NO: 375), XM_018382846.1 (SEQ ID NO: 376), XM_018387720.1 (SEQ ID NO: 377), XM 018395381.1 (SEQ ID NO: 378), XM_018396846.1 (SEQ ID NO: 379), XM_031175419.3 (SEQ ID NO: 380), XM_031175496.2 (SEQ ID NO: 381), XM_031180089.2 (SEQ ID NO: 382), XM 049268181.1 (SEQ ID NO: 383), XM_049270660.1 (SEQ ID NO: 384), XM_049278495.1 (SEQ ID NO: 385), XM_059610870.1 (SEQ ID NO: 386), XM_059611720.1 (SEQ ID NO: 387), XM_016437721.1 (SEQ ID NO: 388), XM_016438349.1 (SEQ ID NO: 389), XM_016786796.1 (SEQ ID NO: 390), XM_018270313.2 (SEQ ID NO: 391), XM_018279972.2 (SEQ ID NO: 392), XM_047904808.1 (SEQ ID NO: 393), XM_047905381.1 (SEQ ID NO: 394), XM_047905883.1 (SEQ ID NO: 395), XM_047907426.1 (SEQ ID NO: 396), OR345267.1 (SEQ ID NO: 397), OR345268.1 (SEQ ID NO: 398), XM_058449357.1 (SEQ ID NO: 399), XM_058451808.1 (SEQ ID NO: 400), XM_058455776.1 (SEQ ID NO: 401), XM_058475411.1 (SEQ ID NO: 402), XM_058475989.1 (SEQ ID NO: 403), XM_058502786.1 (SEQ ID NO: 404), XM_058506857.1 (SEQ ID NO: 405), ON604788.1 (SEQ ID NO: 406), XM_057063121.1 (SEQ ID NO: 407), XM 057066554.1 (SEQ ID NO: 408), XM 057078543.1 (SEQ ID NO: 409), XM 057080335.1 (SEQ ID NO: 410), XM_057081389.1 (SEQ ID NO: 411), XM_057082143.1 (SEQ ID NO: 412), XM_057095013.1 (SEQ ID NO: 413), XM_057095988.1 (SEQ ID NO: 414), XM_057098297.1 (SEQ ID NO: 415), XM_057105019.1 (SEQ ID NO: 416), XM_057107898.1 (SEQ ID NO: 417), XM_057109329.1 (SEQ ID NO: 418), XM_057113935.1 (SEQ ID NO: 419), XM_057119178.1 (SEQ ID NO: 420), XM_057135768.1 (SEQ ID NO: 421), XM_057171180.1 (SEQ ID NO: 422), XM_057173545.1 (SEQ ID NO: 423), XM_057174492.1 (SEQ ID NO: 424), XM_057199491.1 (SEQ ID NO: 425), XM_057200161.1 (SEQ ID NO: 426), XM_057230934.1 (SEQ ID NO: 427), XM_057237356.1 (SEQ ID NO: 428), XM_057252129.1 (SEQ ID NO: 429), XM_057257185.149323665488vlAttorney Docket No. 243735.000480(SEQ ID NO: 430), XM_057261889.1 (SEQ ID NO: 431 ), XM_057261983.1 (SEQ ID NO: 432), XM_057273717.1 (SEQ ID NO: 433), XM_057275260.1 (SEQ ID NO: 434), XM_057297615.1 (SEQ ID NO: 435), XM 057152962.1 (SEQ ID NO: 436), XM 057154820.1 (SEQ ID NO: 437), XM_057157945.1 (SEQ ID NO: 438), XM_057166069.1 (SEQ ID NO: 439), XM_057188752.1 (SEQ ID NO: 440), XM_057219031.1 (SEQ ID NO: 441), XM_056612709.1 (SEQ ID NO: 442), XM_056629963.1 (SEQ ID NO: 443), XM_056632488.1 (SEQ ID NO: 444), XM_056637302.1 (SEQ ID NO: 445), XM_056886984.1 (SEQ ID NO: 446), XM_056895588.1 (SEQ ID NO: 447), XM_056899221.1 (SEQ ID NO: 448), XM_056899479.1 (SEQ ID NO: 449), XM_056903880.1 (SEQ ID NO: 450), XM_056908496.1 (SEQ ID NO: 451), XM_056918632.1 (SEQ ID NO: 452), XM_056925349.1 (SEQ ID NO: 453), XM_056932198.1 (SEQ ID NO: 454), XM_056936385.1 (SEQ ID NO: 455), XM 056938591.1 (SEQ ID NO: 456), XM_056958618.1 (SEQ ID NO: 457), XM 056965886.1 (SEQ ID NO: 458), XM 056967131.1 (SEQ ID NO: 459), XM_056968085.1 (SEQ ID NO: 460), XM_056977862.1 (SEQ ID NO: 461), XM_056979471.1 (SEQ ID NO: 462), XM_056981763.1 (SEQ ID NO: 463), XM_056645690.1 (SEQ ID NO: 464), XM_056662548.1 (SEQ ID NO: 465), XM_056674510.1 (SEQ ID NO: 466), XM_056679617.1 (SEQ ID NO: 467), XM_056683366.1 (SEQ ID NO: 468), XM_056687238.1 (SEQ ID NO: 469), XM_056689833.1 (SEQ ID NO: 470), XM_056690060.1 (SEQ ID NO: 471), XM_056693344.1 (SEQ ID NO: 472), XM_056693452.1 (SEQ ID NO: 473), XM_056698320.1 (SEQ ID NO: 474), XM_056699554.1 (SEQ ID NO: 475), XM_056708810.1 (SEQ ID NO: 476), XM_056718649.1 (SEQ ID NO: 477), XM-056723511.1 (SEQ ID NO: 478), XM_056167322.1 (SEQ ID NO: 479), XM_056167584.1 (SEQ ID NO: 480), XM_056172822.1 (SEQ ID NO: 481), XM_056174333.1 (SEQ ID NO: 482), XM 056175477.1 (SEQ ID NO: 483), XM 056176559.1 (SEQ ID NO: 484), XM 056177722.1 (SEQ ID NO: 485), XM_056181318.1 (SEQ ID NO: 486), XM_056181325.1 (SEQ ID NO: 487), XM_056210974.1 (SEQ ID NO: 488), XM_056212424.1 (SEQ ID NO: 489), OQ869645.1 (SEQ ID NO: 490), OQ189712.1 (SEQ ID NO: 491), OP087311.1 (SEQ ID NO: 492), OP087312.1 (SEQ ID NO: 493), OP087313.1 (SEQ ID NO: 494), XM_002492030.1 (SEQ ID NO: 495), ON724034.1 (SEQ ID NO: 496), XM_053082365.1 (SEQ ID NO: 497), XM_053097871.1 (SEQ ID NO: 498), XM_053098804.1 (SEQ ID NO: 499), XM_053147659.1 (SEQ ID NO: 500), XM_053147705.1 (SEQ ID NO: 501), XM_053151294.1 (SEQ ID NO: 502), XM_053151602.1 (SEQ ID NO: 503), XM_053154568.1 (SEQ ID NO: 504), XM_053157350.1 (SEQ ID NO: 505),50323665488vlAttorney Docket No. 243735.000480XM_053158430.1 (SEQ ID NO: 506), XM_053159615.1 (SEQ ID NO: 507), XM_053181722.1 (SEQ IDNO: 508), XM_053184859.1 (SEQ ID NO: 509), XM_053052044.1 (SEQ ID NO: 510), XM 053052091.1 (SEQ ID NO: 511), XM 053056081.1 (SEQ ID NO: 512), XM 053056401.1 (SEQ IDNO: 513), XM_053059157.1 (SEQ ID NO: 514), XM_053061683.1 (SEQ IDNO: 515), XM_053062744.1 (SEQ ID NO: 516), XM_053063903.1 (SEQ ID NO: 517), XM_053072546.1 (SEQ IDNO: 518), XM_053089100.1 (SEQ ID NO: 519), XM_053132214.1 (SEQ IDNO: 520), XM_053135366.1 (SEQ ID NO: 521), XM_053135615.1 (SEQ ID NO: 522), XM_053141439.1 (SEQ IDNO: 523), XM_053143427.1 (SEQ IDNO: 524), XM_051734500.1 (SEQ IDNO: 525), XM_051433974.1 (SEQ ID NO: 526), XM_051445523.1 (SEQ ID NO: 527), XM_051456304.1 (SEQ IDNO: 528), XM_051463414.1 (SEQ IDNO: 529), XM_051463964.1 (SEQ IDNO: 530), XM_051464062.1 (SEQ ID NO: 531), XM_051474421.1 (SEQ ID NO: 532), XM_051498179.1 (SEQ IDNO: 533), XM_051505155.1 (SEQ ID NO: 534), XM_051520978.1 (SEQ IDNO: 535), XM_051527155.1 (SEQ ID NO: 536), XM_051531649.1 (SEQ ID NO: 537), XM_051538501.1 (SEQ IDNO: 538), XM_051538869.1 (SEQ ID NO: 539), XM_051541208.1 (SEQ IDNO: 540), XM_051545402.1 (SEQ ID NO: 541), XM_051553859.1 (SEQ ID NO: 542), XM_051554566.1 (SEQ IDNO: 543), XM_051558937.1 (SEQ IDNO: 544), XM_051565446.1 (SEQ IDNO: 545), XM_051574923.1 (SEQ ID NO: 546), XM_051579600.1 (SEQ ID NO: 547), XM_051604689.1 (SEQ ID NO: 548), XM_051607502.1 (SEQ ID NO: 549), XM_658430.2 (SEQ ID NO: 550), XM_676814.2 (SEQ ID NO: 551), XM_677516.2 (SEQ ID NO: 552), XM_050111155.1 (SEQ ID NO: 553), XM_050117994.1 (SEQ ID NO: 554), XM_049257797.1 (SEQ ID NO: 555), XM_049259915.1 (SEQ ID NO: 556), XM_049265078.1 (SEQ ID NO: 557), XM_049282334.1 (SEQ ID NO: 558), XM 049283132.1 (SEQ ID NO: 559), XM 049283530.1 (SEQ ID NO: 560), XM_049292238.1 (SEQ ID NO: 561), XM_049295969.1 (SEQ ID NO: 562), XM_049241160.1 (SEQ ID NO: 563), XM_049242478.1 (SEQ ID NO: 564), XM_049242794.1 (SEQ ID NO: 565), XM_049244899.1 (SEQ ID NO: 566), XM_049249642.1 (SEQ ID NO: 567), XM_049250482.1 (SEQ ID NO: 568), XM_049250792.1 (SEQ ID NO: 569), XM_049297448.1 (SEQ ID NO: 570), XM_049303451.1 (SEQ ID NO: 571), XM_049303567.1 (SEQ ID NO: 572), XM_049304045.1 (SEQ ID NO: 573), XM_049307355.1 (SEQ ID NO: 574), XM_049334470.1 (SEQ ID NO: 575), XM_049346431.1 (SEQ ID NO: 576), XM_049357941.1 (SEQ ID NO: 577), XM_049373830.1 (SEQ IDNO: 578), XM_049391513.1 (SEQ ID NO: 579), XM_049398063.1 (SEQ IDNO: 580),51323665488vlAttorney Docket No. 243735.000480MH430562.1 (SEQ ID NO: 581), MH430568.1 (SEQ ID NO: 582), XM_047924808.1 (SEQ ID NO: 583), XM_047928346.1 (SEQ ID NO: 584), XM_047929234.1 (SEQ ID NO: 585), XM 047931139.1 (SEQ ID NO: 586), XM 047931424.1 (SEQ ID NO: 587), XM 047936096.1 (SEQ ID NO: 588), XM_047938941.1 (SEQ ID NO: 589), XM_047959078.1 (SEQ ID NO: 590), XM_047968306.1 (SEQ ID NO: 591), XM_047979311.1 (SEQ ID NO: 592), XM_047979316.1 (SEQ ID NO: 593), XM_047980897.1 (SEQ ID NO: 594), XM_047981771.1 (SEQ ID NO: 595), XM_047981772.1 (SEQ ID NO: 596), XM_047981931.1 (SEQ ID NO: 597), XM_047991433.1 (SEQ ID NO: 598), XM_047992718.1 (SEQ ID NO: 599), XM_047994394.1 (SEQ ID NO: 600), XM_047994978.1 (SEQ ID NO: 601), XM_047996387.1 (SEQ ID NO: 602), XM_048002857.1 (SEQ ID NO: 603), XM_048004317.1 (SEQ ID NO: 604), XM_048009929.1 (SEQ ID NO: 605), XM_048012052.1 (SEQ ID NO: 606), XM_048012441.1 (SEQ ID NO: 607), XM_048014055.1 (SEQ ID NO: 608), XM_048018947.1 (SEQ ID NO: 609), XM_048026223.1 (SEQ ID NO: 610), XM_048026657.1 (SEQ ID NO: 611), XM_048032216.1 (SEQ ID NO: 612), XM_048040865.1 (SEQ ID NO: 613), XM_048043714.1 (SEQ ID NO: 614), XM_001239135.2 (SEQ ID NO: 615), XM_001244894.2 (SEQ ID NO: 616), XM_045422485.1 (SEQ ID NO: 617), XM_045422486.1 (SEQ ID NO: 618), XM_045423088.1 (SEQ ID NO: 619), XM_045425203.1 (SEQ ID NO: 620), XM_045425204.1 (SEQ ID NO: 621), XM_045425205.1 (SEQ ID NO: 622), XM_045429890.1 (SEQ ID NO: 623), XM_045434185.1 (SEQ ID NO: 624), XM_045435448.1 (SEQ ID NO: 625), OK469300.1 (SEQ ID NO: 626), XM_003193207.1 (SEQ ID NO: 627), XM_003193223.1 (SEQ ID NO: 628), XM_003196461.1 (SEQ ID NO: 629), XM_003239223.2 (SEQ ID NO: 630), XM_008034773.1 (SEQ ID NO: 631), XM_008043278.1 (SEQ ID NO: 632), XM_010757480.1 (SEQ ID NO: 633), XM 010762053.1 (SEQ ID NO: 634), XM 011391773.1 (SEQ ID NO: 635), XM_023606481.1 (SEQ ID NO: 636), XM_023608888.1 (SEQ ID NO: 637), XM_023613890.1 (SEQ ID NO: 638), XM_040889366.1 (SEQ ID NO: 639), XM_040891481.1 (SEQ ID NO: 640), XM_047749259.1 (SEQ ID NO: 641), XM_713725.2 (SEQ ID NO: 642), XM_742595.1 (SEQ ID NO: 643), XM_743457.1 (SEQ ID NO: 644), XM_744063.1 (SEQ ID NO: 645), XM_751047.1 (SEQ ID NO: 646), XM_046176544.1 (SEQ ID NO: 647), XM_046178571.1 (SEQ ID NO: 648), XM_046225200.1 (SEQ ID NO: 649), XM_046241678.1 (SEQ ID NO: 650), XM_046241770.1 (SEQ ID NO: 651), XM_046252827.1 (SEQ ID NO: 652), XM_046212681.1 (SEQ ID NO: 653), XM_046215502.1 (SEQ ID NO: 654), XM_046216811.1 (SEQ ID NO: 655),52323665488vlAttorney Docket No. 243735.000480XM_046219439.1 (SEQ ID NO: 656), XM_046220306.1 (SEQ ID NO: 657), XM_046221030.1 (SEQ IDNO: 658), XM_018297125.1 (SEQ ID NO: 659), XM_018297410.1 (SEQ ID NO: 660), XM 018298034.1 (SEQ ID NO: 661), XM 018298345.1 (SEQ ID NO: 662), XM 018300484.1 (SEQ ID NO: 663), XM_018300485.1 (SEQ ID NO: 664), XM_018300487.1 (SEQ IDNO: 665), XM_018300488.1 (SEQ ID NO: 666), XM_018301788.1 (SEQ ID NO: 667), XM_018308838.1 (SEQ ID NO: 668), XM_035472870.1 (SEQ ID NO: 669), XM_035474598.1 (SEQ ID NO: 670), XM_035475379.1 (SEQ ID NO: 671), XM_035475946.1 (SEQ ID NO: 672), XM_035476846.1 (SEQ ID NO: 673), XM_035482674.1 (SEQ ID NO: 674), XM_036633128.1 (SEQ ID NO: 675), XM_036646719.1 (SEQ ID NO: 676), XM_037316542.1 (SEQ ID NO: 677), XM_037329238.1 (SEQ ID NO: 678), XM_045406143.1 (SEQ ID NO: 679), XM_045407197.1 (SEQ ID NO: 680), XM_008090712.1 (SEQ ID NO: 681), XM_008091197.1 (SEQ ID NO: 682), XM_008091580.1 (SEQ ID NO: 683), XM_008092892.1 (SEQ ID NO: 684), XM_008096363.1 (SEQ IDNO: 685), XM_008098680.1 (SEQ ID NO: 686), XM_022617662.1 (SEQ ID NO: 687), XM_022618005.1 (SEQ ID NO: 688), XM_022620717.1 (SEQ ID NO: 689), XM_022623399.1 (SEQ IDNO: 690), XM_022625435.1 (SEQ ID NO: 691), XM_036721525.1 (SEQ ID NO: 692), XM_036722019.1 (SEQ ID NO: 693), XM_036724564.1 (SEQ ID NO: 694), XM_036726936.1 (SEQ ID NO: 695), XM_036730062.1 (SEQ ID NO: 696), XM_036730889.1 (SEQ ID NO: 697), XM_036732544.1 (SEQ ID NO: 698), XM_036733819.1 (SEQ ID NO: 699), XM_038885082.1 (SEQ ID NO: 700), XM_038887719.1 (SEQ ID NO: 701), XM_038889893.1 (SEQ ID NO: 702), XM_038892518.1 (SEQ ID NO: 703), MW618003.1 (SEQ ID NO: 704), MW618004.1 (SEQ ID NO: 705), MW618005.1 (SEQ ID NO: 706), MW618006.1 (SEQ IDNO: 707), XM_046081701.1 (SEQ ID NO: 708), XM 046083968.1 (SEQ ID NO: 709), XM 046089673.1 (SEQ ID NO: 710), XM_046090776.1 (SEQ ID NO: 711), XM_046097926.1 (SEQ ID NO: 712), XM_046102681.1 (SEQ IDNO: 713), XM_046108319.1 (SEQ IDNO: 714), XM_046124008.1 (SEQ IDNO: 715), XM_046130787.1 (SEQ ID NO: 716), XM_046135074.1 (SEQ ID NO: 717), XM_046149211.1 (SEQ IDNO: 718), XM_046151549.1 (SEQ ID NO: 719), XM_046164795.1 (SEQ IDNO: 720), XM_046166564.1 (SEQ ID NO: 721), XM_046173339.1 (SEQ ID NO: 722), XM_046174837.1 (SEQ IDNO: 723), XM_046191691.1 (SEQ ID NO: 724), XM_046192582.1 (SEQ IDNO: 725), XM 046196391.1 (SEQ IDNO: 726), XM_046257822.1 (SEQ ID NO: 727), LC597468.1 (SEQ ID NO: 728), LC597473.1 (SEQ ID NO: 729), XM_018208348.1 (SEQ ID NO: 730),53323665488vlAttorney Docket No. 243735.000480XM_018209017.1 (SEQ ID NO: 731), XM_018209756.1 (SEQ ID NO: 732), XM_018210848.1 (SEQ IDNO: 733), XM_018211318.1 (SEQ ID NO: 734), XM_018217858.1 (SEQ ID NO: 735), XM 018220571.1 (SEQ ID NO: 736), MZ851807.1 (SEQ ID NO: 737), MZ851808.1 (SEQ ID NO: 738), MZ851809.1 (SEQ ID NO: 739), MZ851810.1 (SEQ IDNO: 740), MZ851811.1 (SEQ ID NO: 741), MZ851812.1 (SEQ ID NO: 742), MZ851813.1 (SEQ ID NO: 743), MZ851814.1 (SEQ ID NO: 744), MZ851815.1 (SEQ ID NO: 745), MZ851816.1 (SEQ ID NO: 746), MZ851817.1 (SEQ ID NO: 747), MZ851818.1 (SEQ ID NO: 748), MZ851819.1 (SEQ ID NO: 749), MZ851820.1 (SEQ ID NO: 750), MZ851821.1 (SEQ ID NO: 751), MZ851822.1 (SEQ ID NO: 752), MZ851823.1 (SEQ ID NO: 753), MZ851824.1 (SEQ IDNO: 754), MZ851825.1 (SEQ ID NO: 755), MZ851826.1 (SEQ ID NO: 756), MZ851827.1 (SEQ ID NO: 757), MZ851828.1 (SEQ ID NO: 758), MZ851829.1 (SEQ ID NO: 759), MZ851830.1 (SEQ ID NO: 760), MZ851831.1 (SEQ ID NO: 761), MZ851832.1 (SEQ ID NO: 762), MZ851833.1 (SEQ ID NO: 763), MZ851834.1 (SEQ ID NO: 764), MZ851835.1 (SEQ ID NO: 765), MZ851836.1 (SEQ ID NO: 766), MZ851837.1 (SEQ ID NO: 767), MZ851838.1 (SEQ IDNO: 768), MZ851839.1 (SEQ ID NO: 769), MZ851840.1 (SEQ ID NO: 770), MZ851841.1 (SEQ ID NO: 771), MZ851842.1 (SEQ ID NO: 772), MZ851843.1 (SEQ ID NO: 773), MZ851844.1 (SEQ ID NO: 774), MZ851845.1 (SEQ ID NO: 775), MZ851846.1 (SEQ ID NO: 776), MZ851847.1 (SEQ ID NO: 777), MZ851848.1 (SEQ ID NO: 778), MZ851849.1 (SEQ ID NO: 779), MZ851850.1 (SEQ ID NO: 780), MZ851851.1 (SEQ ID NO: 781), MZ851852.1 (SEQ IDNO: 782), MZ851853.1 (SEQ ID NO: 783), MZ851854.1 (SEQ ID NO: 784), MZ851855.1 (SEQ ID NO: 785), MZ851856.1 (SEQ IDNO: 786), XM_044819923.1 (SEQ IDNO: 787), XM_044854652.1 (SEQ IDNO: 788), XM 044854873.1 (SEQ ID NO: 789), XM 044863931.1 (SEQ ID NO: 790), XM 044864061.1 (SEQ IDNO: 791), XM_043183825.1 (SEQ ID NO: 792), XM_043185888.1 (SEQ IDNO: 793), XM_043188800.1 (SEQ ID NO: 794), XM_043195800.1 (SEQ ID NO: 795), XM_041282182.1 (SEQ IDNO: 796), XM_041555812.1 (SEQ ID NO: 797), XM_041556872.1 (SEQ IDNO: 798), XM_041686205.1 (SEQ ID NO: 799), XM_041689126.1 (SEQ ID NO: 800), XM_041706340.1 (SEQ ID NO: 801), XM_043276556.1 (SEQ ID NO: 802), XM_043277777.1 (SEQ ID NO: 803), XM_043278817.1 (SEQ ID NO: 804), XM_043284998.1 (SEQ ID NO: 805), XM_041550965.1 (SEQ IDNO: 806), XM_043325815.1 (SEQ IDNO: 807), XM_040771202.1 (SEQ IDNO: 808), XM_040773386.1 (SEQ ID NO: 809), XM_041019338.1 (SEQ ID NO: 810), XM_041019543.154323665488vlAttorney Docket No. 243735.000480(SEQ IDNO: 811), XM_041021327.1 (SEQ ID NO: 812), XM_041023992.1 (SEQ IDNO: 813), XM_041025145.1 (SEQ ID NO: 814), XM_041028588.1 (SEQ ID NO: 815), XM_040759950.1 (SEQ IDNO: 816), XM 040760746.1 (SEQ ID NO: 817), XM 040761357.1 (SEQ IDNO: 818), XM_040763216.1 (SEQ ID NO: 819), XM_040779645.1 (SEQ ID NO: 820), XM_040779842.1 (SEQ ID NO: 821), XM_040780067.1 (SEQ ID NO: 822), XM_040780366.1 (SEQ ID NO: 823), XM_040783290.1 (SEQ ID NO: 824), XM_040785167.1 (SEQ ID NO: 825), XM_040785356.1 (SEQ IDNO: 826), XM_040785442.1 (SEQ ID NO: 827), XM_040785510.1 (SEQ IDNO: 828), XM_040788621.1 (SEQ ID NO: 829), XM_040790245.1 (SEQ ID NO: 830), XM_040791165.1 (SEQ IDNO: 831), XM_040792213.1 (SEQ ID NO: 832), XM_040795663.1 (SEQ ID NO: 833), XM_040798491.1 (SEQ ID NO: 834), XM_040821100.1 (SEQ ID NO: 835), XM_040822581.1 (SEQ ID NO: 836), XM_040825240.1 (SEQ ID NO: 837), XM_040826868.1 (SEQ ID NO: 838), XM_040857166.1 (SEQ ID NO: 839), XM_040905712.1 (SEQ ID NO: 840), XM_040910862.1 (SEQ IDNO: 841), XM_040911204.1 (SEQ IDNO: 842), XM_040919529.1 (SEQ IDNO: 843), XM_040927945.1 (SEQ ID NO: 844), XM_040935698.1 (SEQ ID NO: 845), XM_040941200.1 (SEQ IDNO: 846), XM_040941746.1 (SEQ ID NO: 847), XM_040942118.1 (SEQ IDNO: 848), XM_040942926.1 (SEQ ID NO: 849), XM_040946671.1 (SEQ ID NO: 850), XM_025594847.1 (SEQ ID NO: 851), XM_025597269.1 (SEQ ID NO: 852), XM_025599234.1 (SEQ ID NO: 853), XM_032086623.1 (SEQ ID NO: 854), XM_032087452.1 (SEQ ID NO: 855), XM_038921351.1 (SEQ IDNO: 856), XM_038929279.1 (SEQ ID NO: 857), XM_038929575.1 (SEQ IDNO: 858), XM_038933583.1 (SEQ ID NO: 859), XM_038933695.1 (SEQ ID NO: 860), XM_038934092.1 (SEQ IDNO: 861), XM_038936055.1 (SEQ IDNO: 862), XM_039066780.1 (SEQ IDNO: 863), LC602265.1 (SEQ ID NO: 864), MN933614.1 (SEQ ID NO: 865), XM 037336789.1 (SEQ ID NO: 866), XM_037337444.1 (SEQ ID NO: 867), XM_037337803.1 (SEQ ID NO: 868), XM_037338683.1 (SEQ ID NO: 869), XM_037339130.1 (SEQ ID NO: 870), XM_037340227.1 (SEQ IDNO: 871), XM_037340353.1 (SEQ ID NO: 872), XM_037341484.1 (SEQ IDNO: 873), XM_037342212.1 (SEQ ID NO: 874), XM_037343562.1 (SEQ ID NO: 875), XM_037344870.1 (SEQ IDNO: 876), XM_037350038.1 (SEQ IDNO: 877), XM_037352611.1 (SEQ IDNO: 878), XM_037355222.1 (SEQ ID NO: 879), XM_037356334.1 (SEQ ID NO: 880), XM_037360309.1 (SEQ ID NO: 881), MT056136.1 (SEQ ID NO: 882), MT056137.1 (SEQ ID NO: 883), MT056138.1 (SEQ ID NO: 884), MT056139.1 (SEQ ID NO: 885), MT056140.1 (SEQ ID NO:55323665488vlAttorney Docket No. 243735.000480886), MT056141.1 (SEQ ID NO: 887), MT056142.1 (SEQ ID NO: 888), MT056143.1 (SEQ ID NO: 889), MT056144.1 (SEQ ID NO: 890), MT056145.1 (SEQ ID NO: 891), MT056146.1 (SEQ ID NO: 892), MT056147.1 (SEQ ID NO: 893), MT056148.1 (SEQ ID NO: 894), MT056149.1 (SEQ ID NO: 895), MT056150.1 (SEQ ID NO: 896), MT056151.1 (SEQ ID NO: 897), MN661342.1 (SEQ ID NO: 898), AB069960.1 (SEQ ID NO: 899), XM_001257594.1 (SEQ ID NO: 900), XM_001258884.1 (SEQ ID NO: 901), XM_001265571.1 (SEQ ID NO: 902), MT635034.1 (SEQ ID NO: 903), MN460419.1 (SEQ ID NO: 904), MN460420.1 (SEQ ID NO: 905), MN460421.1 (SEQ ID NO: 906), MN460422.1 (SEQ ID NO: 907), MN460423.1 (SEQ ID NO: 908), MN460424.1 (SEQ ID NO: 909), MN460425.1 (SEQ ID NO: 910), MN460426.1 (SEQ ID NO: 911), MN460427.1 (SEQ ID NO: 912), MN460428.1 (SEQ ID NO: 913), MN460429.1 (SEQ ID NO: 914), MN460430.1 (SEQ ID NO: 915), MN460431.1 (SEQ ID NO: 916), MN460432.1 (SEQ ID NO: 917), MN460433.1 (SEQ ID NO: 918), MN460434.1 (SEQ ID NO: 919), MN460435.1 (SEQ ID NO: 920), MN460436.1 (SEQ ID NO: 921), MN460437.1 (SEQ ID NO: 922), MN460438.1 (SEQ ID NO: 923), MN460439.1 (SEQ ID NO: 924), MN460440.1 (SEQ ID NO: 925), MN460441.1 (SEQ ID NO: 926), MN460442.1 (SEQ ID NO: 927), MN460443.1 (SEQ ID NO: 928), MN460444.1 (SEQ ID NO: 929), MN460445.1 (SEQ ID NO: 930), MN460446.1 (SEQ ID NO: 931), MN460447.1 (SEQ ID NO: 932), MN460448.1 (SEQ ID NO: 933), MN460449.1 (SEQ ID NO: 934), MN460450.1 (SEQ ID NO: 935), MN460451.1 (SEQ ID NO: 936), MN460452.1 (SEQ ID NO: 937), MN460453.1 (SEQ ID NO: 938), MN460454.1 (SEQ ID NO: 939), MN460455.1 (SEQ ID NO: 940), MN460456.1 (SEQ ID NO: 941), MN460457.1 (SEQ ID NO: 942), MN460458.1 (SEQ ID NO: 943), MN460459.1 (SEQ ID NO: 944), MN460460.1 (SEQ ID NO: 945), MN460461.1 (SEQ ID NO: 946), MN460462.1 (SEQ ID NO: 947), MN460463.1 (SEQ ID NO: 948), MN460464.1 (SEQ ID NO: 949), MN460465.1 (SEQ ID NO: 950), XM_031199740.1 (SEQ ID NO: 951), XM_031204009.1 (SEQ ID NO: 952), XM_031209820.1 (SEQ ID NO: 953), XM_031213175.1 (SEQ ID NO: 954), XM_031215845.1 (SEQ ID NO: 955), XM_031217158.1 (SEQ ID NO: 956), XM_035464248.1 (SEQ ID NO: 957), XM_035464826.1 (SEQ ID NO: 958), XM_035468729.1 (SEQ ID NO: 959), XM_035496273.1 (SEQ ID NO: 960), XM_035496337.1 (SEQ ID NO: 961), XM_035500210.1 (SEQ ID NO: 962), XM_035500235.1 (SEQ ID NO: 963), XM_035500244.1 (SEQ ID NO: 964), XM_035500263.1 (SEQ ID NO: 965), XM_035501231.1 (SEQ ID NO: 966), XM_035503507.1 (SEQ ID NO: 967),56323665488vlAttorney Docket No. 243735.000480XM_035505546.1 (SEQ ID NO: 968), XM_035506265.1 (SEQ ID NO: 969), XM_035513403.1 (SEQ IDNO: 970), XM_035515438.1 (SEQ ID NO: 971), XM_035516800.1 (SEQ ID NO: 972), XM 035519430.1 (SEQ ID NO: 973), XM 035519476.1 (SEQ ID NO: 974), XM 035519477.1 (SEQ ID NO: 975), MN654901.1 (SEQ ID NO: 976), MN581927.1 (SEQ ID NO: 977), MN581932.1 (SEQ ID NO: 978), MN581936.1 (SEQ ID NO: 979), XM_032057570.1 (SEQ ID NO: 980), XM_032076616.1 (SEQ ID NO: 981), XM_033798495.1 (SEQ ID NO: 982), XM_033799378.1 (SEQ ID NO: 983), XM 033800381.1 (SEQ ID NO: 984), XM_033819776.1 (SEQ IDNO: 985), XM_033823514.1 (SEQ IDNO: 986), XM_033834237.1 (SEQ IDNO: 987), XM_033547592.1 (SEQ ID NO: 988), XM_033549145.1 (SEQ ID NO: 989), XM_033552187.1 (SEQ ID NO: 990), XM_033663053.1 (SEQ ID NO: 991), XM_033664760.1 (SEQ ID NO: 992), XM_033666376.1 (SEQ ID NO: 993), XM_033671581.1 (SEQ ID NO: 994), XM_033671591.1 (SEQ ID NO: 995), XM_033671955.1 (SEQ ID NO: 996), XM_033674714.1 (SEQ IDNO: 997), XM_033679938.1 (SEQ ID NO: 998), XM_033680529.1 (SEQ ID NO: 999), XM_033681578.1 (SEQ ID NO: 1000), XM_033690235.1 (SEQ ID NO: 1001), XM_033692984.1 (SEQ ID NO: 1002), XM_0336 371.1 (SEQ ID NO: 1C 1), XM_033703948 1 (SEQ ID NO: 1004), XM_033704238.1 (SEQ ID NO: 1005), XM_033708094.1 (SEQ ID NO: 1006), XM_033708192.1 (SEQ ID NO: 1007), XM_033708995.1 (SEQ ID NO: 1008), XM_033714995.1 (SEQ ID NO: 1009), XM_033717945.1 (SEQ ID NO: 1010), XM_033720045.1 (SEQ ID NO: 1011), XM_033720376.1 (SEQ ID NO: 1012), XM_033727513.1 (SEQ ID NO: 1013), XM_033745404.1 (SEQ ID NO: 1014), XM_033746798.1 (SEQ ID NO: 1015), XM_033523183.1 (SEQ ID NO: 1016), XM 033527840.1 (SEQ ID NO: 1017), XM 033556963.1 (SEQ ID NO: 1018), XM_033558706.1 (SEQ ID NO: 1019), XM_033562860.1 (SEQ ID NO: 1020), XM_033563806.1 (SEQ ID NO: 1021), XM_033578157.1 (SEQ ID NO: 1022), XM_033579175.1 (SEQ ID NO: 1023), XM_O33580068.1 (SEQ ID NO: 1024), XM 033583961.1 (SEQ ID NO: 1025), XM_033585407.1 (SEQ ID NO: 1026), XM_033590620.1 (SEQ ID NO: 1027), XM_033590683.1 (SEQ ID NO: 1028), XM_033591474.1 (SEQ ID NO: 1029), XM_033591515.1 (SEQ ID NO: 1030), XM_033593431.1 (SEQ ID NO: 1031), XM_033596409.1 (SEQ ID NO: 1032), XM_033598281.1 (SEQ ID NO: 1033), XM_033604102.1 (SEQ ID NO: 1034),323665488vlAttorney Docket No. 243735.000480XM_033606817.1 (SEQ ID NO: 1035), LC510309.1 (SEQ ID NO: 1036), XM_015609280.1 (SEQ ID NO: 1037), XM_015546647.1 (SEQ ID NO: 1038), XM_015547417.1 (SEQ ID NO: 1039), XM 015550591.1 (SEQ ID NO: 1040), XM 015552970.1 (SEQ ID NO: 1041), XM_015554841.1 (SEQ ID NO: 1042), MK416184.1 (SEQ ID NO: 1043), XM_025499953.1 (SEQ ID NO: 1044), XM_025500165.1 (SEQ ID NO: 1045), XM_025501926.1 (SEQ ID NO: 1046), XM_024877129.1 (SEQ ID NO: 1047), XM_024878390.1 (SEQ ID NO: 1048), XM_024885643.1 (SEQ ID NO: 1049), XM_024887688.1 (SEQ ID NO: 1050), XM_024888361.1 (SEQ ID NO 1051), XM_006961568.1 (SEQ ID NO: 1052), XM_006962827.1 (SEQ ID NO 1053), XM 006963711.1 (SEQ ID NO: 1054), XM_006964395.1 (SEQ ID NO 1055), XM_006968252.1 (SEQ ID NO: 1056), XM_006969678.1 (SEQ ID NO 1057), XM_016902853.1 (SEQ ID NO: 1058), XM_016905085.1 (SEQ ID NO 1059), XM 016905446.1 (SEQ ID NO: 1060), XM_016907254.1 (SEQ ID NO 1061), XM 016910320.2 (SEQ ID NO: 1062), XM_018357762.1 (SEQ ID NO 1063), XM 019168275.1 (SEQ ID NO: 1064), XM_019169122.1 (SEQ ID NO 1065), XM 019169405.1 (SEQ ID NO: 1066), XM_007261640.1 (SEQ ID NO 1067), XM 007363618.1 (SEQ ID NO: 1068), XM_007370471.1 (SEQ ID NO 1069), XM 024823054.1 (SEQ ID NO: 1070), XM_024827070.1 (SEQ ID NO 1071), XM 024828460.1 (SEQ ID NO: 1072), XM 024837681.1 (SEQ ID NO 1073), XM 024846739.1 (SEQ ID NO: 1074), XM_024853688.1 (SEQ ID NO 1075), XM 025539344.1 (SEQ ID NO: 1076), XM_025543032.1 (SEQ ID NO 1077), XM 025545489.1 (SEQ ID NO: 1078), XM 025547456.1 (SEQ ID NO 1079), XM 009655189.1 (SEQ ID NO: 1080), XM_009655417.1 (SEQ ID NO 1081), XM 009656944.1 (SEQ ID NO: 1082), XM_032012709.1 (SEQ ID NO: 1083), XM_032015530.1 (SEQ ID NO: 1084), MN194197.1 (SEQ ID NO: 1085), MK069671.1 (SEQ ID NO: 1086), XM_003654947.1 (SEQ ID NO: 1087), XM_020210252.1 (SEQ ID NO: 1088), XM_002620835.2 (SEQ ID NO: 1089), XM_002622550.2 (SEQ ID NO: 1090), XM_002843817.1 (SEQ ID NO: 1091), XM_002846136.1 (SEQ ID NO: 1092), XM_002847563.1 (SEQ ID NO: 1093), XM_002849171.1 (SEQ ID NO: 1094), XM_003662984.1 (SEQ ID NO: 1095), XM_031722078.1 (SEQ ID NO: 1096), XM_031722079.1 (SEQ ID NO: 1097),58323665488vlAttorney Docket No. 243735.000480XM_031722080.1 (SEQ ID NO: 1098), XM_031723676.1 (SEQ ID NO: 1099), XM_031723677.1 (SEQ ID NO: 1100), XM_031725345.1 (SEQ ID NO: 1101), XM 031725346.1 (SEQ ID NO: 1102), MK728826.1 (SEQ ID NO: 1103), MK728827.1 (SEQ ID NO: 1104), MK728828.1 (SEQ ID NO: 1105), MK457239.1 (SEQ ID NO: 1106), MK457240.1 (SEQ ID NO: 1107), MK457241.1 (SEQ ID NO: 1108), MK457243.1 (SEQ ID NO: 1109), MK457244.1 (SEQ ID NO: 1110), MK457245.1 (SEQ ID NO: 1111), MK457246.1 (SEQ ID NO: 1112), MK457247.1 (SEQ ID NO: 1113), MK457248.1 (SEQ ID NO: 1114), MK457249.1 (SEQ ID NO: 1115), MK457250.1 (SEQ ID NO: 1116),MK457254.1 (SEQ ID NO: 1117), MK457255.1 (SEQ ID NO: 1118), MK457256.1 (SEQ ID NO: 1119), MK457257.1 (SEQ ID NO: 1120), MK457258.1 (SEQ ID NO: 1121), MK457259.1 (SEQ ID NO: 1122), MK457260.1 (SEQ ID NO: 1123), MK457261.1 (SEQ ID NO: 1124), MK457262.1 (SEQ ID NO: 1125), MK457263.1 (SEQ ID NO: 1126), MK457264.1 (SEQ ID NO: 1127), MK457265.1 (SEQ ID NO: 1128), MK457267.1 (SEQ ID NO: 1129), MK457268.1 (SEQ ID NO: 1130), MK457269.1 (SEQ ID NO: 1131), MK457278.1 (SEQ ID NO: 1132), MK457279.1 (SEQ ID NO: 1133), MK457280.1 (SEQ ID NO: 1134), MK457281.1 (SEQ ID NO: 1135), MK457282.1 (SEQ ID NO: 1136), MK457283.1 (SEQ ID NO: 1137), MK457284.1 (SEQ ID NO: 1138), MK457285.1 (SEQ ID NO: 1139), MK457286.1 (SEQ ID NO: 1140), MK457287.1 (SEQ ID NO: 1141), MK457291.1 (SEQ ID NO: 1142), MK457297.1 (SEQ ID NO: 1143), MK457298.1 (SEQ ID NO: 1144), MK457299.1 (SEQ ID NO: 1145), MK457300.1 (SEQ ID NO: 1146), MK457301.1 (SEQ ID NO: 1147), MK457303.1 (SEQ ID NO: 1148), MK457306.1 (SEQ ID NO: 1149), MK457307.1 (SEQ ID NO: 1150), MK457308.1 (SEQ ID NO: 1151), MK457309.1 (SEQ ID NO: 1152), MK457310.1 (SEQ ID NO: 1153), MK457311.1 (SEQ ID NO: 1154), MK457312.1 (SEQ ID NO: 1155), MK457317.1 (SEQ ID NO: 1156), MK457327.1 (SEQ ID NO: 1157), MK457328.1 (SEQ ID NO: 1158), MK457329.1 (SEQ ID NO: 1159), MK457330.1 (SEQ ID NO: 1160), MK457344.1 (SEQ ID NO: 1161), LR726118.1 (SEQ ID NO: 1162), LR726122.1 (SEQ ID NO: 1163), LR728875.1 (SEQ ID NO: 1164), MK704506.1 (SEQ ID NO: 1165), MK723905.1 (SEQ ID NO: 1166), MK723906.1 (SEQ ID NO: 1167), MK723907.1 (SEQ ID NO: 1168), MK723908.1 (SEQ ID NO: 1169), XM_031149641.1 (SEQ ID NO: 1170), XM_031150492.1 (SEQ ID NO: 1171), LY588984.1 (SEQ ID NO: 1172), LY588985.1 (SEQ ID NO: 1173), LY588986.1 (SEQ ID NO: 1174), LY589002.1 (TGTTATCAT), LY589015.159323665488vlAttorney Docket No. 243735.000480(TTGTTT), LY589025.1 (SEQ ID NO: 1175), LY589071.1 (SEQ ID NO: 1176), MK368958.1 (SEQ ID NO: 1177), MK368959.1 (SEQ ID NO: 1178), MK368960.1 (SEQ ID NO: 1179), MK368961.1 (SEQ ID NO: 1180), MK368962.1 (SEQ ID NO: 1181), MK368963.1 (SEQ ID NO: 1182), MK368964.1 (SEQ ID NO: 1183), MK368965.1 (SEQ ID NO: 1184), MK368966.1 (SEQ ID NO: 1185), MK368967.1 (SEQ ID NO: 1186), MK368968.1 (SEQ ID NO: 1187), MK368969.1 (SEQ ID NO: 1188), MK368970.1 (SEQ ID NO: 1189), MK368971.1 (SEQ ID NO: 1190), MK368972.1 (SEQ ID NO: 1191), MK368973.1 (SEQ ID NO: 1192), MK368974.1 (SEQ ID NO: 1193), MK368975.1 (SEQ ID NO: 1194), MK368976.1 (SEQ ID NO: 1195), MK368977.1 (SEQ ID NO: 1196), MK368978.1 (SEQ ID NO: 1197), MK368979.1 (SEQ ID NO: 1198), MK368980.1 (SEQ ID NO: 1199), MK368981.1 (SEQ ID NO: 1200), MK368982.1 (SEQ ID NO: 1201), MK368983.1 (SEQ ID NO: 1202), MK368984.1 (SEQ ID NO: 1203), MK368985.1 (SEQ ID NO: 1204), MK368986.1 (SEQ ID NO: 1205), MK368987.1 (SEQ ID NO: 1206), MK368988.1 (SEQ ID NO: 1207), MK368989.1 (SEQ ID NO: 1208), MK368990.1 (SEQ ID NO: 1209), MK368991.1 (SEQ ID NO: 1210), MK368992.1 (SEQ ID NO: 1211), MK368993.1 (SEQ ID NO: 1212), MK368994.1 (SEQ ID NO: 1213), MK368995.1 (SEQ ID NO: 1214), MK368996.1 (SEQ ID NO: 1215), MK368997.1 (SEQ ID NO: 1216), MK368998.1 (SEQ ID NO: 1217), MK368999.1 (SEQ ID NO: 1218), MK369000.1 (SEQ ID NO: 1219), MK369001.1 (SEQ ID NO: 1220), MK369002.1 (SEQ ID NO: 1221), MK369003.1 (SEQ ID NO: 1222), MK369004.1 (SEQ ID NO: 1223), MK369005.1 (SEQ ID NO: 1224), MK369006.1 (SEQ ID NO: 1225), MK369007.1 (SEQ ID NO: 1226), MK369008.1 (SEQ ID NO: 1227), MK369009.1 (SEQ ID NO: 1228), MK369010.1 (SEQ ID NO: 1229), MK369011.1 (SEQ ID NO: 1230), MK369012.1 (SEQ ID NO: 1231), MK369013.1 (SEQ ID NO: 1232), MK369014.1 (SEQ ID NO: 1233), MK369015.1 (SEQ ID NO: 1234), MK369016.1 (SEQ ID NO: 1235), MK369017.1 (SEQ ID NO: 1236), MK369018.1 (SEQ ID NO: 1237), MK369019.1 (SEQ ID NO: 1238), MK369020.1 (SEQ ID NO: 1239), MK369021.1 (SEQ ID NO: 1240), MK369022.1 (SEQ ID NO: 1241), MK369023.1 (SEQ ID NO: 1242), MK369024.1 (SEQ ID NO: 1243), MK369025.1 (SEQ ID NO: 1244), MK369026.1 (SEQ ID NO: 1245), MK369027.1 (SEQ ID NO: 1246), MK369028.1 (SEQ ID NO: 1247), MK369029.1 (SEQ ID NO: 1248), MK369030.1 (SEQ ID NO: 1249), XM_029900919.1 (SEQ ID NO: 1250), XM_029902259.1 (SEQ ID NO: 1251), XM_029902946.1 (SEQ ID NO: 1252), XM_029906484.1 (SEQ ID NO: 1253),60323665488vlAttorney Docket No. 243735.000480XM_029907925.1 (SEQ ID NO: 1254), XM_029909917.1 (SEQ ID NO: 1255), XM_029909940.1 (SEQ ID NO: 1256), MA878595.1 (SEQ ID NO: 1257), MA878596.1 (SEQ ID NO: 1258), MA878597.1 (SEQ ID NO: 1259), MA878613.1 (TGTTATCAT), MA878626.1 (TTGTTT), MA878636.1 (SEQ ID NO: 1260), MA878682.1 (SEQ ID NO: 1261), XM_025483182.1 (SEQ ID NO: 1262), MK305860.1 (SEQ ID NO: 1263), XM_025488807.1 (SEQ ID NO: 1264), XM_028610904.1 (SEQ ID NO: 1265), XM_028613132.1 (SEQ ID NO: 1266), XM_028626644.1 (SEQ ID NO: 1267), XM_028627302.1 (SEQ ID NO: 1268), XM_028627855.1 (SEQ ID NO: 1269), XM_028631551.1 (SEQ ID NO: 1270), XM_028644333.1 (SEQ ID NO: 1271), XM_028648003.1 (SEQ ID NO: 1272), XM_028648259.1 (SEQ ID NO: 1273), XM_028648304.1 (SEQ ID NO: 1274), MH645357.1 (SEQ ID NO: 1275), MH645358.1 (SEQ ID NO: 1276), MH667308.1 (SEQ ID NO: 1277), MK248686.1 (SEQ ID NO: 1278), XM_027753159.1 (SEQ ID NO: 1279), XM_027758442.1 (SEQ ID NO: 1280), XM_027759777.1 (SEQ ID NO: 1281), MH986724.1 (SEQ ID NO: 1282), XM_026744567.1 (SEQ ID NO: 1283), XM_026746426.1 (SEQ ID NO: 1284), XM_026749878.1 (SEQ ID NO: 1285), XM_026750766.1 (SEQ ID NO: 1286), XM_026771634.1 (SEQ ID NO: 1287), XM_026776867.1 (SEQ ID NO: 1288), LC229567.1 (SEQ ID NO: 1289), LC229568.1 (SEQ ID NO: 1290), LC229569.1 (SEQ ID NO: 1291), LC229570.1 (SEQ ID NO: 1292), MH178171.1 (SEQ ID NO: 1293), MH178172.1 (SEQ ID NO: 1294), MH178173.1 (SEQ ID NO: 1295), MH675762.1 (SEQ ID NO: 1296), MH675763.1 (SEQ ID NO: 1297), MH675764.1 (SEQ ID NO: 1298), MH675765.1 (SEQ ID NO: 1299), MG676220.1 (SEQ ID NO: 1300), XM_025609083.1 (SEQ ID NO: 1301), XM_025609480.1 (SEQ ID NO: 1302), XM 025610129.1 (SEQ ID NO: 1303), XM 025610332.1 (SEQ ID NO: 1304), XM_025610359.1 (SEQ ID NO: 1305), XM_025611970.1 (SEQ ID NO: 1306), XM_025614265.1 (SEQ ID NO: 1307), XM_025616969.1 (SEQ ID NO: 1308), XM_025740980.1 (SEQ ID NO: 1309), XM_025745631.1 (SEQ ID NO: 1310), XM_025666147.1 (SEQ ID NO: 1311), XM_025668298.1 (SEQ ID NO: 1312), XM_025670644.1 (SEQ ID NO: 1313), XM_025675424.1 (SEQ ID NO: 1314), XM_025677241.1 (SEQ ID NO: 1315), XM_025679223.1 (SEQ ID NO: 1316), XM_025680477.1 (SEQ ID NO: 1317), XM_025681299.1 (SEQ ID NO: 1318), XM_025682045.1 (SEQ ID NO: 1319), XM_025686185.1 (SEQ ID NO: 1320),323665488vlAttorney Docket No. 243735.000480XM_025686432.1 (SEQ ID NO: 1321), XM_025687480.1 (SEQ ID NO: 1322), XM_025687665.1 (SEQ ID NO: 1323), XM_025691628.1 (SEQ ID NO: 1324), XM 025692521.1 (SEQ ID NO: 1325), XM 025694828.1 (SEQ ID NO: 1326), XM_025696240.1 (SEQ ID NO: 1327), XM_025697409.1 (SEQ ID NO: 1328), XM_025699191.1 (SEQ ID NO: 1329), XM_025699549.1 (SEQ ID NO: 1330), XM_025703915.1 (SEQ ID NO: 1331), XM_025704422.1 (SEQ ID NO: 1332), XM_025704622.1 (SEQ ID NO: 1333), XM_025704925.1 (SEQ ID NO: 1334), XM_025705085.1 (SEQ ID NO: 1335), XM_025705914.1 (SEQ ID NO: 1336), XM_025706721.1 (SEQ ID NO: 1337), XM_025707135.1 (SEQ ID NO: 1338), XM_025707216.1 (SEQ ID NO: 1339), XM_025717493.1 (SEQ ID NO: 1340), XM_025717595.1 (SEQ ID NO: 1341), XM_025717639.1 (SEQ ID NO: 1342), XM_025717939.1 (SEQ ID NO: 1343), XM_025719637.1 (SEQ ID NO: 1344), XM_025719765.1 (SEQ ID NO: 1345), XM_025721400.1 (SEQ ID NO: 1346), XM_025723331.1 (SEQ ID NO: 1347), XM_025723710.1 (SEQ ID NO: 1348), XM_025724128.1 (SEQ ID NO: 1349), XM_025489086.1 (SEQ ID NO: 1350), XM_025491071.1 (SEQ ID NO: 1351), XM_025504243.1 (SEQ ID NO: 1352), XM_025508687.1 (SEQ ID NO: 1353), XM_025511730.1 (SEQ ID NO: 1354), XM_025518688.1 (SEQ ID NO: 1355), XM_025522271.1 (SEQ ID NO: 1356), XM_025522707.1 (SEQ ID NO: 1357), XM_025523330.1 (SEQ ID NO: 1358), XM_025524852.1 (SEQ ID NO: 1359), XM_025571906.1 (SEQ ID NO: 1360), XM_025572062.1 (SEQ ID NO: 1361), XM_025572655.1 (SEQ ID NO: 1362), XM 025573653.1 (SEQ ID NO: 1363), XM 025574504.1 (SEQ ID NO: 1364), XM_025574583.1 (SEQ ID NO: 1365), XM_025575379.1 (SEQ ID NO: 1366), XM_025580499.1 (SEQ ID NO: 1367), XM_025581082.1 (SEQ ID NO: 1368), XM_025585369.1 (SEQ ID NO: 1369), XM_025587133.1 (SEQ ID NO: 1370), XM_025590218.1 (SEQ ID NO: 1371), XM_025591370.1 (SEQ ID NO: 1372), XM_025619892.1 (SEQ ID NO: 1373), XM_025620394.1 (SEQ ID NO: 1374), XM_025621446.1 (SEQ ID NO: 1375), XM_025621508.1 (SEQ ID NO: 1376), XM_025621630.1 (SEQ ID NO: 1377), XM_025624510.1 (SEQ ID NO: 1378), XM_025625893.1 (SEQ ID NO: 1379), XM_025629259.1 (SEQ ID NO: 1380),62323665488vlAttorney Docket No. 243735.000480XM_025631690.1 (SEQ ID NO: 1381), XM_025632928.1 (SEQ ID NO: 1382), XM_025635682.1 (SEQ ID NO: 1383), XM_025638717.1 (SEQ ID NO: 1384), XM 025639244.1 (SEQ ID NO: 1385), XM 025641099.1 (SEQ ID NO: 1386), XM_025643975.1 (SEQ ID NO: 1387), XM_025644685.1 (SEQ ID NO: 1388), XM_025648998.1 (SEQ ID NO: 1389), XM_025650564.1 (SEQ ID NO: 1390), XM_025651661.1 (SEQ ID NO: 1391), XM_025655217.1 (SEQ ID NO: 1392), XM_025656947.1 (SEQ ID NO: 1393), XM_025657765.1 (SEQ ID NO: 1394), XM_025657870.1 (SEQ ID NO: 1395), XM_025658460.1 (SEQ ID NO: 1396), XM_025660022.1 (SEQ ID NO: 1397), XM_025661218.1 (SEQ ID NO: 1398), XM_025661823.1 (SEQ ID NO: 1399), KY626336.1 (SEQ ID NO: 1400), MG266704.1 (SEQ ID NO: 1401), MG280824.1 (SEQ ID NO: 1402), MG280825.1 (SEQ ID NO: 1403), MG019932.1 (SEQ ID NO: 1404), MG019933.1 (SEQ ID NO: 1405), MG019934.1 (SEQ ID NO: 1406), MG019935.1 (SEQ ID NO: 1407), MG019936.1 (SEQ ID NO: 1408), MG019937.1 (SEQ ID NO: 1409), MG019938.1 (SEQ ID NO: 1410), MG019939.1 (SEQ ID NO: 1411), MG019940.1 (SEQ ID NO: 1412), MG019941.1 (SEQ ID NO: 1413), MG019942.1 (SEQ ID NO: 1414), MG019943.1 (SEQ ID NO: 1415), MG019944.1 (SEQ ID NO: 1416), MG019945.1 (SEQ ID NO: 1417), MG019946.1 (SEQ ID NO: 1418), MG019947.1 (SEQ ID NO: 1419), MG019948.1 (SEQ ID NO: 1420), MG019949.1 (SEQ ID NO: 1421), MG019950.1 (SEQ ID NO: 1422), MG019951.1 (SEQ ID NO: 1423), MG019952.1 (SEQ ID NO: 1424), MG019953.1 (SEQ ID NO: 1425), MG019954.1 (SEQ ID NO: 1426), MG019955.1 (SEQ ID NO: 1427), MH213512.1 (SEQ ID NO: 1428), XM_024892497.1 (SEQ ID NO: 1429), XM_024892603.1 (SEQ ID NO: 1430), XM 024893051.1 (SEQ ID NO: 1431), XM 024895171.1 (SEQ ID NO: 1432), XM_024808447.1 (SEQ ID NO: 1433), XM_024810075.1 (SEQ ID NO: 1434), XM_024820269.1 (SEQ ID NO: 1435), XM_024859287.1 (SEQ ID NO: 1436), MF076818.1 (SEQ ID NO: 1437), MF076819.1 (SEQ ID NO: 1438), MF076820.1 (SEQ ID NO: 1439), MF076821.1 (SEQ ID NO: 1440), MF076822.1 (SEQ ID NO: 1441), MF076823.1 (SEQ ID NO: 1442), MF076824.1 (SEQ ID NO: 1443), MF076825.1 (SEQ ID NO: 1444), MF076826.1 (SEQ ID NO: 1445), MF076827.1 (SEQ ID NO: 1446), MF076828.1 (SEQ ID NO: 1447), MF076829.1 (SEQ ID NO: 1448), MF076830.1 (SEQ ID NO: 1449), XM_002549860.1 (SEQ ID NO: 1450), XM_024657747.1 (SEQ ID NO: 1451), XM_566883.2 (SEQ ID NO: 1452), XM_568133.2 (SEQ63323665488vlAttorney Docket No. 243735.000480ID NO: 1453), XM_568158.1 (SEQ ID NO: 1454), XM_012191425.1 (SEQ ID NO: 1455), XM_012193248.1 (SEQ ID NO: 1456), XM_012193267.1 (SEQ ID NO: 1457), XM 012193416.1 (SEQ ID NO: 1458), XM 018800194.1 (SEQ ID NO: 1459), XM_018801543.1 (SEQ ID NO: 1460), XM_018802387.1 (SEQ ID NO: 1461), XM_018804147.1 (SEQ ID NO: 1462), XM_018805144.1 (SEQ ID NO: 1463), XM_018805377.1 (SEQ ID NO: 1464), XM_006697396.1 (SEQ ID NO: 1465), MF838703.1 (SEQ ID NO: 1466), XM_023569262.1 (SEQ ID NO: 1467), XM_023570337.1 (SEQ ID NO: 1468), XM_023570375.1 (SEQ ID NO: 1469), XM_023570635.1 (SEQ ID NO: 1470), XM_023573921.1 (SEQ ID NO: 1471), XM_023576626.1 (SEQ ID NO: 1472), XM_023768931.1 (SEQ ID NO: 1473), XM_023776052.1 (SEQ ID NO: 1474), KY937969.1 (SEQ ID NO: 1475), MG561374.1 (SEQ ID NO: 1476), KC989583.1 (SEQ ID NO: 1477), KY776555.1 (SEQ ID NO: 1478), MG011725.1 (SEQ ID NO: 1479), MF491446.1 (SEQ ID NO: 1480), MF491447.1 (SEQ ID NO: 1481), XM_022820414.1 (SEQ ID NO: 1482), XM_022821074.1 (SEQ ID NO: 1483), KY587223.1 (SEQ ID NO: 1484), AJ438208.1 (SEQ ID NO: 1485), XM_002175862.2 (SEQ ID NO: 1486), XM_002793624.2 (SEQ ID NO: 1487), XM_002796400.2 (SEQ ID NO: 1488), XM_002796499.1 (SEQ ID NO: 1489), XM_956780.2 (SEQ ID NO: 1490), XM_003171316.1 (SEQ ID NO: 1491), XM_003172468.1 (SEQ ID NO: 1492), XM_003176142.1 (SEQ ID NO: 1493), MF276887.1 (SEQ ID NO: 1494), KX911470.1 (SEQ ID NO: 1495), XM_003866491.1 (SEQ ID NO: 1496), XM_022528288.1 (SEQ ID NO: 1497), XM_022528430.1 (SEQ ID NO: 1498), XM_022530565.1 (SEQ ID NO: 1499), XM 022531922.1 (SEQ ID NO: 1500), XM 022534571.1 (SEQ ID NO: 1501), KX960341.1 (SEQ ID NO: 1502), KU9 1038.1 (SEQ ID NO: 1503), XM 01828 183.1 (SEQ ID NO: 1504), XM_018282726.1 (SEQ ID NO: 1505), XM_018283116.1 (SEQ ID NO: 1506), XM_018287868.1 (SEQ ID NO: 1507), XM_018288151.1 (SEQ ID NO: 1508), XM_022428299.1 (SEQ ID NO: 1509), XM_018890965.1 (SEQ ID NO: 1510), XM_018893768.1 (SEQ ID NO: 1511), XM_018894199.1 (SEQ ID NO: 1512), XM_018901279.1 (SEQ ID NO: 1513), XM_018901280.1 (SEQ ID NO: 1514), XM_018901961.1 (SEQ ID NO: 1515), XM_018906628.1 (SEQ ID NO: 1516), XM_001831757.2 (SEQ ID NO: 1517), XM_001832703.1 (SEQ ID NO: 1518), XM 001833621.2 (SEQ ID NO: 1519), XM_001834983.2 (SEQ ID NO: 1520),323665488vlAttorney Docket No. 243735.000480XM 002417253.1 (SEQ ID NO: 1521), XM 016739174.1 (SEQ ID NO: 1522), XM 016740823.1 (SEQ ID NO: 1523), XM 016741108.1 (SEQ ID NO: 1524), XM 016742484.1 (SEQ ID NO: 1525), XM 016742812.1 (SEQ ID NO: 1526), XM 016747446.1 (SEQ ID NO: 1527), XM 016748162.1 (SEQ ID NO: 1528), XM 018844759.1 (SEQ ID NO: 1529), XM 018845665.1 (SEQ ID NO: 1530), XM 018851807.1 (SEQ ID NO: 1531), XM 018858763.1 (SEQ ID NO: 1532), XM 019173594.1 (SEQ ID NO: 1533), XM 020262494.1 (SEQ ID NO: 1534), XM 020269140.1 (SEQ ID NO: 1535), XM 022021953.1 (SEQ ID NO: 1536), XM 022026258.1 (SEQ ID NO: 1537), XM_022027318.1 (SEQ ID NO: 1538), MF581925.1 (SEQ ID NO: 1539), MF581926.1 (SEQ ID NO: 1540), MF405144.1 (SEQ ID NO: 1541), XM 001589370.1 (SEQ ID NO: 1542), XM 001598408.1 (SEQ ID NO: 1543), XM 001536905.1 (SEQ ID NO: 1544), XM 001537219.1 (SEQ ID NO: 1545), XM 001539592.1 (SEQ ID NO: 1546), XM 003000363.1 (SEQ ID NO: 1547), XM 003003123.1 (SEQ ID NO: 1548), XM 007913162.1 (SEQ ID NO: 1549), XM 007914562.1 (SEQ ID NO: 1550), XM 007914841.1 (SEQ ID NO: 1551), XM 007916089.1 (SEQ ID NO: 1552), XM 007918771.1 (SEQ ID NO: 1553), XM 007919640.1 (SEQ ID NO: 1554), XM 001382870.1 (SEQ ID NO: 1555), XM 020216783.1 (SEQ ID NO: 1556), XM 020218103.1 (SEQ ID NO: 1557), XM 018523978.1 (SEQ ID NO: 1558), XM 018525742.1 (SEQ ID NO: 1559), XM 018527020.1 (SEQ ID NO: 1560), XM 018531390.1 (SEQ ID NO: 1561), XM 018332571.1 (SEQ ID NO: 1562), XM 018332784.1 (SEQ ID NO: 1563), XM 018333906.1 (SEQ ID NO: 1564), KX489465.1 (SEQ ID NO: 1565), KU641394.1 (SEQ ID NO: 1566), KU641395.1 (SEQ ID NO: 1567), KU641396.1 (SEQ ID NO: 1568), KU641397.1 (SEQ ID NO: 1569), KU641398.1 (SEQ ID NO: 1570), KU641399.1 (SEQ ID NO: 1571), KU641400.1 (SEQ ID NO: 1572), AH000868.2 (SEQ ID NO: 1573), AB011415.1 (SEQ ID NO: 1574), AB020341.1 (SEQ ID NO: 1575), AB080844.1 (SEQ ID NO: 1576), AF133262.1 (SEQ ID NO: 1577), AF258797.2 (SEQ ID NO: 1578), AJ010496.1 (SEQ ID NO: 1579), AY364315.1 (SEQ ID NO: 1580), AY364316.1 (SEQ ID NO: 1581), AY449687.1 (SEQ ID NO: 1582), AY453792.1 (SEQ ID NO: 1583), AY571719.1 (SEQ ID NO: 1584), AY571720.1 (SEQ ID NO: 1585), AY571721.1 (SEQ ID NO: 1586), AY571722.1 (SEQ ID NO: 1587), AY571723.1 (SEQ65323665488vlAttorney Docket No. 243735.000480ID NO: 1588), AY571724.1 (SEQ IDNO: 1589), AY571725.1 (SEQ IDNO: 1590), AY571726.1 (SEQ ID NO: 1591), AY571727.1 (SEQ ID NO: 1592), AY571728.1 (SEQ ID NO: 1593), AY571729.1 (SEQ IDNO: 1594), AY571730.1 (SEQ ID NO: 1595), AY571731.1 (SEQ IDNO: 1596), AY571732.1 (SEQ ID NO: 1597), AY571733.1 (SEQ ID NO: 1598), AY571734.1 (SEQ ID NO: 1599), AY571735.1 (SEQ IDNO: 1600), AY571736.1 (SEQ ID NO: 1601), AY571737.1 (SEQ ID NO: 1602), AY571738.1 (SEQ ID NO: 1603), AY571739.1 (SEQ ID NO: 1604), AY571740.1 (SEQ ID NO: 1605), AY571741.1 (SEQ ID NO: 1606), AY571742.1 (SEQ IDNO: 1607), AY571743.1 (SEQ ID NO: 1608), AY687335.1 (SEQ ID NO: 1609), AY687336.1 (SEQ ID NO: 1610), AY748443.1 (SEQ ID NO: 1611), D63898.1 (SEQ ID NO: 1612), DQ182487.1 (SEQ ID NO: 1613), DQ333889.1 (SEQ ID NO: 1614), EU101420.1 (SEQ ID NO: 1615), EU101421.1 (SEQ ID NO: 1616), EU101422.1 (SEQ ID NO: 1617), EU101423.1 (SEQ ID NO: 1618), EU101424.1 (SEQ ID NO: 1619), EU101425.1 (SEQ ID NO: 1620), EU101426.1 (SEQ ID NO: 1621), EU101427.1 (SEQ IDNO: 1622), EU259832.1 (SEQ ID NO: 1623), EU489458.1 (SEQ ID NO: 1624), EU827519.1 (SEQ ID NO: 1625), EU827520.1 (SEQ ID NO: 1626), EU827521.1 (SEQ ID NO: 1627), EU827522.1 (SEQ ID NO: 1628), EU827523.1 (SEQ ID NO: 1629), EU836738.1 (SEQ ID NO: 1630), EU907989.1 (SEQ ID NO: 1631), EU907990.1 (SEQ ID NO: 1632), EU907991.1 (SEQ IDNO: 1633), EU907992.1 (SEQ ID NO: 1634), EU907993.1 (SEQ ID NO: 1635), EU907994.1 (SEQ ID NO: 1636), EU907995.1 (SEQ ID NO: 1637), EU907996.1 (SEQ ID NO: 1638), EU907997.1 (SEQ ID NO: 1639), EU907998.1 (SEQ ID NO: 1640), EU907999.1 (SEQ ID NO: 1641), EU908000.1 (SEQ ID NO: 1642), EU908001.1 (SEQ ID NO: 1643), EU908002.1 (SEQ IDNO: 1644), EU908003.1 (SEQ ID NO: 1645), EU908004.1 (SEQ ID NO: 1646), EU908005.1 (SEQ ID NO: 1647), EU908006.1 (SEQ ID NO: 1648), EU908007.1 (SEQ ID NO: 1649), EU908008.1 (SEQ ID NO: 1650), EU908009.1 (SEQ ID NO: 1651), EU908010.1 (SEQ ID NO: 1652), EU908011.1 (SEQ ID NO: 1653), EU908012.1 (SEQ ID NO: 1654), FJ460503.1 (SEQ ID NO: 1655), FM172990.1 (SEQ ID NO: 1656), FM172991.1 (SEQ ID NO: 1657), FM180250.1 (SEQ ID NO: 1658), FM180251.1 (SEQ ID NO: 1659), FM180252.1 (SEQ IDNO: 1660), FM180253.1 (SEQ IDNO: 1661), FM180254.1 (SEQ IDNO: 1662), FM180255.1 (SEQ ID NO: 1663), FM180256.1 (SEQ ID NO: 1664), FM180257.1 (SEQ ID NO: 1665), FM180258.1 (SEQ IDNO: 1666), FM180259.1 (SEQ IDNO: 1667), FM180260.1 (SEQ ID NO: 1668), FM180261.1 (SEQ ID NO: 1669), FM180262.1 (SEQ ID NO: 1670),66323665488vlAttorney Docket No. 243735.000480FM180263.1 (SEQ IDNO: 1671), FM180264.1 (SEQ IDNO: 1672), FM180265.1 (SEQ IDNO: 1673), FM180266.1 (SEQ ID NO: 1674), FM180267.1 (SEQ ID NO: 1675), FM180268.1 (SEQ ID NO: 1676), FM180269.1 (SEQ IDNO: 1677), FM180270.1 (SEQ IDNO: 1678), FM180271.1 (SEQ ID NO: 1679), FM180272.1 (SEQ ID NO: 1680), FM180273.1 (SEQ ID NO: 1681), FM180274.1 (SEQ IDNO: 1682), FM180275.1 (SEQ IDNO: 1683), FM180276.1 (SEQ IDNO: 1684), FM180277.1 (SEQ ID NO: 1685), FM180278.1 (SEQ ID NO: 1686), FM180279.1 (SEQ ID NO: 1687), FM180280.1 (SEQ ID NO: 1688), FM180281.1 (SEQ ID NO: 1689), U72068.1 (SEQ ID NO: 1690), AF047025.1 (SEQ ID NO: 1691), AF239158.1 (SEQ ID NO: 1692), AF524895.1 (SEQ ID NO: 1693), AY297845.1 (SEQ ID NO: 1694), AY297846.1 (SEQ ID NO: 1695), AY297847.1 (SEQ ID NO: 1696), AY297848.1 (SEQ ID NO: 1697), AY297850.1 (SEQ ID NO: 1698), AY297851.1 (SEQIDNO: 1699), HM042668.1 (SEQIDNO: 1700), HM042669.1 (SEQ ID NO: 1701), HM042670.1 (SEQ ID NO: 1702), HM042671.1 (SEQ ID NO: 1703), HM042672.1 (SEQIDNO: 1704), HM042673.1 (SEQ IDNO: 1705), HM042674.1 (SEQIDNO: 1706), HM042675.1 (SEQ ID NO: 1707), HM042676.1 (SEQ ID NO: 1708), HM042677.1 (SEQ ID NO: 1709), HM178967.1 (SEQ ID NO: 1710), HM178968.1 (SEQ ID NO: 1711), HM178969.1 (SEQIDNO: 1712), HM178970.1 (SEQ IDNO: 1713), HM178971.1 (SEQIDNO: 1714), HM178972.1 (SEQ ID NO: 1715), HM178973.1 (SEQ IDNO: 1716), HM178974.1 (SEQ ID NO: 1717), HM178975.1 (SEQ ID NO: 1718), HM178976.1 (SEQ ID NO: 1719), HM178977.1 (SEQIDNO: 1720), HM178978.1 (SEQ IDNO: 1721), HM178979.1 (SEQIDNO: 1722), HM 178980.1 (SEQ IDNO: 1723), HM178981.1 (SEQ IDNO: 1724), HM178982.1 (SEQ ID NO: 1725), HM178983.1 (SEQ ID NO: 1726), HM178984.1 (SEQ ID NO: 1727), HM178985.1 (SEQIDNO: 1728), HM178986.1 (SEQ IDNO: 1729), HM178987.1 (SEQIDNO: 1730), HM178988.1 (SEQ IDNO: 1731), HM178989.1 (SEQ IDNO: 1732), HM178990.1 (SEQ ID NO: 1733), HM178991.1 (SEQ ID NO: 1734), HM178992.1 (SEQ ID NO: 1735), HM178993.1 (SEQIDNO: 1736), HM178994.1 (SEQ IDNO: 1737), HM178995.1 (SEQ IDNO: 1738), HM178996.1 (SEQ IDNO: 1739), HM178997.1 (SEQ IDNO: 1740), HM178998.1 (SEQ ID NO: 1741), HM178999.1 (SEQ ID NO: 1742), HM179000.1 (SEQ ID NO: 1743), HM179001.1 (SEQIDNO: 1744), HM179002.1 (SEQ IDNO: 1745), HM179003.1 (SEQ IDNO: 1746), HM 179004.1 (SEQ IDNO: 1747), HM179005.1 (SEQ IDNO: 1748), HM179006.1 (SEQ ID NO: 1749), HM179007.1 (SEQ ID NO: 1750), HM179008.1 (SEQ ID NO: 1751),67323665488vlAttorney Docket No. 243735.000480HM179009.1 (SEQIDNO: 1752), HM179010.1 (SEQ IDNO: 1753), HM179011.1 (SEQ IDNO: 1754), HM179012.1 (SEQ IDNO: 1755), HM179013.1 (SEQ IDNO: 1756), HM179014.1 (SEQ ID NO: 1757), HM179015.1 (SEQ ID NO: 1758), HM179016.1 (SEQ ID NO: 1759), HM179017.1 (SEQIDNO: 1760), HM179018.1 (SEQ IDNO: 1761), HM179019.1 (SEQ IDNO: 1762), HM 179020.1 (SEQ IDNO: 1763), HM179021.1 (SEQ IDNO: 1764), HM 179022.1 (SEQ ID NO: 1765), HM179023.1 (SEQ ID NO: 1766), HM179024.1 (SEQ ID NO: 1767), HM179025.1 (SEQIDNO: 1768), HM179026.1 (SEQ IDNO: 1769), HM179027.1 (SEQIDNO: 1770), HM239366.1 (SEQ IDNO: 1771), HM239367.1 (SEQ IDNO: 1772), HM239368.1 (SEQ ID NO: 1773), HM239369.1 (SEQ ID NO: 1774), HM239370.1 (SEQ ID NO: 1775), HM239371.1 (SEQIDNO: 1776), HM239372.1 (SEQ IDNO: 1777), HM239373.1 (SEQIDNO: 1778), HM239374.1 (SEQ IDNO: 1779), HM239375.1 (SEQ IDNO: 1780), HM239376.1 (SEQ ID NO: 1781), HM239377.1 (SEQ ID NO: 1782), HM239378.1 (SEQ ID NO: 1783), HM239379.1 (SEQIDNO: 1784), HM239380.1 (SEQ IDNO: 1785), HM239381.1 (SEQIDNO: 1786), HM239382.1 (SEQ IDNO: 1787), HM239383.1 (SEQ IDNO: 1788), HM239384.1 (SEQ ID NO: 1789), HM239385.1 (SEQ ID NO: 1790), HM239386.1 (SEQ ID NO: 1791), HM239387.1 (SEQIDNO: 1792), HM239388.1 (SEQ IDNO: 1793), HM239389.1 (SEQIDNO: 1794), HM239390.1 (SEQ ID NO: 1795), HM239391.1 (SEQ IDNO: 1796), HM239392.1 (SEQ ID NO: 1797), HM239393.1 (SEQ ID NO: 1798), HM239394.1 (SEQ ID NO: 1799), HM239395.1 (SEQIDNO: 1800), HM239396.1 (SEQ IDNO: 1801), HM239397.1 (SEQIDNO: 1802), HM239398.1 (SEQ IDNO: 1803), HM239399.1 (SEQ IDNO: 1804), HM239400.1 (SEQ ID NO: 1805), HM239401.1 (SEQ ID NO: 1806), HM239402.1 (SEQ ID NO: 1807), HM239403.1 (SEQIDNO: 1808), HM239404.1 (SEQ IDNO: 1809), HM239405.1 (SEQIDNO: 1810), HM239406.1 (SEQ IDNO: 1811), HM239407.1 (SEQ IDNO: 1812), HM239408.1 (SEQ ID NO: 1813), HM239409.1 (SEQ ID NO: 1814), HM239410.1 (SEQ ID NO: 1815), HM239411.1 (SEQIDNO: 1816), HM239412.1 (SEQ IDNO: 1817), HM239413.1 (SEQ IDNO: 1818), HM239414.1 (SEQ IDNO: 1819), HM239415.1 (SEQ IDNO: 1820), HM239416.1 (SEQ ID NO: 1821), HM239417.1 (SEQ ID NO: 1822), HM239418.1 (SEQ ID NO: 1823), HM239419.1 (SEQIDNO: 1824), HM239420.1 (SEQ IDNO: 1825), HM239421.1 (SEQ IDNO: 1826), HM239422.1 (SEQ IDNO: 1827), HM239423.1 (SEQ IDNO: 1828), HM239424.1 (SEQ ID NO: 1829), HM239425.1 (SEQ ID NO: 1830), HM239426.1 (SEQ ID NO: 1831),68323665488vlAttorney Docket No. 243735.000480HM239427.1 (SEQIDNO: 1832), HM239428.1 (SEQ IDNO: 1833), HM239429.1 (SEQ IDNO: 1834), HM239430.1 (SEQ IDNO: 1835), HM239431.1 (SEQ IDNO: 1836), HM239432.1 (SEQ ID NO: 1837), HM239433.1 (SEQ ID NO: 1838), HM239434.1 (SEQ ID NO: 1839), HM239435.1 (SEQIDNO: 1840), HM239436.1 (SEQ IDNO: 1841), HM239437.1 (SEQ IDNO: 1842), HM239438.1 (SEQ IDNO: 1843), HM239439.1 (SEQ IDNO: 1844), HM239440.1 (SEQ ID NO: 1845), HM239441.1 (SEQ ID NO: 1846), HM239442.1 (SEQ ID NO: 1847), HM239443.1 (SEQIDNO: 1848), HM239444.1 (SEQ IDNO: 1849), HM239445.1 (SEQIDNO: 1850), HM239446.1 (SEQ IDNO: 1851), HM239447.1 (SEQ IDNO: 1852), HM239448.1 (SEQ ID NO: 1853), HM239449.1 (SEQ ID NO: 1854), HM239450.1 (SEQ ID NO: 1855), HM239451.1 (SEQIDNO: 1856), HM239452.1 (SEQ IDNO: 1857), HM239453.1 (SEQIDNO: 1858), HM239454.1 (SEQ IDNO: 1859), HM239455.1 (SEQ IDNO: 1860), HM239456.1 (SEQ ID NO: 1861), HM239457.1 (SEQ ID NO: 1862), HM239458.1 (SEQ ID NO: 1863), HM239459.1 (SEQIDNO: 1864), HM239460.1 (SEQ IDNO: 1865), HM589565.1 (SEQIDNO: 1866), HM589566.1 (SEQ IDNO: 1867), HM589567.1 (SEQ IDNO: 1868), HM589568.1 (SEQ ID NO: 1869), HM589569.1 (SEQ ID NO: 1870), HM589570.1 (SEQ ID NO: 1871), HM589571.1 (SEQIDNO: 1872), HM589572.1 (SEQ IDNO: 1873), HM589573.1 (SEQIDNO: 1874), HM589574.1 (SEQ ID NO: 1875), HQ292193.1 (SEQ ID NO: 1876), HQ343313.1 (SEQ ID NO: 1877), HQ452886.1 (SEQ IDNO: 1878), HQ595331.1 (SEQ IDNO: 1879), HQ595332.1 (SEQ ID NO: 1880), HQ595333.1 (SEQ ID NO: 1881), HQ595334.1 (SEQ ID NO: 1882), HQ595335.1 (SEQ ID NO: 1883), HQ595336.1 (SEQ ID NO: 1884), HQ595337.1 (SEQ IDNO: 1885), HQ595338.1 (SEQ IDNO: 1886), HQ595339.1 (SEQ IDNO: 1887), JF320952.1 (SEQ ID NO: 1888), JF412513.1 (SEQ IDNO: 1889), JN416575.1 (SEQ IDNO: 1890), JN416576.1 (SEQ ID NO: 1891), JN416577.1 (SEQ ID NO: 1892), JN416578.1 (SEQ ID NO: 1893), AB006328.1 (SEQ ID NO: 1894), AF035966.1 (SEQ ID NO: 1895), FM955148.2 (SEQ ID NO: 1896), FN433100.1 (SEQ ID NO: 1897), GQ250582.1 (SEQ ID NO: 1898), GQ250583.1 (SEQ ID NO: 1899), GQ507048.1 (SEQ ID NO: 1900), GQ507049.1 (SEQ ID NO: 1901), GQ507050.1 (SEQ IDNO: 1902), GQ507051.1 (SEQ IDNO: 1903), GQ507052.1 (SEQ IDNO: 1904), GQ507053.1 (SEQ ID NO: 1905), GQ507054.1 (SEQ ID NO: 1906), GQ507055.1 (SEQ ID NO: 1907), GQ507056.1 (SEQ IDNO: 1908), GQ507057.1 (SEQ ID NO: 1909), GQ507058.1 (SEQ IDNO: 1910), GQ507059.1 (SEQ ID NO: 1911), GQ507060.1 (SEQ ID NO: 1912), GQ507061.1 (SEQ69323665488vlAttorney Docket No. 243735.000480ID NO: 1913), GQ507062.1 (SEQ IDNO: 1914), GQ507063.1 (SEQ IDNO: 1915), GQ507064.1 (SEQ ID NO: 1916), GQ507065.1 (SEQ ID NO: 1917), GQ507066.1 (SEQ ID NO: 1918), EF362619.1 (SEQ ID NO: 1919), AB232351.1 (SEQ ID NO: 1920), AB232352.1 (SEQ ID NO: 1921), AB232353.1 (SEQ ID NO: 1922), AB232354.1 (SEQ ID NO: 1923), AB232355.1 (SEQ ID NO: 1924), AB232356.1 (SEQ IDNO: 1925), AB232357.1 (SEQ IDNO: 1926), AF324341.1 (SEQ ID NO: 1927), AM384986.2 (SEQ ID NO: 1928), AM497807.1 (SEQ ID NO: 1929), AY007644.1 (SEQ ID NO: 1930), DQ682921.1 (SEQ ID NO: 1931), EF100121.1 (SEQ ID NO: 1932), EF208994.1 (SEQ ID NO: 1933), KU510282.1 (SEQ ID NO: 1934), KX094558.1 (SEQ ID NO: 1935), KX094559.1 (SEQ IDNO: 1936), KX094560.1 (SEQ IDNO: 1937), KX243361.1 (SEQ ID NO: 1938), KX243362.1 (SEQ ID NO: 1939), KX243363.1 (SEQ ID NO: 1940), KX243364.1 (SEQ IDNO: 1941), KX243365.1 (SEQ ID NO: 1942), KX243366.1 (SEQ IDNO: 1943), KX274267.1 (SEQ ID NO: 1944), KX274268.1 (SEQ ID NO: 1945), KX274269.1 (SEQ ID NO: 1946), KX274270.1 (SEQ IDNO: 1947), KX274271.1 (SEQ IDNO: 1948), KX274272.1 (SEQ ID NO: 1949), KX274273.1 (SEQ ID NO: 1950), KU350659.1 (SEQ ID NO: 1951), KF857271.1 (SEQ ID NO: 1952), KF857272.1 (SEQ ID NO: 1953), KF857273.1 (SEQ ID NO: 1954), KF857274.1 (SEQ ID NO: 1955), KT963080.1 (SEQ ID NO: 1956), KU756586.1 (SEQ ID NO: 1957), KU575254.1 (SEQ IDNO: 1958), KU575261.1 (SEQ IDNO: 1959), KU575268.1 (SEQ ID NO: 1960), KU575275.1 (SEQ ID NO: 1961), KU575282.1 (SEQ ID NO: 1962), KU575289.1 (SEQ ID NO: 1963), KU575296.1 (SEQ ID NO: 1964), KU575303.1 (SEQ IDNO: 1965), KU575310.1 (SEQ ID NO: 1966), KU575317.1 (SEQ ID NO: 1967), KU575324.1 (SEQ ID NO: 1968), KU575331.1 (SEQ IDNO: 1969), KU575338.1 (SEQ IDNO: 1970), KU575345.1 (SEQ ID NO: 1971), KU575352.1 (SEQ ID NO: 1972), KU575359.1 (SEQ ID NO: 1973), KU575365.1 (SEQ ID NO: 1974), KU575372.1 (SEQ ID NO: 1975), KU575379.1 (SEQ IDNO: 1976), KU575385.1 (SEQ ID NO: 1977), KU575392.1 (SEQ ID NO: 1978), KU575399.1 (SEQ ID NO: 1979), KU575406.1 (SEQ IDNO: 1980), KU575413.1 (SEQ IDNO: 1981), KU575420.1 (SEQ ID NO: 1982), KU575427.1 (SEQ ID NO: 1983), KU575434.1 (SEQ ID NO: 1984), KU575441.1 (SEQ IDNO: 1985), KU575447.1 (SEQ ID NO: 1986), KU575454.1 (SEQ IDNO: 1987), KU575461.1 (SEQ ID NO: 1988), KU575468.1 (SEQ ID NO: 1989), KU575475.1 (SEQ ID NO: 1990), KU575482.1 (SEQ IDNO: 1991), KU575489.1 (SEQ IDNO: 1992), KU575496.1 (SEQ ID NO: 1993), KU575503.1 (SEQ ID NO: 1994), KU575510.1 (SEQ ID NO: 1995),70323665488vlAttorney Docket No. 243735.000480KU575517.1 (SEQ ID NO: 1996), KU575524.1 (SEQ ID NO: 1997), KU575531.1 (SEQ IDNO: 1998), KU575538.1 (SEQ ID NO: 1999), KU575545.1 (SEQ ID NO: 2000), KU575552.1 (SEQ ID NO: 2001), KU575558.1 (SEQ ID NO: 2002), KU575565.1 (SEQ ID NO: 2003), KU575572.1 (SEQ ID NO: 2004), KU575579.1 (SEQ ID NO: 2005), KU575586.1 (SEQ ID NO: 2006), KU575593.1 (SEQ ID NO: 2007), KU575600.1 (SEQ ID NO: 2008), KU575607.1 (SEQ ID NO: 2009), KU575614.1 (SEQ ID NO: 2010), KU575621.1 (SEQ ID NO: 2011), KU575628.1 (SEQ ID NO: 2012), KU575635.1 (SEQ ID NO: 2013), KU575642.1 (SEQ ID NO: 2014), KU575648.1 (SEQ ID NO: 2015), KU575655.1 (SEQ ID NO: 2016), KU575662.1 (SEQ ID NO: 2017), KU575669.1 (SEQ ID NO: 2018), KU575676.1 (SEQ ID NO: 2019), KU575682.1 (SEQ IDNO: 2020), KU575689.1 (SEQ ID NO: 2021), KU575696.1 (SEQ ID NO: 2022), KU575703.1 (SEQ ID NO: 2023), KU575710.1 (SEQ ID NO: 2024), KU575716.1 (SEQ ID NO: 2025), KU575723.1 (SEQ ID NO: 2026), KU575730.1 (SEQ ID NO: 2027), KU575737.1 (SEQ ID NO: 2028), KU575744.1 (SEQ ID NO: 2029), KU575751.1 (SEQ ID NO: 2030), KU575758.1 (SEQ ID NO: 2031), KU575765.1 (SEQ ID NO: 2032), KU575772.1 (SEQ ID NO: 2033), KU575779.1 (SEQ ID NO: 2034), KU575786.1 (SEQ ID NO: 2035), KU575793.1 (SEQ ID NO: 2036), KU575800.1 (SEQ ID NO: 2037), KU575807.1 (SEQ ID NO: 2038), KU575814.1 (SEQ ID NO: 2039), KU575821.1 (SEQ ID NO: 2040), KU575828.1 (SEQ ID NO: 2041), KU575835.1 (SEQ IDNO: 2042), KU575842.1 (SEQ ID NO: 2043), KU575849.1 (SEQ ID NO: 2044), KU575856.1 (SEQ ID NO: 2045), KU575863.1 (SEQ ID NO: 2046), AB786728.1 (SEQ ID NO: 2047), KT337311.1 (SEQ ID NO: 2048), KP863735.1 (SEQ ID NO: 2049), KP872307.1 (SEQ ID NO: 2050), KP872308.1 (SEQ ID NO: 2051), KP872309.1 (SEQ ID NO: 2052), KP872310.1 (SEQ ID NO: 2053), KP872311.1 (SEQ ID NO: 2054), KP872312.1 (SEQ ID NO: 2055), KP872313.1 (SEQ ID NO: 2056), KP872314.1 (SEQ ID NO: 2057), KU056479.1 (SEQ ID NO: 2058), KU056480.1 (SEQ ID NO: 2059), KU056481.1 (SEQ ID NO: 2060), KU056482.1 (SEQ ID NO: 2061), KU140666.1 (SEQ ID NO: 2062), KR105769.1 (SEQ ID NO: 2063), KJ725128.1 (SEQ ID NO: 2064), XM_012336953.1 (SEQ ID NO: 2065), KM925018.1 (SEQ ID NO: 2066), KP202252.1 (SEQ ID NO: 2067), KM036425.1 (SEQ ID NO: 2068), KF921060.1 (SEQ ID NO: 2069), KF921061.1 (SEQ ID NO: 2070), KF921062.1 (SEQ ID NO: 2071), KF921063.1 (SEQ ID NO: 2072), KF921064.1 (SEQ ID NO: 2073), KF921065.1 (SEQ ID NO: 2074), KF921066.1 (SEQ ID NO: 2075), KF921067.1 (SEQ ID NO: 2076), KF921068.1 (SEQ ID NO: 2077), KF921069.171323665488vlAttorney Docket No. 243735.000480(SEQ ID NO: 2078), KF921070.1 (SEQ ID NO: 2079), KJ947312.1 (SEQ ID NO: 2080), KJ463410.1 (SEQ ID NO: 2081), KF421252.1 (SEQ ID NO: 2082), KF421253.1 (SEQ ID NO: 2083), KF421254.1 (SEQ ID NO: 2084), KF421255.1 (SEQ ID NO: 2085), KF421256.1 (SEQ ID NO: 2086), KF421257.1 (SEQ ID NO: 2087), KF421258.1 (SEQ ID NO: 2088), KF421259.1 (SEQ ID NO: 2089), KF421260.1 (SEQ ID NO: 2090), KF421261.1 (SEQ ID NO: 2091), KF421262.1 (SEQ ID NO: 2092), KF421263.1 (SEQ ID NO: 2093), KF421264.1 (SEQ ID NO: 2094), KF421265.1 (SEQ ID NO: 2095), KF421266.1 (SEQ ID NO: 2096), KF421267.1 (SEQ ID NO: 2097), KF421268.1 (SEQ ID NO: 2098), KF421269.1 (SEQ ID NO: 2099), KF421270.1 (SEQ ID NO: 2100), KF421271.1 (SEQ ID NO: 2101), KF421272.1 (SEQ ID NO: 2102), KF421273.1 (SEQ ID NO: 2103), KF421274.1 (SEQ ID NO: 2104), KF421275.1 (SEQ ID NO: 2105), KF421276.1 (SEQ ID NO: 2106), KF421277.1 (SEQ ID NO: 2107), KF421278.1 (SEQ ID NO: 2108), KF421279.1 (SEQ ID NO: 2109), KF421280.1 (SEQ ID NO: 2110), KF421281.1 (SEQ ID NO: 2111), KF421282.1 (SEQ ID NO: 2112), KF421283.1 (SEQ ID NO: 2113), KF421284.1 (SEQ ID NO: 2114), KF421285.1 (SEQ ID NO: 2115), KF421286.1 (SEQ ID NO: 2116), KF421287.1 (SEQ ID NO: 2117), KF421288.1 (SEQ ID NO: 2118), KF421289.1 (SEQ ID NO: 2119), KF421290.1 (SEQ ID NO: 2120), KF421291.1 (SEQ ID NO: 2121), KF421292.1 (SEQ ID NO: 2122), KF421293.1 (SEQ ID NO: 2123), KF421294.1 (SEQ ID NO: 2124), KF421295.1 (SEQ ID NO: 2125), KF421296.1 (SEQ ID NO: 2126), KF421297.1 (SEQ ID NO: 2127), KF421298.1 (SEQ ID NO: 2128), KF421299.1 (SEQ ID NO: 2129), KF421300.1 (SEQ ID NO : 2130), JN411081.1 (SEQ ID NO : 2131 ), KJ577568.1 (SEQ ID NO : 2132), KJ612073.1 (SEQ ID NO: 2133), JK744864.1 (SEQ ID NO: 2134), JK744865.1 (SEQ ID NO: 2135), JK744866.1 (SEQ ID NO: 2136), KC514623.1 (SEQ ID NO: 2137), KC514621.1 (SEQ ID NO: 2138), KC514622.1 (SEQ ID NO: 2139), KF787148.1 (SEQ ID NO: 2140), XM_006456258.1 (SEQ ID NO: 2141), XM_006458490.1 (SEQ ID NO: 2142), XM_006458491.1 (SEQ ID NO: 2143), DI196444.1 (SEQ ID NO: 2144), DI196445.1 (SEQ ID NO: 2145), DI211739.1 (SEQ ID NO: 2146), AB840698.1 (SEQ ID NO: 2147), AB840699.1 (SEQ ID NO: 2148), AB840700.1 (SEQ ID NO: 2149), AB840701.1 (SEQ ID NO: 2150), AB840702.1 (SEQ ID NO: 2151), AB840703.1 (SEQ ID NO: 2152), AB840704.1 (SEQ ID NO: 2153), AB840705.1 (SEQ ID NO: 2154), AB840706.1 (SEQ ID NO: 2155), AB840707.1 (SEQ ID NO: 2156), AB840708.1 (SEQ ID NO: 2157), AB840709.1 (SEQ ID NO: 2158), AB840710.1 (SEQ ID NO: 2159), AB840711.1 (SEQ72323665488vlAttorney Docket No. 243735.000480ID NO: 2160), AB840712.1 (SEQ TDNO: 2161), AB840713.1 (SEQ TDNO: 2162), AB840714.1 (SEQ ID NO: 2163), AB840715.1 (SEQ ID NO: 2164), AB840716.1 (SEQ ID NO: 2165), AB840717.1 (SEQ ID NO: 2166), AB840718.1 (SEQ ID NO: 2167), AB840719.1 (SEQ ID NO: 2168), AB840720.1 (SEQ ID NO: 2169), AB840721.1 (SEQ ID NO: 2170), AB840722.1 (SEQ ID NO: 2171), AB840723.1 (SEQ ID NO: 2172), AB840724.1 (SEQ ID NO: 2173), AB840725.1 (SEQ ID NO: 2174), AB840726.1 (SEQ ID NO: 2175), AB840727.1 (SEQ ID NO: 2176), AB840728.1 (SEQ ID NO: 2177), AB840729.1 (SEQ ID NO: 2178), AB840730.1 (SEQ ID NO: 2179), AB840731.1 (SEQ ID NO: 2180), AB840732.1 (SEQ ID NO: 2181), AB840733.1 (SEQ ID NO: 2182), AB840734.1 (SEQ ID NO: 2183), AB840735.1 (SEQ ID NO: 2184), AB840736.1 (SEQ ID NO: 2185), AB840737.1 (SEQ ID NO: 2186), AB840738.1 (SEQ ID NO: 2187), AB840739.1 (SEQ ID NO: 2188), AB840740.1 (SEQ ID NO: 2189), AB840741.1 (SEQ ID NO: 2190), AB840742.1 (SEQ ID NO: 2191), AB840743.1 (SEQ ID NO: 2192), AB840744.1 (SEQ ID NO: 2193), AB840745.1 (SEQ ID NO: 2194), AB840746.1 (SEQ ID NO: 2195), AB840747.1 (SEQ ID NO: 2196), AB840748.1 (SEQ ID NO: 2197), AB840749.1 (SEQ ID NO: 2198), AB840750.1 (SEQ ID NO: 2199), AB840751.1 (SEQ ID NO: 2200), AB840752.1 (SEQ ID NO: 2201), AB840753.1 (SEQ ID NO: 2202), AB840754.1 (SEQ ID NO: 2203), AB840755.1 (SEQ ID NO: 2204), AB840756.1 (SEQ ID NO: 2205), AB840757.1 (SEQ ID NO: 2206), AB840758.1 (SEQ ID NO: 2207), AB840759.1 (SEQ ID NO: 2208), AB840760.1 (SEQ ID NO: 2209), AB840761.1 (SEQ ID NO: 2210), AB840762.1 (SEQ ID NO: 2211), AB840763.1 (SEQ ID NO: 2212), AB840764.1 (SEQ ID NO: 2213), AB840765.1 (SEQ ID NO: 2214), AB840766.1 (SEQ ID NO: 2215), AB840767.1 (SEQ ID NO: 2216), AB 840768.1 (SEQ ID NO: 2217), KF476604.1 (SEQ ID NO: 2218), KF476605.1 (SEQ ID NO: 2219), KF476606.1 (SEQ ID NO: 2220), KF476607.1 (SEQ ID NO: 2221), KF476608.1 (SEQ ID NO: 2222), KF476609.1 (SEQ ID NO: 2223), KF476610.1 (SEQ ID NO: 2224), KF476611.1 (SEQ ID NO: 2225), KF476612.1 (SEQ ID NO: 2226), KF476613.1 (SEQ ID NO: 2227), KF476614.1 (SEQ ID NO: 2228), KF476615.1 (SEQ ID NO: 2229), KC989563.1 (SEQ ID NO: 2230), KC989568.1 (SEQ ID NO: 2231), KC989573.1 (SEQ ID NO: 2232), KC989578.1 (SEQ ID NO: 2233), KC989608.1 (SEQ ID NO: 2234), KC989610.1 (SEQ ID NO: 2235), JX987891.1 (SEQ ID NO: 2236), KF042039.1 (SEQ ID NO: 2237), JX439640.1 (SEQ ID NO: 2238), KC782747.1 (SEQ ID NO: 2239), KC692356.1 (SEQ ID NO: 2240), KC692357.1 (SEQ ID NO: 2241), KC692358.1 (SEQ ID NO: 2242),73323665488vlAttorney Docket No. 243735.000480AB736169.1 (SEQ ID NO: 2243), JXO5O138.1 (SEQ ID NO: 2244), JXO5O139.1 (SEQ ID NO: 2245), JX050140.1 (SEQ ID NO: 2246), JX050141.1 (SEQ ID NO: 2247), JX050142.1 (SEQ ID NO: 2248), FR717672.1 (SEQ ID NO: 2249), FR717673.1 (SEQ ID NO: 2250), KC197358.1 (SEQ ID NO: 2251), KC122363.1 (SEQ ID NO: 2252), KC122364.1 (SEQ ID NO: 2253), KC122365.1 (SEQ ID NO: 2254), KC122366.1 (SEQ ID NO: 2255), KC122367.1 (SEQ ID NO: 2256), KC122368.1 (SEQ ID NO: 2257), KC122369.1 (SEQ ID NO: 2258), KC122370.1 (SEQ ID NO: 2259), KC122371.1 (SEQ ID NO: 2260), KC122372.1 (SEQ ID NO: 2261), KC122373.1 (SEQ ID NO: 2262), KC122374.1 (SEQ ID NO: 2263), KC122375.1 (SEQ ID NO: 2264), KC122376.1 (SEQ ID NO: 2265), KC122377.1 (SEQ ID NO: 2266), KC122378.1 (SEQ ID NO: 2267), JX995363.1 (SEQ ID NO: 2268), JX995364.1 (SEQ ID NO: 2269), JX995365.1 (SEQ ID NO: 2270), AB741645.1 (SEQ ID NO: 2271), AB548860.1 (SEQ ID NO: 2272), JX303255.1 (SEQ ID NO: 2273), JX303256.1 (SEQ ID NO: 2274), JX303257.1 (SEQ ID NO: 2275), JX303258.1 (SEQ ID NO: 2276), JX303259.1 (SEQ ID NO: 2277), JX303260.1 (SEQ ID NO: 2278), JX303261.1 (SEQ ID NO: 2279), JX303262.1 (SEQ ID NO: 2280), JX303263.1 (SEQ ID NO: 2281), JX303264.1 (SEQ ID NO: 2282), JX303265.1 (SEQ IDNO: 2283), JX303266.1 (SEQ ID NO: 2284), JX303267.1 (SEQ ID NO: 2285), JX303268.1 (SEQ ID NO: 2286), JX303269.1 (SEQ ID NO: 2287), JX303270.1 (SEQ ID NO: 2288), JX303271.1 (SEQ ID NO: 2289), JX303272.1 (SEQ ID NO: 2290), JX303273.1 (SEQ ID NO: 2291), JX303274.1 (SEQ ID NO: 2292), JX303275.1 (SEQ ID NO: 2293), JX303276.1 (SEQ ID NO: 2294), JX303277.1 (SEQ ID NO: 2295), JX303278.1 (SEQ IDNO: 2296), JX303279.1 (SEQ IDNO: 2297), JX303280.1 (SEQ IDNO: 2298), JX666363.1 (SEQ IDNO: 2299), HV933040.1 (SEQ IDNO: 2300), HV933041.1 (SEQ ID NO: 2301), HV933042.1 (SEQ ID NO: 2302), JX024740.1 (SEQ ID NO: 2303), EU259819.1 (SEQ ID NO: 2304), EU259820.1 (SEQ ID NO: 2305), EU259821.1 (SEQ ID NO: 2306), EU259822.1 (SEQ ID NO: 2307), EU259823.1 (SEQ ID NO: 2308), EU259824.1 (SEQ ID NO: 2309), EU259825.1 (SEQ ID NO: 2310), EU259826.1 (SEQ ID NO: 2311), EU259827.1 (SEQ ID NO: 2312), EU259828.1 (SEQ ID NO: 2313), EU259829.1 (SEQ ID NO: 2314), EU259830.1 (SEQ ID NO: 2315), EU259831.1 (SEQ ID NO: 2316), EU259833.1 (SEQ ID NO: 2317), EU259834.1 (SEQ ID NO: 2318), EU259835.1 (SEQ ID NO: 2319), EU259836.1 (SEQ IDNO: 2320), EU259837.1 (SEQ IDNO: 2321), EU259838.1 (SEQ ID NO: 2322), EU259839.1 (SEQ ID NO: 2323), EU259840.1 (SEQ ID NO: 2324), EU259841.2 (SEQ ID NO: 2325),74323665488vlAttorney Docket No. 243735.000480EU259842.1 (SEQ ID NO: 2326), EU259843.1 (SEQ ID NO: 2327), EU259844.1 (SEQ ID NO: 2328), EU259845.1 (SEQ ID NO: 2329), EU259846.1 (SEQ ID NO: 2330), EU259847.1 (SEQ ID NO: 2331), EU259848.1 (SEQ ID NO: 2332), EU259849.1 (SEQ ID NO: 2333), EU259850.1 (SEQ ID NO: 2334), EU259851.1 (SEQ ID NO: 2335), EU259852.1 (SEQ ID NO: 2336), EU259853.1 (SEQ ID NO: 2337), EU259854.1 (SEQ ID NO: 2338), EU259855.1 (SEQ ID NO: 2339), EU259856.1 (SEQ ID NO: 2340), JN182229.1 (SEQ ID NO: 2341), JN037847.1 (SEQ ID NO: 2342), JN049495.1 (SEQ ID NO: 2343), JN049496.1 (SEQ ID NO: 2344), JQ303323.2 (SEQ ID NO: 2345), JQ342975.1 (SEQ ID NO: 2346), JQ342976.1 (SEQ ID NO: 2347), JQ342977.1 (SEQ ID NO: 2348), JQ342978.1 (SEQ ID NO: 2349), JQ342979.1 (SEQ ID NO: 2350), JF691577.1 (SEQ ID NO: 2351), JF691578.1 (SEQ ID NO: 2352), JF691579.1 (SEQ ID NO: 2353), JF691580.1 (SEQ ID NO: 2354), JF691581.1 (SEQ ID NO: 2355), GU291849.1 (SEQ ID NO: 2356), JN416570.1 (SEQ ID NO: 2357), JN416571.1 (SEQ ID NO: 2358), JN416572.1 (SEQ ID NO: 2359), JN416573.1 (SEQ ID NO: 2360), JN416574.1 (SEQ ID NO: 2361), JF509841.1 (SEQ ID NO: 2362), JF509842.1 (SEQ ID NO: 2363), JF509843.1 (SEQ ID NO: 2364), JF509844.1 (SEQ ID NO: 2365), JF509845.1 (SEQ ID NO: 2366), JF509846.1 (SEQ ID NO: 2367), JF509847.1 (SEQ ID NO: 2368), JF509848.1 (SEQ ID NO: 2369), JF509849.1 (SEQ ID NO: 2370), JF509850.1 (SEQ ID NO: 2371), JF509851.1 (SEQ ID NO: 2372), JF509852.1 (SEQ ID NO: 2373), JF509853.1 (SEQ ID NO: 2374), JF509854.1 (SEQ ID NO: 2375), JN882712.1 (SEQ ID NO: 2376), GU222349.1 (SEQ ID NO: 2377), JN182232.1 (SEQ ID NO: 2378), JN167226.1 (SEQ ID NO: 2379), AY158249.1 (SEQ ID NO: 2380), AY158250.1 (SEQ ID NO: 2381), AY158251.1 (SEQ ID NO: 2382), AY158252.1 (SEQ ID NO: 2383), AY158253.1 (SEQ ID NO: 2384), AY158254.1 (SEQ ID NO: 2385), AY158255.1 (SEQ ID NO: 2386), AY158256.1 (SEQ ID NO: 2387), AY158257.1 (SEQ ID NO: 2388), AY158258.1 (SEQ ID NO: 2389), AY158259.1 (SEQ ID NO: 2390), AY158260.1 (SEQ ID NO: 2391), AY158261.1 (SEQ ID NO: 2392), AY158262.1 (SEQ ID NO: 2393), AY158263.1 (SEQ ID NO: 2394), AY158264.1 (SEQ ID NO: 2395), JF740689.1 (SEQ ID NO: 2396), JN426845.1 (SEQ ID NO: 2397), HQ407402.1 (SEQ ID NO: 2398), BJ998196.1 (SEQ ID NO: 2399), BJ998234.1 (SEQ ID NO: 2400), BJ999034.1 (SEQ ID NO: 2401), EX148762.1 (SEQ ID NO: 2402), EX148766.1 (SEQ ID NO: 2403), CO135963.1 (SEQ ID NO: 2404), CO141334.1 (SEQ ID NO: 2405), CD645756.1 (SEQ ID NO: 2406), HQ696388.1 (SEQ ID NO: 2407), AW 180906.1 (SEQ ID NO: 2408), AW 180963.175323665488vlAttorney Docket No. 243735.000480(SEQ ID NO: 2409), AI392552.1 (SEQ ID NO: 2410), GW996358.1 (SEQ ID NO: 2411), DN591769.1 (SEQ ID NO: 2412), FJ665431.2 (SEQ ID NO: 2413), FN641683.1 (SEQ ID NO: 2414), HM068611.1 (SEQ ID NO: 2415), FI166230.1 (SEQ ID NO: 2416), EI702709.1 (SEQ ID NO: 2417), GU549477.1 (SEQ ID NO: 2418), AY702101.2 (SEQ ID NO: 2419), DM384229.1 (SEQ ID NO: 2420), DM384230.1 (SEQ ID NO: 2421), DM384248.1 (SEQ ID NO: 2422), EU475909.1 (SEQ ID NO: 2423), DM130424.1 (SEQ ID NO: 2424), FJ716792.1 (SEQ ID NO: 2425), EU900120.1 (SEQ ID NO: 2426), EU900121.1 (SEQ ID NO: 2427), EU900122.1 (SEQ ID NO: 2428), EU900123.1 (SEQ ID NO: 2429), EU900124.1 (SEQ ID NO: 2430), AB472085.1 (SEQ ID NO: 2431), DM056697.1 (SEQ ID NO: 2432), DM056698.1 (SEQ ID NO: 2433), DM056703.1 (SEQ ID NO: 2434), DM056704.1 (SEQ ID NO: 2435), FJ594409.1 (SEQ ID NO: 2436), DQ021914.1 (SEQ ID NO: 2437), EU364509.1 (SEQ ID NO: 2438), FJ455138.1 (SEQ ID NO: 2439), FJ455140.1 (SEQ ID NO: 2440), AB370115.1 (SEQ ID NO: 2441), AB355642.1 (SEQ ID NO: 2442), AB266484.1 (SEQ ID NO: 2443), FI143217.1 (SEQ ID NO: 2444), FI143557.1 (SEQ ID NO: 2445), FI144010.1 (SEQ ID NO: 2446), EU543218.1 (SEQ ID NO: 2447), U11439.1 (SEQ ID NO: 2448), EF661665.1 (SEQ ID NO: 2449), EF661666.1 (SEQ ID NO : 2450), EF661667.1 (SEQ ID NO : 2451 ), EF661668.1 (SEQ ID NO : 2452), EF661669.1 (SEQ ID NO: 2453), EF661670.1 (SEQ ID NO: 2454), EF661671.1 (SEQ ID NO: 2455), EF661672.1 (SEQ ID NO: 2456), EF661673.1 (SEQ ID NO: 2457), EF661674.1 (SEQ ID NO: 2458), EF661675.1 (SEQ ID NO: 2459), EF661676.1 (SEQ ID NO: 2460), EF661677.1 (SEQ ID NO: 2461), EF661678.1 (SEQ ID NO: 2462), EF661679.1 (SEQ ID NO: 2463), EF661680.1 (SEQ ID NO : 2464), EF661681.1 (SEQ ID NO : 2465), EF661682.1 (SEQ ID NO : 2466), EF661683.1 (SEQ ID NO: 2467), EF661684.1 (SEQ ID NO: 2468), EF661685.1 (SEQ ID NO: 2469), EF661686.1 (SEQ ID NO: 2470), EF661687.1 (SEQ ID NO: 2471), EF661688.1 (SEQ ID NO: 2472), EF661689.1 (SEQ ID NO: 2473), EF661690.1 (SEQ ID NO: 2474), EF661691.1 (SEQ ID NO: 2475), EF661692.1 (SEQ ID NO: 2476), EF661693.1 (SEQ ID NO: 2477), EF661694.1 (SEQ ID NO : 2478), EF661695.1 (SEQ ID NO : 2479), EF661696.1 (SEQ ID NO : 2480), EF661697.1 (SEQ ID NO: 2481), EF661698.1 (SEQ ID NO: 2482), EF661699.1 (SEQ ID NO: 2483), EF661700.1 (SEQ ID NO: 2484), EF661701.1 (SEQ ID NO: 2485), EF661702.1 (SEQ ID NO: 2486), EF661703.1 (SEQ ID NO: 2487), EF661704.1 (SEQ ID NO: 2488), EF661705.1 (SEQ ID NO: 2489), EF661706.1 (SEQ ID NO: 2490), DQ438623.1 (SEQ ID NO: 2491), DQ438624.1 (SEQ76323665488vlAttorney Docket No. 243735.000480ID NO: 2492), DQ438625.1 (SEQ IDNO: 2493), DQ438626.1 (SEQ IDNO: 2494), DQ438627.1 (SEQ ID NO: 2495), DQ438628.1 (SEQ ID NO: 2496), DQ438629.1 (SEQ ID NO: 2497), DQ438630.1 (SEQ ID NO: 2498), DQ438631.1 (SEQ ID NO: 2499), DQ438632.1 (SEQ IDNO: 2500), DQ438633.1 (SEQ ID NO: 2501), DQ438634.1 (SEQ ID NO: 2502), DQ438635.1 (SEQ ID NO: 2503), DQ438636.1 (SEQ ID NO: 2504), DQ438637.1 (SEQ ID NO: 2505), DQ438638.1 (SEQ ID NO: 2506), DQ438639.1 (SEQ ID NO: 2507), DQ438640.1 (SEQ ID NO: 2508), DQ438641.1 (SEQ ID NO: 2509), DQ438642.1 (SEQ ID NO: 2510), DQ438643.1 (SEQ IDNO: 2511), DQ438644.1 (SEQ ID NO: 2512), DQ438645.1 (SEQ ID NO: 2513), DQ438646.1 (SEQ ID NO: 2514), DQ438647.1 (SEQ ID NO: 2515), DQ438648.1 (SEQ ID NO: 2516), DQ438649.1 (SEQ ID NO: 2517), DQ438650.1 (SEQ ID NO: 2518), DQ438651.1 (SEQ ID NO: 2519), DQ438652.1 (SEQ ID NO: 2520), DQ438653.1 (SEQ ID NO: 2521), DQ438654.1 (SEQ IDNO: 2522), DQ438655.1 (SEQ ID NO: 2523), DQ438656.1 (SEQ ID NO: 2524), DQ438657.1 (SEQ ID NO: 2525), DQ438658.1 (SEQ ID NO: 2526), DQ438659.1 (SEQ ID NO: 2527), DQ438660.1 (SEQ ID NO: 2528), DQ438661.1 (SEQ ID NO: 2529), DQ438662.1 (SEQ ID NO: 2530), DQ438663.1 (SEQ ID NO: 2531), DQ438664.1 (SEQ ID NO: 2532), DQ438665.1 (SEQ IDNO: 2533), DQ438666.1 (SEQ ID NO: 2534), DQ438667.1 (SEQ ID NO: 2535), DQ438668.1 (SEQ ID NO: 2536), DQ438669.1 (SEQ ID NO: 2537), DQ438670.1 (SEQ ID NO: 2538), DQ438671.1 (SEQ ID NO: 2539), DQ438672.1 (SEQ ID NO: 2540), DQ438673.1 (SEQ ID NO: 2541), DQ438674.1 (SEQ ID NO: 2542), DQ438675.1 (SEQ ID NO: 2543), DQ438676.1 (SEQ IDNO: 2544), DQ438677.1 (SEQ ID NO: 2545), DQ438678.1 (SEQ ID NO: 2546), DQ438679.1 (SEQ ID NO: 2547), DQ438680.1 (SEQ ID NO: 2548), DQ438681.1 (SEQ ID NO: 2549), AB033631.1 (SEQ ID NO: 2550), DJ083802.1 (SEQ ID NO: 2551), DJ053777.1 (SEQ ID NO: 2552), DJ053778.1 (SEQ ID NO: 2553), AY748852.1 (SEQ ID NO: 2554), AB020064.1 (SEQ ID NO: 2555), AB020065.1 (SEQ ID NO: 2556), AB020066.1 (SEQ ID NO: 2557), AB020067.1 (SEQ ID NO: 2558), AB020068.1 (SEQ ID NO: 2559), AB020069.1 (SEQ ID NO: 2560), AB020070.1 (SEQ ID NO: 2561), AB020071.1 (SEQ ID NO: 2562), AB020072.1 (SEQ ID NO: 2563), AB020073.1 (SEQ ID NO: 2564), AB020074.1 (SEQ ID NO: 2565), AB020075.1 (SEQ ID NO: 2566), AB020076.1 (SEQ ID NO: 2567), AB020077.1 (SEQ ID NO: 2568), AB020078.1 (SEQ ID NO: 2569), AB020079.1 (SEQ ID NO: 2570), AB020080.1 (SEQ ID NO: 2571), AB020081.1 (SEQ ID NO: 2572), AB020082.1 (SEQ ID NO: 2573), AB020083.1 (SEQ ID NO: 2574),77323665488vlAttorney Docket No. 243735.000480AB020084.1 (SEQ ID NO: 2575), AB020085.1 (SEQ ID NO: 2576), AB020086.1 (SEQ ID NO: 2577), AB020087.1 (SEQ ID NO: 2578), AB020088.1 (SEQ ID NO: 2579), AB020089.1 (SEQ ID NO: 2580), AB020090.1 (SEQ ID NO: 2581), AB020091.1 (SEQ ID NO: 2582), AB020092.1 (SEQ ID NO: 2583), AB020093.1 (SEQ ID NO: 2584), AB020094.1 (SEQ ID NO: 2585), AB020095.1 (SEQ ID NO: 2586), AB020096.1 (SEQ ID NO: 2587), AB020097.1 (SEQ ID NO: 2588), AB020098.1 (SEQ ID NO: 2589), AB020099.1 (SEQ ID NO: 2590), AB020100.1 (SEQ ID NO: 2591), AB020101.1 (SEQ ID NO: 2592), AB020102.1 (SEQ ID NO: 2593), AB020103.1 (SEQ ID NO: 2594), AB020104.1 (SEQ ID NO: 2595), AB020105.1 (SEQ ID NO: 2596), AB020106.1 (SEQ ID NO: 2597), AB020107.1 (SEQ ID NO: 2598), AB020108.1 (SEQ ID NO: 2599), AB020109.1 (SEQ ID NO: 2600), AB020110.1 (SEQ ID NO: 2601), AB020111.1 (SEQ ID NO: 2602), AB020112.1 (SEQ ID NO: 2603), AB020113.1 (SEQ ID NO: 2604), AB020114.1 (SEQ ID NO: 2605), AB020115.1 (SEQ ID NO: 2606), AB020116.1 (SEQ ID NO: 2607), AB020117.1 (SEQ ID NO: 2608), AB020118.1 (SEQ ID NO: 2609), AB020119.1 (SEQ ID NO: 2610), AB020120.1 (SEQ ID NO: 2611), AB020121.1 (SEQ ID NO: 2612), AB020122.1 (SEQ ID NO : 2613 ), AB020123.1 (SEQ ID NO : 2614), AB020124.1 (SEQ ID NO : 2615), AB020125.1 (SEQ ID NO: 2616), AB020126.1 (SEQ ID NO: 2617), AB020127.1 (SEQ ID NO: 2618), AB020128.1 (SEQ ID NO: 2619), AB020129.1 (SEQ ID NO: 2620), AB020130.1 (SEQ ID NO: 2621), AB020131.1 (SEQ ID NO: 2622), AB020132.1 (SEQ ID NO: 2623), AB020133.1 (SEQ ID NO: 2624), AB020134.1 (SEQ ID NO: 2625), AB020135.1 (SEQ ID NO: 2626), AB020136.1 (SEQ ID NO: 2627), AB020137.1 (SEQ ID NO: 2628), AB020138.1 (SEQ ID NO: 2629), AB020139.1 (SEQ ID NO: 2630), AB020140.1 (SEQ ID NO: 2631), AB020141.1 (SEQ ID NO: 2632), AB020142.1 (SEQ ID NO: 2633), AB020143.1 (SEQ ID NO: 2634), AB020144.1 (SEQ ID NO: 2635), AB020145.1 (SEQ ID NO: 2636), AB020146.1 (SEQ ID NO: 2637), AB020147.1 (SEQ ID NO: 2638), AB020148.1 (SEQ ID NO: 2639), AB020149.1 (SEQ ID NO: 2640), AB020150.1 (SEQ ID NO: 2641), AB020151.1 (SEQ ID NO: 2642), AB020152.1 (SEQ ID NO: 2643), AB020153.1 (SEQ ID NO: 2644), AB020154.1 (SEQ ID NO: 2645), AB020155.1 (SEQ ID NO: 2646), AB020156.1 (SEQ ID NO: 2647), AB020157.1 (SEQ ID NO: 2648), AB020158.1 (SEQ ID NO: 2649), AB020159.1 (SEQ ID NO: 2650), AB020160.1 (SEQ ID NO: 2651), AB020161.1 (SEQ ID NO: 2652), AB020162.1 (SEQ ID NO: 2653), AB020163.1 (SEQ ID NO: 2654), AB020164.1 (SEQ ID NO: 2655), AB020165.1 (SEQ ID NO: 2656), AB020234.1 (SEQ78323665488vlAttorney Docket No. 243735.000480ID NO: 2657), AB020235.1 (SEQ ID NO: 2658), DQ000663.1 (SEQ ID NO: 2659), EF140590.1 (SEQ ID NO: 2660), EF028076.1 (SEQ ID NO: 2661), ES322390.1 (SEQ ID NO: 2662), AM490531.1 (SEQ ID NO: 2663), D55675.1 (SEQ ID NO: 2664), AJ311709.1 (SEQ ID NO: 2665), AJ703808.1 (SEQ ID NO: 2666), Y07763.1 (SEQ ID NO: 2667), EE486190.1 (SEQ ID NO: 2668), EE487724.1 (SEQ ID NO: 2669), DQ205930.1 (SEQ ID NO: 2670), DQ468109.1 (SEQ ID NO: 2671), DQ468110.1 (SEQ ID NO: 2672), DQ468111.1 (SEQ ID NO: 2673), DQ468112.1 (SEQ ID NO: 2674), DQ304650.1 (SEQ ID NO: 2675), DQ060343.1 (SEQ ID NO: 2676), DQ060344.1 (SEQ ID NO: 2677), DQ060345.1 (SEQ ID NO: 2678), DQ060346.1 (SEQ ID NO: 2679), DQ060347.1 (SEQ ID NO: 2680), DQ060348.1 (SEQ ID NO: 2681), DQ393583.1 (SEQ ID NO: 2682), DD212874.1 (SEQ ID NO: 2683), DD212883.1 (SEQ ID NO: 2684), DQ350644.1 (SEQ ID NO: 2685), DQ301862.1 (SEQ ID NO: 2686), DQ288844.1 (SEQ ID NO: 2687), BD313063.1 (SEQ ID NO: 2688), BD313064.1 (SEQ ID NO: 2689), DD046677.1 (SEQ ID NO: 2690), DD046678.1 (SEQ ID NO: 2691), E01922.1 (SEQ ID NO: 2692), AY779519.1 (SEQ ID NO: 2693), AB078864.2 (SEQ ID NO: 2694), AB079611.1 (SEQ ID NO: 2695), AB030821.1 (SEQ ID NO: 2696), AB046412.1 (SEQ ID NO: 2697), U07800.1 (SEQ ID NO: 2698), X04625.1 (SEQ ID NO: 2699), X05604.1 (SEQ ID NO: 2700), X05886.1 (SEQ ID NO: 2701), X06660.1 (SEQ ID NO: 2702), X13978.1 (SEQ ID NO: 2703), X56501.1 (SEQ ID NO: 2704), X82176.1 (SEQ ID NO: 2705), X85130.1 (SEQ ID NO: 2706), X85182.1 (SEQ ID NO: 2707), Z54346.1 (SEQ ID NO: 2708), AJ000471.1 (SEQ ID NO: 2709), AJ000472.1 (SEQ ID NO : 2710), AJ289167.1 (SEQ ID NO : 2711 ), AJ291330.1 (SEQ ID NO : 2712), AJ551423.1 (SEQ ID NO: 2713), AB181389.1 (SEQ ID NO: 2714), AB181390.1 (SEQ ID NO: 2715), AB181391.1 (SEQ ID NO: 2716), AY494834.2 (SEQ ID NO: 2717), AF428076.2 (SEQ ID NO: 2718), AY375759.1 (SEQ ID NO: 2719), AY369262.1 (SEQ ID NO: 2720), AY369263.1 (SEQ ID NO: 2721), AY369264.1 (SEQ ID NO: 2722), AY326437.1 (SEQ ID NO: 2723), AJ576036.1 (SEQ ID NO: 2724), AY178620.1 (SEQ ID NO: 2725), AY178621.1 (SEQ ID NO: 2726), AY078506.2 (SEQ ID NO: 2727), AY178619.1 (SEQ ID NO: 2728), CC927347.1 (SEQ ID NO: 2729), CC927348.1 (SEQ ID NO: 2730), AF395816.3 (SEQ ID NO: 2731), AF461425.1 (SEQ ID NO: 2732), BD171865.1 (SEQ ID NO: 2733), BD171867.1 (SEQ ID NO: 2734), BD171868.1 (SEQ ID NO: 2735), AB083039.1 (SEQ ID NO: 2736), AY103479.1 (SEQ ID NO: 2737), AF540951.1 (SEQ ID NO: 2738), AF243853.1 (SEQ ID NO: 2739), BD057317.1 (SEQ ID NO: 2740),79323665488vlAttorney Docket No. 243735.000480AY103480.1 (SEQ ID NO: 2741), AF139985.1 (SEQ ID NO: 2742), AF189368.1 (SEQ ID NO: 2743), AF189369.1 (SEQ ID NO: 2744), AB057656.1 (SEQ ID NO: 2745), E59610.1 (SEQ ID NO: 2746), AB045340.1 (SEQ ID NO: 2747), AF327335.1 (SEQ ID NO: 2748), AB064338.1 (SEQ ID NO: 2749), U56239.1 (SEQ ID NO: 2750), AW789645.1 (SEQ ID NO: 2751), AW790338.1 (SEQ ID NO: 2752), AW790404.1 (SEQ IDNO: 2753), AW790413.1 (SEQ ID NO: 2754), AW790437.1 (SEQ ID NO: 2755), AW792142.1 (SEQ ID NO: 2756), AW792217.1 (SEQ ID NO: 2757), AF316033.1 (SEQ ID NO: 2758), AF286097.1 (SEQ ID NO: 2759), AF222055.1 (SEQ ID NO: 2760), AF222056.1 (SEQ ID NO: 2761), U97574.1 (SEQ ID NO: 2762), AF000419.2 (SEQ ID NO: 2763), AF170449.1 (SEQ ID NO: 2764), AF162654.1 (SEQ ID NO: 2765), AF121348.1 (SEQ ID NO: 2766), U75451.2 (SEQ ID NO: 2767), AF001355.2 (SEQ ID NO: 2768), D83990.1 (SEQ IDNO: 2769), U75450.1 (SEQ IDNO: 2770), AF069070.1 (SEQ ID NO: 2771), M84015.1 (SEQ ID NO: 2772), L41246.1 (SEQ ID NO: 2773), U67458.1 (SEQ ID NO: 2774), U40704.1 (SEQ IDNO: 2775), AF011784.1 (SEQ IDNO: 2776), U63511.1 (SEQ ID NO: 2777), AB006327.1 (SEQ ID NO: 2778), U80672.1 (SEQ ID NO: 2779), M75944.1 (SEQ ID NO: 2780), U89384.1 (SEQ ID NO: 2781), U87850.1 (SEQ ID NO: 2782), U87630.1 (SEQ ID NO: 2783), U83329.1 (SEQ ID NO: 2784), U82622.1 (SEQ ID NO: 2785), U59271.1 (SEQ ID NO: 2786), L48340.1 (SEQ ID NO: 2787), U35457.1 (SEQ ID NO: 2788), U06258.1 (SEQ ID NO: 2789), U37803.1 (SEQ ID NO: 2790), U34896.1 (SEQ ID NO: 2791), U18676.1 (SEQ ID NO: 2792), L15474.1 (SEQ ID NO: 2793), U02682.1 (SEQ ID NO: 2794), U06259.1 (SEQ ID NO: 2795), U06260.1 (SEQ ID NO: 2796), U06261.1 (SEQ ID NO: 2797), U06262.1 (SEQ ID NO: 2798), U06263.1 (SEQ ID NO: 2799), U06264.1 (SEQ ID NO: 2800), U06265.1 (SEQ ID NO: 2801), U06266.1 (SEQ ID NO: 2802), U06267.1 (SEQ ID NO: 2803), U06268.1 (SEQ ID NO: 2804), U06269.1 (SEQ ID NO: 2805), U06270.1 (SEQ ID NO: 2806), U06271.1 (SEQ ID NO: 2807), U06272.1 (SEQ ID NO: 2808), X13028.1 (SEQ ID NO: 2809), M80796.1 (SEQ ID NO: 2810), M29876.1 (SEQ ID NO: 2811), M55161.1 (SEQ ID NO: 2812), M30256.1 (SEQ ID NO: 2813), M21516.1 (SEQ ID NO: 2814), M18832.1 (SEQ ID NO: 2815).

[0168] In some embodiments, the bacterial strain or consortium of bacterial strains elicit an anti-tumor response.

[0169] In some embodiments, the bacterial strain or consortium of bacterial strains augment an anti-tumor response.80323665488vlAttorney Docket No. 243735.000480

[0170] In some embodiments, the anti-tumor response is i) reduced tumor growth, ii) tumor reduction, iii), tumor eradication, iv) enhanced anti-tumor immune response, v) tumor genomic composition alteration, and / or vi) tumor phenotype alteration.

[0171] Tumor genomic composition alteration may be defined as an alteration as measured by the total DNA sequence space observed in the tumor, e.g., via absolute k-mer diversity. Tumor genomic composition alteration may be evidence of an effect of the method, e.g., the method leads to a greater variety of DNA (e.g., that includes additional DNA from bacteria or other bacteria whose detection may have been enabled through the method).

[0172] In some embodiments, the altered tumor phenotype is characterized by i) altered gene expression in a bulk of the tumor, ii) altered gene expression in a tumor single cell subset, iii) altered tumor cell composition, and / or iv) altered tumor response to an anti-tumor therapy.

[0173] In some embodiments, the altered gene expression is characterized by increased gene signatures associated with anti -tumor immunity.

[0174] In some embodiments, the increased gene signatures associated with anti-tumor immunity comprise increased expression of PDL1, CXCL9, CXCL10, and / or CXCL11.

[0175] PDL1 is also known as PD-L1, Programmed Cell Death Ligand 1, Programmed Death Ligand 1, B7 homolog 1, B7-H1, B7-H, and CD274. CXCL9 is also known as C-X-C motif chemokine ligand 9, CMK, HuMIG, MIG, monokine induced by interferon-gamma, SCYB9, Small inducible cytokine B9, and erg- 10. CXCL10 is also known as C-X-C motif chemokine ligand 10, Interferon gamma-induced protein 10, IP- 10, GIP-10, Small inducible cytokine B10, SCYB10, and crg-2. CXCL11 is also known as C-X-C motif chemokine ligand 11, Interferon-inducible T-cell alpha chemoattractant, LTAC, Interferon-gamma-inducible protein 9, IP-9, Small inducible cytokine B 11, and SCYB 11.

[0176] The increased expression of PDL1 may be increased by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, or more.

[0177] The increased expression of CXCL9 may be increased by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%,81323665488vlAttorney Docket No. 243735.000480120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, or more.

[0178] The increased expression of CXCL10 may be increased by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, or more.

[0179] The increased expression of CXCL11 may be increased by 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 225%, 250%, 275%, 300%, 325%, 350%, 375%, 400%, 425%, 450%, 475%, 500%, or more.

[0180] In some embodiments, the altered tumor cell composition is characterized by increased density and / or proportion of tumor infiltrating leukocytes, increased density and / or proportion of tumor infiltrating lymphocytes, and / or reduced density and / or proportion of tumor suppressive myeloid cells.

[0181] In some embodiments, the altered tumor cell composition is measured by cytometry, by single-cell, by deconvoluted bulk RNA sequencing, by microscopy imaging, by immunohistology, by tumor growth kinetics, by tumor reduction, and / or by altered activity of infiltrating immune cells.

[0182] In some embodiments, the altered activity of infiltrating immune cells comprises increased density and / or proportion of tumor infiltrating leukocytes, increased density and / or proportion of tumor infiltrating lymphocytes, and / or increased anti-tumor phenotypes of infiltrating leukocytes.

[0183] In some embodiments, the anti-tumor phenotype comprises decreased dimension(s) or volume of tumor(s), decreased fluorodeoxyglucose uptake, decreased number of tumors, decreased number of metastases, increased proportion or density of dying or dead cancer cells in the tumor or at the tumor border, decreased proportion or density of proliferating cancer cells in the tumor or at the tumor border, increased proportion or density of tumor-infiltrating lymphocytes in the tumor or at the tumor border, increased proportion or density of infiltrating CD8 T cells in the tumor or at the tumor border, increased proportion or density of infiltrating TBX21 -expressing CD4 T cells in the tumor or at the tumor border, decreased proportion or density of infiltrating82323665488vlAttorney Docket No. 243735.000480regulatory T cells in the tumor or at the tumor border, increased proportion or density of infdtrating natural killer T cells in the tumor or at the tumor border, increased proportion or density of infdtrating mucosal-associated invariant T cells in the tumor or at the tumor border, increased proportion or density of infdtrating transplanted autologous or off-the-shelf anti-tumor immune cells in the tumor or at the tumor border, increased proportion or density of infdtrating Ml macrophages in the tumor or at the tumor border, decreased proportion or density of infdtrating M2 macrophages in the tumor or at the tumor border, increased proportion or density of conventional type 1 dendritic cells in the tumor or at the tumor border, decreased proportion or density of myeloid-derived suppressor cells in the tumor or at the tumor border, increased formation of tertiary lymphoid structures in the tumor or in proximity to the tumor, increased percell level of expression or proportion of tumor-infdtrating dendritic cells expressing interleukin 12, and / or increased per-cell level of expression or proportion of tumor-infdtrating CD8 T cells expressing interferon gamma, granzyme B, or tumor necrosis factor.

[0184] In some embodiments, the anti-tumor phenotypes of infdtrating leukocytes are caused via anti-tumor mechanisms. The anti-tumor mechanisms can be, for example, direct antitumor mechanisms or indirect anti-tumor mechanisms. Direct anti-tumor mechanisms include, but are not limited to, upregulated cytotoxicity-associated genes, and indirect anti-tumor mechanisms include, but are not limited to, alteration of immune cell presence (e.g., immune cells that support such anti-tumor activities).

[0185] In some embodiments, the method further comprises administering one or more treatments to the subject.

[0186] In some embodiments, the one or more treatments comprises administering the bacterial strain or consortium of bacterial strains.

[0187] In some embodiments, the bacterial strain or consortium of bacterial strains can comprise live bacterial cells, conditionally lethal bacterial cells, inactivated bacterial cells, killed bacterial cells, spores (e.g., germination-competent spores), recombinant carrier strains, cell extract, or bacterially-derived products (natural or synthetic bacterially-derived products such as, e.g., bacterial antigens or metabolic products).

[0188] In some embodiments, the bacterial strain or consortium of bacterial strains can be administered as one or more than one different bacterial inoculants. The bacterial inoculants may83323665488vlAttorney Docket No. 243735.000480be administered simultaneously or sequentially, including administering at different times. The bacterial strain or consortium of bacterial strains can be isolated from the gut microbiota and grown in culture using known techniques.

[0189] In some embodiments, the consortium of bacterial strains can comprise different bacterial strains in equal amounts or in various proportions needed for achieving the maximal biological activity. In some embodiments, the consortium of bacterial strains is sourced from strain banks, human microbiome isolates from the gut, skin, or other epithelia, or are cGMP manufactured human commensal strains.

[0190] In some embodiments, the one or more treatments comprises administering an effective amount of a composition that stimulates growth and / or activity of the bacterial strain or consortium of bacterial strains.

[0191] In some embodiments, the effective amount of a composition that stimulates growth and / or activity of the bacterial strain or consortium of bacterial strains can be administered with the bacterial strain or consortium of bacterial strains simultaneously or sequentially, including administering at different times.

[0192] In some embodiments, the one or more treatments further comprises administering an anti-tumor therapy.

[0193] In some embodiments, the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody to a cancer and / or tumor antigen, a molecularly targeted small molecule therapeutic to a cancer and / or tumor, an immune checkpoint inhibitor, or cellular therapy.

[0194] In some embodiments, the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infiltrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

[0195] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody,84323665488vlAttorney Docket No. 243735.000480anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TTGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

[0196] In some embodiments, the anti-tumor therapy can be administered with the bacterial strain or consortium of bacterial strains simultaneously or sequentially, including administering at different times.

[0197] In some embodiments, the route of administration for said one or more treatments comprises at least one of intratumoral, intravenous, intravesical, dermal, transdermal, subcutaneous, intrathecal, intranasal, intraperitoneal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

[0198] Upon administration for said one or more treatments, the said one or more treatments may migrate and reach the tumor through the circulatory system. Upon migrating and reaching the tumor, the treatments may be detectable in the tumor. In some embodiments, the treatments may colonize the tumor.

[0199] In some embodiments, the one or more treatment comprises administering nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site.

[0200] In some embodiments, the nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or the nutrients that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site comprise at least one non-caloric sugar.

[0201] In some embodiments, the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.Compositions of bacteria strain(s)

[0202] In a further aspect, provided herein is a bacteria strain composition comprising (i) bacteria from one or more bacterial strains as determined by the methods as described herein or a closely related OTU which has at least 90% (or at least 95%, or at least 97%, or at least 99%)85323665488vlAttorney Docket No. 243735.000480sequence identity to the 16S rRNA gene over its entire length or has at least 90% (or at least 95%, or at least 99%) sequence identity to any single V region of the 16S rRNA gene and (ii) a carrier and / or an excipient and / or one or more additional composition which stimulate growth and / or activity and / or preserve viability of one or more bacteria present in the composition.

[0203] In some embodiments, the bacteria strain composition elicits an anti-tumor response in a patient.

[0204] In some embodiments, the bacteria strain composition augments an anti-tumor response in a patient.

[0205] In some embodiments, the bacteria strain composition comprises (i) gene products as determined by the methods as described herein or a closely related OTU which has at least 90% (or at least 95%, or at least 97%, or at least 99%) sequence identity to sialidase of Akkermansia muciniphila (gene name HXS70 08015), glycopeptidase of Bacteroides thetaiotaomicron (gene name BT4244-M60E) or metalloprotease of Escherichia coli (gene name stcE) and (ii) a carrier and / or an excipient and / or one or more additional composition which stimulate growth and / or activity and / or preserve viability of one or more bacteria present in the composition.

[0206] In some embodiments, the bacteria strain composition can comprise live bacterial cells, conditionally lethal bacterial cells, inactivated bacterial cells, killed bacterial cells, spores (e.g., germination-competent spores), recombinant carrier strains, cell extract, or bacterially-derived products (natural or synthetic bacterially-derived products such as, e.g., bacterial antigens or metabolic products).

[0207] In some embodiments, the bacteria strain composition can comprise different bacterial strains in equal amounts or in various proportions needed for achieving the maximal biological activity. In some embodiments, the composition of bacterial strains is sourced from strain banks, human microbiome isolates from the gut, skin, or other epithelia, or are cGMP manufactured human commensal strains.

[0208] In some embodiments, the additional composition is at least one nutrient that is metabolically inaccessible to the patient and / or the tumor, and / or at least one nutrient that is shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site.

[0209] The nutrient may be selected by identifying substances that do not facilitate the growth of human cancer cell lines (i.e., metabolically inaccessible) but do facilitate the growth of86323665488vlAttorney Docket No. 243735.000480bacteria in carbohydrate-deficient medium. Ability of the substances to promote establishment of the bacteria at the tumor site can be evaluated by testing the ability of the substances to facilitate bacterial tumor colonization when concurrently injected into tumor-bearing mice. The nutrient may serve as an energy substrate for the bacteria. Further, the nutrient may be non-toxic to human cells.

[0210] In some embodiments, the nutrient that is metabolically inaccessible to the patient and / or the tumor, and / or the nutrient that is shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site comprises at least one non-caloric sugar.

[0211] In some embodiments, the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.

[0212] In some embodiments, the composition further comprises or is administered with one or more anti-tumor therapy.

[0213] In some embodiments, the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.

[0214] In some embodiments, the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infiltrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

[0215] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.87323665488vlAttorney Docket No. 243735.000480

[0216] In some embodiments, the one or more bacterial strain is selected from the phylum of: Bacillota (Firmicutes), Bacteroidota (Bacteroidetes), Pseudomonadota (Proteobacteria), Actinomycetota (Actinobacteria), Fusobacteriota (Fusobacteria), Verrucomicrobiota (Verrucomicrobia), Cyanobacteriota (Cyanobacteria), Spirochaetota (Spirochaetes), and My coplasm ota (Teneri cutes), and combinations thereof.

[0217] In some embodiments, the bacterial strain is selected from the genera of Mediterraneibacter, Lactobacillus, Bacteroides, Prevotella, Clostridium, Streptococcus, Escherichia, Enterococcus, Fusobacterium, Ruminococcus, Faecalibacterium, Veillonella, Staphylococcus, Propionibacterium, Peptostreptococcus, Eubacterium, Roseburia, Blautia, Sutterella, Helicobacter, Campylobacter, Haemophilus, Rothia, Akkermansia, Pseudomonas, Neisseria, Porphyromonas, Moraxella, Corynebacterium, Methanobrevibacter, Klebsiella, Proteus, Actinomyces, Bifidobacterium, Dorea, Selenomonas, Tannerella, Treponema, Alistipes, Parabacteroides, Megasphaera, Odoribacter, Mogibacterium, Desulfovibrio, Gemella, Dialister, Lachnospira, Collinsella, Butyrivibrio, Leptotrichia, Capnocytophaga, Bilophila, Vibrio, Slackia, Burkholderia, Rhodobacter, Aeromonas, Alcaligenes, Acidaminococcus, Cloacibacterium, Eggerthella, Coprococcus, Anaerostipes, Oscillospira, Fecalibacterium, Syntrophomonas, Turicibacter, Bamesiella, Victivallis, Tissierella, Veillonellaceae, Sporosarcina, Veillonella, Oribacterium, Desulfitobacterium, Shigella, Gordonibacter, Citrobacter, Anaerostipes, Solobacterium, Flavonifractor, Prevotella, Holdemania, Adlercreutzia, Lactonifactor, Methanosphaera, Phascolarctobacterium, Paraprevotella, Sarcina, Lactococcus, Weissella, Variovorax, Sphingobacterium, Enterobacter, Citrobacter, Klebsiella, Acinetobacter, Janthinobacterium, Providencia, and Stenotrophomonas, and combinations thereof.

[0218] In some embodiments, the bacterial strain is selected from the species of Akkermansia muciniphila, Mediterraneibacter gnavus, Roseburia intestinalis, Streptococcus salivarius, Bacteroides thetaiotaomicron, Bifidobacterium dentium, Bifidobacterium longum, Veillonella parvida, Ruminococcus gnavus, Ruminococcus intestinalis, and Bacillus subtillis, and combinations thereof.Methods for modulating a tumor microenvironment

[0219] In a further aspect, provided herein is a method for modulating a tumor microenvironment in a patient, said method comprising administering to the patient the bacteria88323665488vlAttorney Docket No. 243735.000480from one or more bacterial strains as determined by the methods as described herein or the bacteria strain composition as described herein.

[0220] In some embodiments, the bacteria elicits an anti-tumor response in a patient.

[0221] In some embodiments, wherein the bacteria augments an anti-tumor response in a patient.

[0222] In some embodiments, the tumor microenvironment is the tumor mucin mi croenvironment .

[0223] In some embodiments, the tumor microenvironment is the tumor immune microenvironment.

[0224] In some embodiments, the modulation of the tumor microenvironment increases susceptibility of the tumor to immune cytotoxic cell-mediated killing or phagocytosis.Methods of treatment

[0225] In another aspect, provided herein is a method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the bacteria from one or more bacterial strains as determined by the methods as described herein or the bacteria strain composition as described herein.

[0226] In another aspect, provided herein is a method of reducing size and / or volume of a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the bacteria from one or more bacterial strains as determined by the methods as described herein or the bacteria strain composition as described herein. In some embodiments, the tumor size and / or volume is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0227] In some embodiments, the bacteria elicits an anti-tumor response in a patient.

[0228] In some embodiments, the bacteria augments an anti-tumor response in a patient.

[0229] In some embodiments, the cancer is breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, bladder cancer, skin cancer, central nervous system cancer, nasal cancer, stomach cancer, peritoneal cancer, pancreatic cancer, kidney cancer, liver cancer, esophageal cancer, squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma, basal cell carcinoma, neuroendocrine cancer, bile duct cancer, thyroid cancer, adrenal cancer, soft tissue89323665488vlAttorney Docket No. 243735.000480sarcoma, bone cancer, testicular cancer, nasal cancer, oropharyngeal cancer, anal cancer, penile cancer, vaginal cancer, cervical cancer, thymus cancer, or uveal melanoma.

[0230] In some embodiments, the cancer is characterized by the presence of a tumor. In some embodiments, administration of a therapeutically effective amount of the bacteria from one or more bacterial strains as determined by the methods as described herein or the bacteria strain composition as described herein results in a reduction in size and / or volume of the tumor in the subject. In some embodiments, the tumor size and / or volume is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99%, or 100%.

[0231] In some embodiments, the administration to the patient comprises at least one of oral, intravenous, intraperitoneal, intratumoral, intravesical, dermal, subdermal, subcutaneous, intrathecal, intranasal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

[0232] In some embodiments, the method further comprises administering one or more additional treatments to the patient.

[0233] In some embodiments, the one or more additional treatments may be administered simultaneously or sequentially to the bacteria from one or more bacterial strains, including administering at different times. In some embodiments, the one or more additional treatments may be administered in one composition with the bacteria from one or more bacterial strains. In some embodiments, the one or more additional treatments may be administered in different compositions from the bacteria from one or more bacterial strains.

[0234] In some embodiments, the one or more additional treatments comprises an effective amount of a composition that stimulates growth and / or activity of the bacteria from one or more bacterial strains.

[0235] In some embodiments, the one or more additional treatments comprises an antitumor therapy.

[0236] In some embodiments, the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.90323665488vlAttorney Docket No. 243735.000480

[0237] A chemotherapy or chemotherapeutic agent (i.e., an anti-cancer agent), is used according to its ordinary meaning, referring to a chemical composition, biologic, protein, nucleic acid, drug, inhibitor, antagonist, modulator, and / or compound having the ability to inhibit the growth or proliferation of cells and / or antineoplastic properties. In some aspects, an anti-cancer agent is a therapeutic agent approved by the FDA or equivalent or similar regulatory agency, for treating cancer.

[0238] A chemotherapy which the subject may be further treated include, but are not limited to, adrenocorticoids and corticosteroids, kinase inhibitors, androgens, alkylating agents, estrogens, peptide and peptidomimetic signal transduction inhibitors, aclamycin and aclamycin derivatives, pyrimidine analogs, purine analogs, platinum compounds, antiestrogens, antiandrogens, plant alkaloids, antimetabolites, microtubule inhibitors, amanitins, epothilones, mitomycins, discodermolides, dolastatins, inflammatory and proinflammatory agents, camptothecins, and / or immunotherapies.

[0239] In some embodiments, the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infdtrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

[0240] In some embodiments, the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

[0241] In some embodiments, the one or more additional treatments comprises nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site.

[0242] In some embodiments, the nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site comprise at least one non-caloric sugar.91323665488vlAttorney Docket No. 243735.000480

[0243] In some embodiments, the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.EXAMPLES

[0244] The present invention is also described and demonstrated by way of the following examples. However, the use of these and other examples anywhere in the specification is illustrative only and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to any particular preferred embodiments described here. Indeed, many modifications and variations of the invention may be apparent to those skilled in the art upon reading this specification, and such variations can be made without departing from the invention in spirit or in scope. The invention is therefore to be limited only by the terms of the appended claims along with the full scope of equivalents to which those claims are entitled.EXAMPLE 1. No indication of bacteremia upon treatment with gut commensal microbes.

[0245] Many gut bacteria can cause dangerous bacteremia and sepsis when they enter the blood stream. However, some species, despite extremely large numbers in the gut and a habitat close to the epithelium, which would increase their chance to translocate and cause bacteremia, have never been found to do so. To assess the feasibility of developing such gut commensal microbes as tumor-targeted therapeutics, first their safety was assessed by injecting a high dose of monocultured bacteria into mice and contrasting the gut microbes with potential pathobionts such as E. coli (Fig. 1). E. coll is often used in research studying tumor microbiome modulation via bacteria. While intravenous injection of 2xl09colony forming units of E. coli led to rapid lethality, injecting the same dose of commensals that are less associated with opportunistic bacteremia such as Akkermansia muciniphila, Ruminococcus guavus, Roseburia intestinalis, Streptococcus salivarius, Bacteroides thetaiotaomicron Bifidobacterium dentium and Bifidobacterium longum did not induce sickness or lethality. Of note, the injection of 2xl09CFU constitutes a very high dose; in other experiments targeting tumors with natural or engineered strains, usually a 1, GOO- 92323665488vlAttorney Docket No. 243735.000480fold lower dose of bacteria is required due to their high lethality. This data shows that selecting microbiome symbionts is an effective fdter for selection of safe strains relative to A. coli. Showing selected gut and oral microbiome species were safe for IV injection into mice supports the low risk of this treatment approach.EXAMPLE 2. Private nutrients for selectively enriching therapeutic bacteria in the tumor environment and improving bacteria-mediated anti-tumor effects.

[0246] Gut microbes have evolved specialized nutrient utilization abilities that include the ability to consume carbohydrates that are indigestible to humans. To assess the feasibility of increasing competitive growth of commensal bacterial in the highly cellular tumor microenvironment by supplying such “private” nutrients to the bacteria, their ability to utilize “non-caloric” sugars in vitro was assessed. Non-caloric sugars represent a broad class of monosaccharides and disaccharides that are used as sweeteners but bear little to no caloric value as human cells are incapable of metabolizing them. If these sugars can be utilized by tumorcolonizing microbes, the microbes would confer a competitive advantage in the glucose poor tumor microenvironment. Several commensal bacteria showed robust growth on these non-caloric sugars in the absence of glucose (Fig. 2A). Then, a non-caloric sugar and bacterium pairing (sucrose and . salivarius was tested for its impact on MC38 murine colon adenocarcinoma growth in vitro. First, it was demonstrated that sucrose is a “private nutrient” and a strong promoter of salivarius growth (Fig. 2B), but does not affect MC38 cancer cell growth (Fig. 2C) nor viability (Fig. 2D). Next, in coculture of MC38 and S. salivarius, it was shown that the private nutrient increased growth of S. salivarius (Fig. 2E), and that viability of MC38 was significantly reduced when sucrose was added to the coculture (Fig. 2F). Taken together, it is shown that sucrose is a private nutrient for S. salivarius, enriches S. salivarius in a model system of cancer cell-bacterial co-culture, and enhances S. salivarius-mediated MC38 cytotoxicity. Thus, host-indigestible sugars can promote the growth of the candidate bacterial strains and augment their potential therapeutic effects.EXAMPLE 3. Selected gut bacteria grow in a tumor.

[0247] A. muciniphila, R. gnavus, R. intestinalis, S. salivarius, and B. thetaiotaomicron were injected directly into subcutaneous MC38 colon cancer tumors. The bacterial strains were 93323665488vlAttorney Docket No. 243735.000480able to persist and remain viable for at least 4 days, which was validated by detection of the injected bacteria using genome-specific quantitative PCR and growth on agar plates (Fig.3).EXAMPLE 4. Tumor-induced mice treated with bacteria.

[0248] C57BL / 6 mice maintained in a specific pathogen-free facility were injected subcutaneously with cancer cells to induce a tumor (Fig. 4A). Bifidobacterium dentium, Bacteroides thetaiotaomicron Streptococcus sciHvarius, and Veillonella parvula were injected intravenously. All mice survived this extremely high load of bacteria injected into their blood (Fig.4B) Further survival data on single strain injections support the safety of this procedure in mice. Each of the injected bacterial strains were detectable in the tumor homogenates, supporting the conclusion that the bacteria were actively growing in or on the tumor (Fig.4C).EXAMPLE 5. Modulation of tumor microenvironment with bacteria.

[0249] To test modulation of the tumor immune microenvironment, the immune responses (e g., specific and localized immune responses) elicited by bacterial strains selected from the gut epithelium-microbiome interface and / or identified by the methods described herein are determined. After the bacterial strains accumulate in colonized tumors, it is tested whether the bacterial products can promote inflammation, thereby rendering in vitro immunologically “cold” tumors “hot" and thus causing the tumors to be more susceptible to anti-tumor immune activity.

[0250] To test modulation of the tumor mucin microenvironment, the mucin digestion elicited by bacterial strains selected from the gut epithelium-microbiome interface and / or identified by the methods described herein is determined. It is tested to what extent the bacterial strains can grow on mucin-producing cancer cell lines in vitro. The degradation of cancer-expressed mucins would thereby expose tumor cells for immune clearance.EXAMPLE 6. Intratumoral bacteria selectively expand upon private nutrient provision, and are associated with significantly reduced tumor size.

[0251] Isoflurane-anesthetized C57BL / 6 mice were injected subcutaneously with 5*105KRAS / TP53-mutant lung adenocarcinoma cells. Tumor cells were harvested from cultures maintained in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum and gentamicin. Tumors were allowed to establish and grow for 18 days. Established tumors94323665488vlAttorney Docket No. 243735.000480were injected intratum orally with bacteria selected from Bacteroides thetaiotaomicron^ Streptococcus salivarius ox Bifidobacterium dentium (each 3.33xl08CFU in in 150pL phosphate-buffered saline, PBS). Following bacterial administration, a subset of animals received intratumoral injections of sucrose (10% concentration in 300pL), while control animals received sterile PBS. Sucrose or control injections were administered every 12 hours for a period of 48 hours. Two days after bacterial administration, animals were euthanized by carbon dioxide inhalation, and subcutaneous tumors were aseptically excised. Tumor tissue was processed for genomic DNA isolation using a bacteria-compatible extraction method. Quantitative PCR was performed using primers specific for bacterial genomic sequences and primers targeting a tumorspecific mutant TP53 genomic locus, enabling normalization of bacterial signal to tumor cell content. Mucinolytic Bacteroides thetaiotaomicron exhibited increased intratumoral abundance in sucrose-supplemented tumors relative to phosphate-buffered saline controls and tumors not receiving bacteria (Fig. 5A). Normalization of bacterial quantitative PCR signal to the mutant TP53 tumor genomic marker demonstrated an approximately three-fold increase in bacterial abundance per tumor cell in sucrose-supplemented tumors compared with controls (p = 0.07, onesided t-test). In the sucrose-supplemented group, a significant reduction in tumor volume was observed over the 48 hour period after bacterial injection, whereas pre-treatment volumes were unchanged (Fig. 5B).

[0252] Below are the methods used in the Examples described above.

[0253] Testing bacterial safety in mice (Example 1): Bacteria of interest were grown in BHI medium at 37 °C in an anaerobic chamber. ODeoo was measured after 48-72 hours of culture, and the liquid cultures were plated on agar plates to enumerate the colony forming units (CFU) that correspond to the measured ODeoo. Bacteria of interest, again grown in the same conditions, were harvested after 48-72 hours and pelleted at 2000rcf at 4 °C. The bacterial pellets were washed twice with ice cold phosphate buffered saline and resuspended in phosphate buffered saline to a final dilution of 2xl09CFU / 100 pL. The bacteria suspension was injected retro-orbitally in isofl urane-anesthetized C57BL / 6 mice. The bacteria-inj ected animals were observed for signs of illness and sacrificed upon meeting the humane end point.

[0254] Testing bacterial growth in combination with sugars (Example 2): BHI bacterial culture medium without glucose was supplemented with 5 mM candidate “non-caloric” sugars95323665488vlAttorney Docket No. 243735.000480(i.e ., cellobiose). The “non-caloric” sugar-supplemented media was used to culture bacteria of interest in an anaerobic chamber at 37 °C with interval measurements of ODeoo to assess growth kinetics. Bacterial growth was confirmed by counting colony forming units on agar plates.

[0255] Testing bacterial growth in tumors (Example 3): Isoflurane-anesthetized C57BL / 6 mice were injected subcutaneously with 250,000 MC38 cells that had been harvested from culture in DMEM, 10% fetal bovine serum, and penicillin / streptomycin. The tumors were allowed to grow for 14 days then were injected intratum orally with bacteria of interest suspended in phosphate buffered saline. 4 days after bacterial injection, mice were euthanized by carbon dioxide, and the subcutaneous tumors were sterilely dissected by accessing them from the internal connective tissues. Tumors were diced using sterile scissors, suspended in BHI medium, and homogenized with zirconium beads. The homogenate was spun down at 400rcf to precipitate eukaryotic cells and issue debris. A portion of the supernatant was plated on agar plates to confirm the presence of live bacteria and another part was used to isolate genomic DNA. Quantitative PCR using bacteria specific primers was performed to quantify the presence of specific bacteria.

[0256] Testing bacterial detection in tumor-induced mice (Example 4): Isoflurane-anesthetized C57BL / 6 mice were injected subcutaneously with 250,000 MC38 cells that had been harvested from culture in DMEM, 10% fetal bovine serum, and penicillin / streptomycin. The tumors were allowed to grow for 14 days then the tumor-bearing mice were injected retro-orbitally with bacteria of interest suspended in phosphate buffered saline. 4 days after bacterial injection, mice were euthanized by carbon dioxide, and the subcutaneous tumors were sterilely dissected by accessing them from the internal connective tissues. Tumors were diced using sterile scissors, suspended in BHI medium, and homogenized with zirconium beads. The homogenate was spun down at 400rcf to precipitate eukaryotic cells and issue debris. A portion of the supernatant was plated on agar plates to confirm the presence of live bacteria and another part was used to isolate genomic DNA. Quantitative PCR using bacteria specific primers was performed to quantify the presence of specific bacteria.REFERENCES

[0257] 1. Foster, K., Schluter, J., Coyte, K. et al. The evolution of the host microbiome as an ecosystem on a leash. Nature 548, 43-51 (2017). DOI: 10.1038 / nature2329296323665488vlAttorney Docket No. 243735.000480

[0258] 2. Hooper, L. V., Gordon, J. I. Commensal Host-Bacterial Relationships in the Gut. Science 292, 1115-1118 (2001). DOI: 10.1126 / science.l058709

[0259] 3. Schluter, J., Djukovic, A., Taylor, B. P., Yan, J., Duan, C., Hussey, G. A., Liao, C., Sharma, S., Fontana, E., Amoretti, L. A., Wright, R. J., Dai, A., Peled, J. U., Taur, Y., Perales, M. A., Siranosian, B. A., Bhatt, A. S., van den Brink, M. R. M., Pamer, E. G., Xavier, J. B. The TaxUMAP atlas: Efficient display of large clinical microbiome data reveals ecological competition in protection against bacteremia. Cell Host Microbe. 2023, 31(7): 1126-1139. e6. DOI: 10.1016 / j.chom.2023.05.027

[0260] 4. Kashyap, P. C., Marcobal, A., Ursell, L. K., Smits, S. A., Sonnenburg, E. D., Costello, E. K., Higginbottom, S. K., Domino, S. E., Holmes, S. P., Reiman, D. A., Knight, R., Gordon, J. I., Sonnenburg, J. L. Genetically dictated change in host mucus carbohydrate landscape exerts a diet-dependent effect on the gut microbiota, Proc. Natl. Acad. Sci. U.S.A. 2013, 110 (42), 17059-17064. DOI: 10.1073 / pnas.1306070110

[0261] 5. Sonnenburg, J. L., et al. Glycan Foraging in Vivo by an Intestine-Adapted Bacterial Symbiont. Science 307, 1955-1959 (2005). DOI: 10.1126 / science.1109051

[0262] 6. Winter, S. E., Baumler, A. J. Dysbiosis in the inflamed intestine: Chance favors the prepared microbe. Gut Microbes, 2014, 5 (1), 71-73. DOI: 10.4161 / gmic.27129

[0263] 7 Rakoff-Nahoum, S., Foster, K. R., Comstock, L. E. The evolution of cooperation within the gut microbiota. Nature. 2016, 533 (7602): 255-259. DOI: 10.1038 / naturel7626

[0264] 8. Park, S. Y., Rao, C., Coyte, K. Z., Kuziel, G. A., Zhang, Y., Huang, W., Franzosa, E. A., Weng, J. K., Huttenhower, C., Rakoff-Nahoum, S. Strain-level fitness in the gut microbiome is an emergent property of glycans and a single metabolite. Cell. 2022, 185 (3): 513-529. e21. DOI: 10.1016 / j.cell.2022.01.002

[0265] 9. Stahl, M., Friis, L. M., Nothaft, H., Liu, X., Li, J., Szymanski, C. M., Stintzi, A. L-fucose utilization provides Campylobacter jejuni with a competitive advantage. Proc Natl Acad Sci USA. 2011, 108 (17): 7194-9. DOI: 10.1073 / pnas.l014125108

[0266] 10. Kim, S., Shin, Y. C., Kim, T. Y., Kim, Y., Lee, Y. S., Lee, S. H., Kim M. N., Eunju, O., Kim, K. S., Kweon, M. N. Mucin degrader Akkermansia muciniphila accelerates intestinal stem cell-mediated epithelial development. Gut Microbes, 2021, 73(1). DOI: 10.1080 / 19490976.2021.189244197323665488vlAttorney Docket No. 243735.000480

[0267] 11. Louis, P., Duncan, S. H., Sheridan, P. O., Walker, A. W., Flint, H. J. Microbial lactate utilisation and the stability of the gut microbiome. Gut Microbiome . 2022, 3:e3. DOI:10.1017 / gmb.2022.3

[0268] 12. Redenti, A., Im, J., Redenti, B. et al. Probiotic neoantigen delivery vectors for precision cancer immunotherapy. Nature, 2024. DOI: 10.1038 / s41586-024-08033-4

[0269] 13. Canale, F.P., Basso, C., Antonini, G. et al. Metabolic modulation of tumours with engineered bacteria for immunotherapy. Nature, 2021, 598, 662-666. DOI: 10.1038 / s41586-021-04003-2

[0270] 14. Nguyen, D. H., You, S. H., Ngo, H. T. T. et al. Reprogramming the tumor immune microenvironment using engineered dual-drug loaded Salmonella. Nat Commun, 2024, 15, 6680. DOI: 10.1038 / s41467-024-50950-5* * *

[0271] The present invention is not to be limited in scope by the specific embodiments described herein. Indeed, various modifications of the invention in addition to those described herein will become apparent to those skilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.

[0272] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.98323665488vl

Claims

Attorney Docket No. 243735.000480CLAIMS WHAT IS CLAIMED IS:

1. A method for identifying a bacterial strain or consortium of bacterial strains capable of being detectable in a tumor in a patient, said method comprising:(a) determining whether the bacterial strain or consortium of bacterial strains comprises the ability to digest tumor-associated glycoproteins;(b) determining whether administration of high doses of the bacterial strain or consortium of bacterial strains has an impact on the health of an in vivo animal model;(c) determining whether the bacterial strain or consortium of bacterial strains comprises the ability to consume carbohydrates that are metabolically inaccessible to the patient and / or the tumor, and / or carbohydrates that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site; and / or(d) determining whether the bacterial strain or consortium of bacterial strains can be detected in a tumor.

2. The method of claim 1, wherein step (a) comprises determining whether a gene encoding an enzyme that degrades glycoproteins can be activated in the bacterial strain or consortium of bacterial strains.

3. The method of claim 2, wherein the at least one enzyme is a protease, glycosidase, or glycopeptidase.

4. The method of claim 3, wherein the protease is a mucin-degrading protease.

5. The method of claim 3, wherein the glycosidase is a mucinase, sialidase, galactosidase, and / or fucosidase.99323665488vlAttorney Docket No. 243735.0004806. The method of any one of claims 1-5, wherein step (a) comprises determining whether a gene encoding an enzyme that increases susceptibility of the tumor cells to immune cytotoxic cell-mediated killing or phagocytosis is active in the bacterial strain or consortium of bacterial strains.

7. The method of claim 6, wherein the immune cytotoxic cells are T cells and / or NK cells.

8. The method of any one of claims 1-7, wherein step (a) comprises determining tumorspecific glycoproteins and determining whether the bacterial strain or consortium of bacterial strains can digest the tumor-specific glycoproteins.

9. The method of any one of claims 1-8, wherein step (b) comprises determining whether the high doses of the bacterial strain or consortium of bacterial strains are non-lethal in an in vivo animal model.

10. The method of any one of claims 1 -8, wherein step (b) comprises determining whether the high doses of the bacterial strain or consortium of bacterial strains do not cause acute lung injury, kidney injury, or liver injury in an in vivo animal model.

11. The method of any one of claims 9-10, wherein the high doses of the bacterial strain or consortium of bacterial strains are between 107and 1011colony forming units (CFU) / kg.

12. The method of any one of claims 1-11, wherein the administration of the high doses of the bacterial strain or consortium of bacterial strains in step (b) comprises at least one of oral, intravenous, intraperitoneal, intratumoral, intravesical, dermal, intrathecal, intranasal, upper gastrointestinal routes (UG1) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

13. The method of any one of claims 1-12, wherein step (c) comprises determining whether the bacterial strain or consortium of bacterial strains comprises the ability to utilize non-caloric sugars in the absence of glucose in vitro.100323665488vlAttorney Docket No. 243735.00048014. The method of claim 13, wherein the non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, or N-acetylglucosamine.

15. The method of any one of claims 1-14, wherein step (d) comprises administering the bacterial strain or consortium of bacterial strains in an in vivo model system of the tumor type expressed in the patient and testing a tumor expressed in the in vivo model system for detection of the bacterial strain or consortium of bacterial strains in the tumor.

16. The method of claim 15, wherein detection is tested within 24 hours to 10 days post administration.

17. The method of any one of claims 1-14, wherein step (d) comprises injecting the bacterial strain or consortium of bacterial strains in an isolated tumor and determining whether the bacterial strain remains persistent and viable for at least about 24 hours to at least about 10 days.

18. The method of claim 17, wherein the isolated tumor is the same type of tumor expressed in the patient.

19. The method of claim 17, wherein the isolated tumor is obtained from the patient.

20. The method of any one of claims 1-19, wherein detection of the bacterial strain or consortium of bacterial strains in the tumor includes measuring by qPCR, measuring growth of the bacterial strain or consortium of bacterial strains on agar plates from tumor homogenates, or using high-throughput sequencing methods.

21. The method of claim 20, wherein the high-throughput sequencing methods are selected from the group consisting of using an amplicon sequencing approach, a 454 machine, miSeq, Pacbio, or other related devices, profiling of microbial 16S ribosomal RNA genes (16S rDNA), and next generation sequencing (NGS).101323665488vlAttorney Docket No. 243735.000480l. The method of any one of claims 1-21, wherein the method further comprises determining whether the bacterial strain or consortium of bacterial strains does not express a catalase.

23. The method of any one of claims 1-21, wherein the method further comprises determining whether the bacterial strain or consortium of bacterial strains expresses a catalase.

24. The method of any one of claims 1-23, wherein the bacterial strain or consortium of bacterial strains elicit an anti-tumor response.

25. The method of any one of claims 1-23, wherein the bacterial strain or consortium of bacterial strains augment an anti-tumor response.

26. The method of any one of claims 1-25, wherein the anti-tumor response is i) reduced tumor growth, ii) tumor reduction, iii), tumor eradication, iv) enhanced anti-tumor immune response, v) tumor genomic composition alteration, and / or vi) tumor phenotype alteration.

27. The method of claim 26, wherein the altered tumor phenotype is characterized by i) altered gene expression in a bulk of the tumor, ii) altered gene expression in a tumor single cell subset, iii) altered tumor cell composition, and / or iv) altered tumor response to an anti-tumor therapy.

28. The method of claim 27, wherein the altered gene expression is characterized by increased gene signatures associated with anti-tumor immunity.

29. The method of claim 28, wherein the increased gene signatures associated with anti-tumor immunity comprise increased expression of PDL1, CXCL9, CXCL10, and / or CXCL11.

30. The method of claim 27, wherein the altered tumor cell composition is characterized by increased density and / or proportion of tumor infdtrating leukocytes, increased density and / or proportion of tumor infdtrating lymphocytes, and / or reduced density and / or proportion of tumor suppressive myeloid cells.102323665488vlAttorney Docket No. 243735.00048031. The method of claim 27, wherein the altered tumor cell composition is measured by cytometry, by single-cell, by deconvoluted bulk RNA sequencing, by microscopy imaging, by immunohistology, by tumor growth kinetics, by tumor reduction, and / or by altered activity of infdtrating immune cells.

32. Themethod of claim 31, wherein the altered activity of infiltrating immune cells comprises increased density and / or proportion of tumor infiltrating leukocytes, increased density and / or proportion of tumor infiltrating lymphocytes, and / or increased anti-tumor phenotypes of infiltrating leukocytes.

33. The method of any one of claims 1-32, further comprising administering one or more treatments to the subject.

34. The method of claim 33, wherein the one or more treatments comprises administering the bacterial strain or consortium of bacterial strains.

35. The method of claim 33 or claim 34, wherein the one or more treatments comprises administering an effective amount of a composition that stimulates growth and / or activity of the bacterial strain or consortium of bacterial strains.

36. The method of any one of claims 33-35, wherein the one or more treatments further comprises administering an anti -turn or therapy.

37. The method of claim 27 or claim 36, wherein the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.

38. The method of claim 37, wherein the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infiltrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage103323665488vlAttorney Docket No. 243735.000480therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

39. The method of claim 37, wherein the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

40. The method of any one of claims 33-39, wherein the route of administration for said one or more treatments comprises at least one of intratumoral, intravenous, intravesical, dermal, transdermal, subcutaneous, intrathecal, intranasal, intraperitoneal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

41. The method of any one of claims 33-40, wherein the one or more treatment comprises administering nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site.

42. The method of claim 41, wherein the nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or the nutrients that are shown to promote establishment of the bacterial strain or consortium of bacterial strains at the tumor site comprise at least one non-caloric sugar.

43. The method of claim 42, wherein the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.

44. A bacteria strain composition comprising (i) bacteria from one or more bacterial strains as determined by the methods of any one of claims 1-43 or a closely related OTU which has at least104323665488vlAttorney Docket No. 243735.00048090% (or at least 95%, or at least 97%, or at least 99%) sequence identity to the 16S rRNA gene over its entire length or has at least 90% (or at least 95%, or at least 99%) sequence identity to any single V region of the 16S rRNA gene and (ii) a carrier and / or an excipient and / or one or more additional composition which stimulate growth and / or activity and / or preserve viability of one or more bacteria present in the composition.

45. The strain composition of claim 44, wherein the bacteria strain composition elicits an antitumor response in a patient.

46. The strain composition of claim 44, wherein the bacteria strain composition augments an anti-tumor response in a patient.

47. The strain composition of any one of claims 44-46, wherein the bacteria strain composition comprises (i) gene products as determined by the methods of any one of claims 1-39 or a closely related OTU which has at least 90% (or at least 95%, or at least 97%, or at least 99%) sequence identity to sialidase of Akkermansia nniciniphila (gene name HXS70 08015), glycopeptidase of Bacteroides thetaiotaomicron (gene name BT4244-M60E), or metalloprotease of Escherichia coli (gene name stc ) and (ii) a carrier and / or an excipient and / or one or more additional composition which stimulate growth and / or activity and / or preserve viability of one or more bacteria present in the composition.

48. The strain composition of any one of claims 44-47, wherein the additional composition is at least one nutrient that is metabolically inaccessible to the patient and / or the tumor, and / or at least one nutrient that is shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site.

49. The strain composition of claim 48, wherein the nutrient that is metabolically inaccessible to the patient and / or the tumor, and / or the nutrient that is shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site comprises at least one non-caloric sugar.105323665488vlAttorney Docket No. 243735.00048050. The strain composition of claim 49, wherein the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.

51. The strain composition of any one of claims 44-50, wherein the composition further comprises or is administered with one or more anti-tumor therapy.

52. The strain composition of claim 51, wherein the anti -tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.

53. The strain composition of claim 52, wherein the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumorinfiltrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

54. The strain composition of claim 52, wherein the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

55. The strain composition of any one of claims 44-54, wherein the one or more bacterial strain is selected from the phylum of: Bacillota (Firmicutes), Bacteroidota (Bacteroidetes), Pseudomonadota (Proteobacteria), Actinomycetota (Actinobacteria), Fusobacteriota (Fusobacteria), Verrucomicrobiota (Verrucomicrobia), Cyanobacteriota (Cyanobacteria), Spirochaetota (Spirochaetes), and Mycoplasmota (Teneri cutes), and combinations thereof.106323665488vlAttorney Docket No. 243735.00048056. The strain composition of any one of claims 44-54, wherein the one or more bacterial strain is selected from the genera of Mediterraneibacter, Lactobacillus, Bacteroides, Prevotella, Clostridium, Streptococcus, Escherichia, Enterococcus, Fusobacterium, Ruminococcus, Faecalibacterium, Veillonella, Staphylococcus, Propionibacterium, Peptostreptococcus, Eubacterium, Roseburia, Blautia, Sutterella, Helicobacter, Campylobacter, Haemophilus, Rothia, Akkermansia, Pseudomonas, Neisseria, Porphyromonas, Moraxella, Corynebacterium, Methanobrevibacter, Klebsiella, Proteus, Actinomyces, Bifidobacterium, Dorea, Selenomonas, Tannerella, Treponema, Alistipes, Parabacteroides, Megasphaera, Odoribacter, Mogibacterium, Desulfovibrio, Gemella, Dialister, Lachnospira, Collinsella, Butyrivibrio, Leptotrichia, Capnocytophaga, Bilophila, Vibrio, Slackia, Burkholderia, Rhodobacter, Aeromonas, Alcaligenes, Acidaminococcus, Cloacibacterium, Eggerthella, Coprococcus, Anaerostipes, Oscillospira, Fecalibacterium, Syntrophomonas, Turicibacter, Barnesiella, Victivallis, Tissierella, Veillonellaceae, Sporosarcina, Veillonella, Oribacterium, Desulfitobacterium, Shigella, Gordonibacter, Citrobacter, Anaerostipes, Solobacterium, Flavonifractor, Prevotella, Holdemania, Adlercreutzia, Lactonifactor, Methanosphaera, Phascolarctobacterium, Paraprevotella, Sarcina, Lactococcus, Weissella, Variovorax, Sphingobacterium, Enterobacter, Citrobacter, Klebsiella, Acinetobacter, Janthinobacterium, Providencia, and Stenotrophomonas, and combinations thereof.

57. The strain composition of any one of claims 44-54, wherein the one or more bacterial strain is selected from the species of Akkermansia muciniphila, Mediterraneibacter gnavus, Roseburia intestinalis, Streptococcus salivarius, Bacteroides thetaiotaomicron, Bifidobacterium dentium, Bifidobacterium longum, Veillonella parvula, Ruminococcus gnavus, Ruminococcus intestinalis, and Bacillus subtillis, and combinations thereof.

58. A method for modulating a tumor microenvironment in a patient, said method comprising administering to the patient the bacteria from one or more bacterial strains as determined by the methods of any one of claims 1-43 or the bacteria strain composition according to any one of claims 44-57.

59. The method of claim 58, wherein the bacteria elicits an anti-tumor response in a patient.107323665488vlAttorney Docket No. 243735.00048060. The method of claim 58, wherein the bacteria augments an anti-tumor response in a patient.

61. The method of any one of claims 58-60, wherein the tumor microenvironment is the tumor mucin microenvironment.

62. The method of any one of claims 58-60, wherein the tumor microenvironment is the tumor immune microenvironment.

63. The method of claims 58-62, wherein the modulation of the tumor microenvironment increases susceptibility of the tumor to immune cytotoxic cell-mediated killing or phagocytosis.

64. A method of treating a cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the bacteria from one or more bacterial strains as determined by the methods of any one of claims 1-43 or the bacteria strain composition according to any one of claims 44-57.

65. The method of claim 64, wherein the bacteria elicits an anti -tumor response in a patient.

66. The method of claim 64, wherein the bacteria augments an anti-tumor response in a patient.

67. A method of reducing a size or volume of a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the bacteria from one or more bacterial strains as determined by the methods of any one of claims 1-43 or the bacteria strain composition according to any one of claims 44-57.

68. The method of claim 67, wherein the tumor volume is reduced by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

69. The method of any one of claims 64-66, wherein the cancer is breast cancer, lung cancer, colorectal cancer, prostate cancer, ovarian cancer, bladder cancer, skin cancer, central nervous system cancer, nasal cancer, stomach cancer, peritoneal cancer, pancreatic cancer, kidney cancer, liver cancer, esophageal cancer, squamous cell carcinoma, adenocarcinoma, transitional cell 108323665488vlAttorney Docket No. 243735.000480carcinoma, basal cell carcinoma, neuroendocrine cancer, bile duct cancer, thyroid cancer, adrenal cancer, soft tissue sarcoma, bone cancer, testicular cancer, nasal cancer, oropharyngeal cancer, anal cancer, penile cancer, vaginal cancer, cervical cancer, thymus cancer, or uveal melanoma.

70. The method of any one of claims 64-66, wherein the cancer is characterized by the presence of a tumor.

71. The method of claim 70, wherein a size or volume of the tumor is reduced, optionally by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

72. The method of any one of claims 64-71, wherein the administration to the patient comprises at least one of oral, intravenous, intraperitoneal, intratumoral, intravesical, dermal, transdermal, subcutaneous, intrathecal, intranasal, upper gastrointestinal routes (UGI) (such as nasogastric / nasojejunal tube, endoscopy, or oral capsules) or lower gastrointestinal routes (LGI) (such as retention enema, sigmoidoscopy or colonoscopy).

73. The method of any one of claims 58-72, wherein the method further comprises administering one or more additional treatments to the patient.

74. The method of claim 73, wherein the one or more additional treatments comprises an effective amount of a composition that stimulates growth and / or activity of the bacteria from one or more bacterial strains.

75. The method of claim 73, wherein the one or more additional treatments comprises an antitumor therapy.

76. The method of claim 75, wherein the anti-tumor therapy is chemotherapy, radiation, a targeted radiopharmaceutical drug, a therapeutic vaccine, a therapeutic monoclonal antibody, a molecularly targeted small molecule therapeutic, an immune checkpoint inhibitor, or cellular therapy.109323665488vlAttorney Docket No. 243735.00048077. The method of claim 76, wherein the cellular therapy is autologous hematopoietic cell transplantations, allogeneic hematopoietic cell transplantations, chimeric antigen receptor (CAR) T cell therapy, engineered T cell receptor therapy, autologous tumor-infiltrating lymphocyte therapy, autologous or off-the-shelf NK cell therapy, autologous or off-the-shelf macrophage therapy, autologous or off-the-shelf gamma delta T cell therapy, autologous or off-the-shelf MAIT cell therapy, or autologous or off-the-shelf NKT cell therapy.

78. The method of claim 76, wherein the immune checkpoint inhibitor is selected from the group consisting of anti-PD-1 antibody, anti-PD-Ll antibody, anti-PD2 antibody, anti-TIM-3 antibody, anti-LAG-3 antibody, anti-CTLA4 antibody, anti-TIGIT antibody, anti-CD47 antibody, anti-SIRPla antibody, and a combination thereof.

79. The method of claim 73, wherein the one or more additional treatments comprises nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site.

80. The method of claim 79, wherein the nutrients that are metabolically inaccessible to the patient and / or the tumor, and / or nutrients that are shown to promote establishment of the bacteria from one or more bacterial strains at the tumor site comprise at least one non-caloric sugar.

81. The method of claim 80, wherein the at least one non-caloric sugar is trehalose, isomaltose, methylglucoside, 2-fucosyllactose, psicose, sucrose, maltose, lactose, cellobiose, lactulose, chitobiose, kojibiose, nigerose, sophorose, laminaribiose, gentiobiose, turanose, maltulose, leucrose, isomaltulose, gentiobiulose, mannobiose, melbiose, allolactose, melibiulose, rutinose, rutinulose, xylobiose, N-acetylglucosamine, or a combination thereof.110323665488vl

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