Pharmaceutical compositions containing bacteria

Abstract

Methods and compositions relating to bacteria-containing pharmaceutical products are provided herein.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 172,370, filed April 8, 2021, and U.S. Provisional Patent Application No. 63 / 197,000, filed June 4, 2021, the entire contents of each of which are incorporated herein by reference. Summary of the Invention [Means for solving the problem]

[0002] In certain embodiments, provided herein are pharmaceutical preparations (e.g., powders) comprising bacteria (e.g., lyophilized bacteria), wherein the bacteria in the pharmaceutical preparation are present in an amount of at least 1 x 10 per gram of the pharmaceutical preparation. 11 In some embodiments, the bacteria are present at a total cell count (TCC) of at least 3.3 x 10 cells per gram of pharmaceutical preparation. 11 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of at least 5 x 10 cells per gram of pharmaceutical preparation. 11 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of at least 7 x 10 cells per gram of pharmaceutical preparation. 11 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of at least 1 x 10 cells per gram of pharmaceutical preparation. 12 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of at least 2 x 10 cells per gram of pharmaceutical preparation. 12 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of about 1 x 10 cells per gram of pharmaceutical preparation. 11 cells ~ approx. 2.5 x 10 12 In some embodiments, the bacteria are present in the pharmaceutical formulation at a total cell count (TCC) of about 3.3 x 10 cells per gram of pharmaceutical formulation. 11 cells ~ approx. 2.5 x 10 12In some embodiments, the bacteria are present in the pharmaceutical formulation at a total cell count (TCC) of about 5 x 10 cells per gram of pharmaceutical formulation. 11 cells ~ approx. 2.5 x 10 12 In some embodiments, the bacteria are present in the pharmaceutical formulation at a total cell count (TCC) of about 7 x 10 cells per gram of pharmaceutical formulation. 11 cells ~ approx. 2.4 x 10 12 In some embodiments, the bacteria are present in the pharmaceutical formulation at a total cell count (TCC) of about 2 x 10 cells per gram of pharmaceutical formulation. 12 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of about 1 x 10 cells per gram of pharmaceutical preparation. 12 cells ~ approx. 2 x 10 12 In some embodiments, the bacteria are present in the pharmaceutical formulation at a total cell count (TCC) of about 1.3 x 10 cells per gram of pharmaceutical formulation. 12 cells ~ approx. 2.4 x 10 12 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of about 2.5 x 10 cells per gram of pharmaceutical preparation. 12 In some embodiments, the bacteria are present in the pharmaceutical formulation at a total cell count (TCC) of about 1.2 x 10 cells per gram of pharmaceutical formulation. 12 In some embodiments, the bacteria are present in the pharmaceutical preparation at a total cell count (TCC) of about 1.5 x 10 cells per gram of pharmaceutical preparation. 12 In some embodiments, the bacteria are present in the pharmaceutical formulation at a total cell count (TCC) of about 6 x 10 cells per gram of pharmaceutical formulation. 11 The total cell count (TCC) of cells present in the drug product.

[0003] In certain aspects, provided herein are pharmaceutical preparations (e.g., powders) comprising bacteria (e.g., lyophilized bacteria) and a cryoprotectant.

[0004] In some embodiments, the cryoprotectant comprises sucrose. In some embodiments, the cryoprotectant comprises dextran. In some embodiments, the cryoprotectant comprises sucrose and dextran. In some embodiments, the cryoprotectant comprises equal amounts (e.g., on a weight percent basis) of sucrose and dextran. In some embodiments, the cryoprotectant comprises sucrose and dextran. In some embodiments, the cryoprotectant comprises sucrose, dextran, and L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant does not comprise L-cysteine ​​HCl.

[0005] In some embodiments, the pharmaceutical preparation comprises about 6% to about 12% (wt / wt) sucrose. In some embodiments, the pharmaceutical preparation comprises about 8% to about 12% (wt / wt) sucrose. In some embodiments, the pharmaceutical preparation comprises about 11% (wt / wt) sucrose. In some embodiments, the pharmaceutical preparation comprises about 6% to about 12% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 8% to about 12% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 11% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 6% to about 12% (wt / wt) sucrose and about 6% to about 12% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 8% to about 12% (wt / wt) sucrose and about 8% to about 12% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 11% (wt / wt) sucrose and about 11% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 0.1% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.1% to about 0.3% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.15% to about 0.25% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 10% to about 0.25% or about 0.15% to about 0.35% (wt / wt) L-cysteine ​​HCl.

[0006] In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 15% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 15% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) sucrose and about 7% to about 21% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) sucrose and about 10% to about 19% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 15% (wt / wt) sucrose and about 15% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 0.01% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.1% to about 0.4% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.15% to about 0.35% (wt / wt) L-cysteine ​​HCl.

[0007] In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21). In some embodiments, the cryoprotectant comprises sucrose. In some embodiments, the cryoprotectant comprises dextrose (also called glucose). In some embodiments, the cryoprotectant comprises monosodium glutamate. In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises equal amounts (e.g., on a weight percent basis) of a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and dextrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, dextrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises dextrose and sodium glutamate in equal amounts (e.g., on a weight percent basis).In some embodiments, the cryoprotectant comprises dried (dehydrated) corn glucose syrup (e.g., Glucidex), such as dried corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), sucrose, dextrose, sodium glutamate, and L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant does not comprise L-cysteine ​​HCl.

[0008] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 26% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 21% to about 29% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 23% to about 27% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 25% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 7% to about 10% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 9% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical composition comprises about 5% to about 9% (wt / wt) glutamate. In some embodiments, the pharmaceutical composition comprises about 7% (wt / wt) glutamate.

[0009] In some embodiments, the pharmaceutical composition comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 21% to about 29% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 23% to about 27% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0010] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (w / w) sucrose; about 6% to about 11% (w / w) dextrose; and about 4% to about 10% (w / w) glutamate. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 23% to about 27% (w / w) sucrose; and about 7% to about 10% (w / w) dextrose. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); 23% to about 27% (wt / wt) sucrose; and about 5% to about 9% (wt / wt) glutamate.In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex®), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex® 21); 23% to about 27% (w / w) sucrose; about 7% to about 1% (w / w) dextrose; and about 5% to about 9% (w / w) glutamate. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0011] In certain embodiments, the pharmaceutical product comprises about 40% to about 75% (weight / weight) bacteria (e.g., lyophilized bacteria). In certain embodiments, the pharmaceutical product comprises about 35% to about 70% (weight / weight) bacteria (e.g., lyophilized bacteria). In certain embodiments, the pharmaceutical product comprises about 64% (weight / weight) bacteria (e.g., lyophilized bacteria).

[0012] In certain embodiments, the pharmaceutical product contains about 15% to about 35% (weight / weight) of bacteria (e.g., lyophilized bacteria). In certain embodiments, the pharmaceutical product contains about 18% to about 30% (weight / weight) of bacteria (e.g., lyophilized bacteria). In certain embodiments, the pharmaceutical product contains about 25% (weight / weight) of bacteria (e.g., lyophilized bacteria).

[0013] In certain embodiments, the pharmaceutical agent comprises a Prevotella bacterium.

[0014] In certain embodiments, the pharmaceutical agent comprises a Veillonella bacterium.

[0015] In some embodiments, the pharmaceutical agent has the appearance of a fine, smooth granular powder.

[0016] In some embodiments, the pharmaceutical agent has the appearance of a fine off-white to brown powder.

[0017] In some aspects, the present disclosure provides pharmaceutical compositions comprising a pharmaceutical agent (e.g., a powder) described herein and one or more excipients.

[0018] In some aspects, the present disclosure provides a method comprising combining bacteria (e.g., a pellet containing bacteria) with a cryoprotectant solution, thereby preparing a formulation paste. In some embodiments, the present disclosure provides a formulation paste prepared by this method.

[0019] In some embodiments, the method further comprises lyophilizing the formulation paste, thereby preparing a lyophilized product. In some embodiments, the lyophilization comprises primary drying. In some embodiments, the lyophilization comprises primary drying and secondary drying. In some embodiments, the disclosure provides a lyophilized product prepared by this method.

[0020] In some embodiments, the method further comprises grinding the lyophilized product, thereby preparing a lyophilized powder (e.g., a powder, e.g., a pharmaceutical product). In some embodiments, the disclosure provides a pharmaceutical product prepared by this method.

[0021] In some embodiments, the method further comprises combining the lyophilized powder with one or more excipients, thereby preparing a pharmaceutical composition. In some embodiments, the present disclosure provides a pharmaceutical composition prepared by this method.

[0022] In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.2 to about 0.5 grams (g) of cryoprotectant solution per gram of pellet; about 0.05 to about 0.25 grams (g) of cryoprotectant solution per gram of pellet; about 0.06 to about 0.1 grams (g) of cryoprotectant solution per gram of pellet; or about 0.15 to about 0.2 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.4 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.18 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.1 (e.g., 0.08) grams (g) of cryoprotectant solution per gram of pellet.

[0023] In some embodiments, the cryoprotectant solution is mixed with the pellet at a ratio of 4% to 10% (volume / volume), e.g., 5% to 8% (volume / volume). In some embodiments, the cryoprotectant solution is mixed with the pellet at a ratio of about 6.5% (volume / volume).

[0024] In some embodiments, the cryoprotectant solution includes sucrose. In some embodiments, the cryoprotectant solution includes dextran. In some embodiments, the cryoprotectant solution includes sucrose and dextran. In some embodiments, the cryoprotectant solution includes equal amounts (e.g., on a weight percent basis) of sucrose and dextran. In some embodiments, the cryoprotectant solution includes sucrose, dextran, and L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant solution does not include L-cysteine ​​HCl.

[0025] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) sucrose. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) sucrose. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) sucrose.

[0026] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) dextran.

[0027] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) sucrose and about 10% to about 30% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) sucrose and about 15% to about 35% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) sucrose and about 20% (wt / wt) dextran.

[0028] In some embodiments, the cryoprotectant solution comprises about 40% to about 80% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 50% to about 70% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 55% to about 65% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 60% (wt / wt) water.

[0029] In some embodiments, the cryoprotectant solution comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant solution comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl. In some embodiments, the cryoprotectant solution comprises about 0.15% to about 0.45% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical product comprises about 0.1% to about 0.25% or about 0.15% to about 0.35% (w / w) L-cysteine ​​HCl.

[0030] In some embodiments, the cryoprotectant solution comprises about 0.2% (wt / wt) L-cysteine ​​HCl.

[0031] In some embodiments, the cryoprotectant solution comprises about 59.8% (wt / wt) water.

[0032] In some embodiments, the cryoprotectant solution comprises about 0.4% (wt / wt) L-cysteine ​​HCl.

[0033] In some embodiments, the cryoprotectant solution comprises about 59.6% (wt / wt) water.

[0034] In certain embodiments, the cryoprotectant solution provided herein comprises: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; (iii) about 0.4% (wt / wt) L-cysteine ​​HCl; and (iv) about 59.6% (wt / wt) water.

[0035] In certain embodiments, the cryoprotectant solution provided herein comprises: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; (iii) about 0.2% (wt / wt) L-cysteine ​​HCl; and (iv) about 59.8% (wt / wt) water.

[0036] In certain embodiments, the cryoprotectant solutions provided herein comprise: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; and (iii) about 60% (wt / wt) water.

[0037] In some embodiments, the cryoprotectant (e.g., a water-free dry composition) comprises about 40% to about 60% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) sucrose.

[0038] In some embodiments, the cryoprotectant comprises about 40% to about 60% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) dextran.

[0039] In some embodiments, the cryoprotectant comprises about 40% to about 60% (wt / wt) sucrose and 40% to about 60% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) sucrose and about 45% to about 55% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) sucrose and about 50% (wt / wt) dextran.

[0040] In some embodiments, the cryoprotectant comprises about 0.25% to about 5% (wt / wt) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant comprises about 0.5% to about 2.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.75% to about 1.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 1% (wt / wt) L-cysteine ​​HCl.

[0041] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 50% (wt / wt) sucrose; (ii) about 50% (wt / wt) dextran; and (iii) about 1% (wt / wt) L-cysteine ​​HCl.

[0042] In certain embodiments, the cryoprotectants provided herein comprise: (i) about 50% (wt / wt) sucrose; and (ii) about 50% (wt / wt) dextran.

[0043] In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21). In some embodiments, the cryoprotectant comprises sucrose. In some embodiments, the cryoprotectant comprises dextrose (also called glucose). In some embodiments, the cryoprotectant comprises monosodium glutamate. In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises equal amounts (e.g., on a weight percent basis) of a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and dextrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, dextrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises dextrose and sodium glutamate in equal amounts (e.g., on a weight percent basis).In some embodiments, the cryoprotectant comprises dried (dehydrated) corn glucose syrup (e.g., Glucidex), such as dried corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), sucrose, dextrose, sodium glutamate, and L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant does not comprise L-cysteine ​​HCl.

[0044] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 37% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21).

[0045] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) sucrose.

[0046] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) dextrose.

[0047] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) monosodium glutamate.

[0048] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 37% (wt / wt) sucrose.

[0049] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; about 8% to about 18% (wt / wt) dextrose; and about 8% to about 18% (wt / wt) monosodium glutamate.

[0050] In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; about 11% to about 15% (wt / wt) dextrose; and about 11% to about 15% (wt / wt) monosodium glutamate.

[0051] In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 37% (wt / wt) sucrose; about 13% (wt / wt) dextrose; and about 13% (wt / wt) monosodium glutamate.

[0052] In some embodiments, the cryoprotectant comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.1% to about 0.25% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.2% (wt / wt) L-cysteine ​​HCl.

[0053] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; (iv) about 13% (wt / wt) monosodium glutamate; and (v) about 0.2% (wt / wt) L-cysteine ​​HCl.

[0054] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; and (iv) about 13% (wt / wt) monosodium glutamate.

[0055] In certain aspects, provided herein are pharmaceutical products comprising bacteria. In certain embodiments, the pharmaceutical product maintains its stability, e.g., for 3, 6, 12, 18, and / or 24 months under long-term (2-8°C) and / or accelerated (23-27°C (optionally 60% relative humidity (RH))) storage conditions, e.g., as determined by total cell count (TCC) (e.g., determined by Coulter counter and described herein). In certain embodiments, the pharmaceutical product maintains its stability, e.g., for 3, 6, 12, 18, and / or 24 months under long-term (-20°C) and / or accelerated (2-8°C) storage conditions, e.g., as determined by total cell count (TCC) (e.g., determined by Coulter counter and described herein).

[0056] In certain aspects, provided herein are pharmaceutical products comprising bacteria. In some embodiments, the water content of the pharmaceutical products described herein, as determined, for example, by the Karl Fischer method for water content analysis provided in European Pharmacopoeia (Ph.Eur.) method 2.5.12, is about 0.5% to about 9%, about 1% to about 8%, or about 1% to about 6% (e.g., about 1.7%, such as 1.8%, for example, about 2%, for example, about 2.2%, for example, about 2.3%, for example, about 2.4%, for example, about 2.8%, for example, about 2.9%, for example, about 3%, for example, about 3.1%, for example, about 3.2%, for example, about 3.3%, for example, about 3.5%, for example, about 3.6%, for example, about 4%, for example, about 4.5%, for example, about 5%, for example, about 5.3%, for example, about 5.4%, or for example, about 7.8%). In some embodiments, the pharmaceutical product maintains its water content for, e.g., 3, 6, 12, 18, and / or 24 months under long-term (2-8°C) and / or accelerated (25°C (optionally 60% RH)) storage conditions. In some embodiments, the pharmaceutical product maintains its water content for, e.g., 3, 6, 12, 18, and / or 24 months under long-term (-20°C) and / or accelerated (2-8°C) storage conditions.

[0057] The pharmaceutical product can be derived from bacteria (e.g., a mixture of selected strains or agents (e.g., components) thereof). The pharmaceutical product can be derived from bacteria (e.g., a single selected strain and / or agent (e.g., component) thereof). The pharmaceutical product can be a powder containing bacteria and / or components thereof, and can include additional agents, such as, for example, cryoprotectants. For example, in some embodiments, the pharmaceutical product is a freeze-dried (e.g., lyophilized) powder of bacteria and / or components thereof, optionally including additional agents, such as cryoprotectants.

[0058] In some aspects, the present disclosure provides a solid dosage form (e.g., capsule, tablet, or mini-tablet) comprising a pharmaceutical agent (e.g., powder) described herein. The solid dosage form may be enteric coated.

[0059] In certain embodiments, the solid dosage form comprises a capsule. In some embodiments, the capsule is a size 00, 0, 1, 2, 3, 4, or 5 capsule. In some embodiments, the capsule is a size 0 capsule.

[0060] In some embodiments, the solid dosage form comprises a tablet, hi some embodiments, the tablet (e.g., an enteric-coated tablet) is a 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablet.

[0061] In some embodiments, the solid dosage form comprises mini-tablets. In some embodiments, the mini-tablets (e.g., enteric-coated mini-tablets) are 1 mm mini-tablets, 1.5 mm mini-tablets, 2 mm mini-tablets, 3 mm mini-tablets, or 4 mm mini-tablets. In some embodiments, a plurality of enteric-coated mini-tablets are contained within a capsule (e.g., a size 0 capsule can contain about 31 to about 35 (e.g., 33) mini-tablets, where the mini-tablets are 3 mm in size). In some embodiments, the capsule is a size 00, 0, 1, 2, 3, 4, or 5 capsule. In some embodiments, the capsule comprises HPMC (hydroxypropyl methylcellulose) or gelatin.

[0062] In some embodiments, the enteric coating comprises one enteric coating.

[0063] In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, hi some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, wherein the inner and outer coatings are not identical (e.g., the inner and outer coatings do not contain the same ingredients in the same amounts).

[0064] In some embodiments, the enteric coating (eg, one enteric coating or the inner and / or outer enteric coating) comprises a polymethacrylate-based copolymer.

[0065] In some embodiments, the enteric coating (eg, one enteric coating or the inner and / or outer enteric coating) comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1).

[0066] In some embodiments, one enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[0067] In some embodiments, one enteric coating comprises a Eudragit copolymer, such as Eudragit L (e.g., Eudragit L 100-55; Eudragit L30 D-55), Eudragit S, Eudragit RL, Eudragit RS, Eudragit E, or Eudragit FS (e.g., Eudragit FS 30 D).

[0068] In some embodiments, the enteric coating (e.g., one enteric coating or the inner and / or outer enteric coating) comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), a fatty acid, a wax, shellac (an ester of aryl acid), a plastic, a vegetable fiber, zein, aquazein (an alcohol-free aqueous zein preparation), amylose starch, a starch derivative, dextrin, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

[0069] In some embodiments, the enteric coating (eg, one enteric coating or the inner and / or outer enteric coating) comprises an anionic polymeric material.

[0070] In some embodiments, the pharmaceutical agent comprises a bacteria.

[0071] In some embodiments, the pharmaceutical agent has one or more beneficial immune effects outside the gastrointestinal tract, for example, when a solid dosage form is administered orally.

[0072] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract of a subject, for example, when a solid dosage form is administered orally.

[0073] In some embodiments, the pharmaceutical agent causes a systemic effect (eg, an extra-gastrointestinal effect), for example, when a solid dosage form is administered orally.

[0074] In some embodiments, the pharmaceutical agent acts on immune cells and / or epithelial cells of the small intestine, e.g., when a solid dosage form is administered orally, causing a systemic effect (e.g., an extra-gastrointestinal effect).

[0075] In some embodiments, the pharmaceutical product comprises (e.g., a therapeutically effective amount of) isolated bacteria (e.g., from one or more bacterial strains (e.g., bacteria of interest)). For example, at least 5%, at least 10%, at least 25%, at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the content of the pharmaceutical product is isolated bacteria (e.g., bacteria of interest).

[0076] In some embodiments, the pharmaceutical product comprises bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

[0077] In some embodiments, the pharmaceutical agent comprises live bacteria.

[0078] In some embodiments, the pharmaceutical agent comprises killed bacteria.

[0079] In some embodiments, the pharmaceutical agent comprises a non-replicating bacterium.

[0080] In some embodiments, the pharmaceutical comprises bacteria from one bacterial strain.

[0081] In some embodiments, the bacteria are lyophilized (eg, in powder form) (eg, the lyophilized product further comprises a pharmaceutically acceptable excipient).

[0082] In some embodiments, the bacteria are gamma irradiated.

[0083] In some embodiments, the bacteria are UV irradiated.

[0084] In some embodiments, the bacteria are heat inactivated (eg, 50° C. for 2 hours or 90° C. for 2 hours).

[0085] In some embodiments, the bacteria is acid-treated.

[0086] In some embodiments, the bacteria are sparged with oxygen (eg, 0.1 vvm for 2 hours).

[0087] In some embodiments, the bacteria is a gram-positive bacterium.

[0088] In some embodiments, the bacteria is a gram-negative bacterium.

[0089] In some embodiments, the bacteria are aerobic.

[0090] In some embodiments, the bacteria are anaerobes. In some embodiments, the anaerobes include obligate anaerobes. In some embodiments, the anaerobes include facultative anaerobes. In some embodiments, the bacteria are acidophilic bacteria.

[0091] In some embodiments, the bacterium is an alkaliphile.

[0092] In some embodiments, the bacteria is a neutrophilic bacterium.

[0093] In some embodiments, the bacterium is a fastidious bacterium.

[0094] In some embodiments, the bacterium is a non-fastidious bacterium.

[0095] In some embodiments, the bacteria is of a taxonomic group (eg, a class, order, family, genus, species, or strain) listed in Table 1, Table 2, Table 3, or Table 4.

[0096] In some embodiments, the bacterium is a bacterial strain listed in Table 1, Table 2, Table 3, or Table 4.

[0097] In some embodiments, the bacteria is of a taxonomic group (eg, a class, order, family, genus, species, or strain) listed in Table J.

[0098] In some embodiments, the bacterium is a bacterial strain listed in Table J.

[0099] In some embodiments, the Gram-negative bacteria belong to the class Negativicutes.

[0100] In some embodiments, the Gram-negative bacterium belongs to the family Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, or Sporomusaceae.

[0101] In some embodiments, the bacterium is of the genus Megasphaera, Selenomonas, Propionospora, or Acidaminococcus.

[0102] In some embodiments, the bacterium is a Megasphaera sp. bacterium, a Selenomonas felix bacterium, an Acidaminococcus intestini bacterium, or a Propionospora sp. bacterium.

[0103] In some embodiments, the bacteria is of the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

[0104] In some embodiments, the bacterium is a Lactococcus lactis cremoris bacterium.

[0105] In some embodiments, the bacterium is a Prevotella histicola bacterium.

[0106] In some embodiments, the bacterium is a Bifidobacterium animalis bacterium.

[0107] In some embodiments, the bacterium is a Veillonella parvula bacterium.

[0108] In some embodiments, the bacterium is a Lactococcus lactis cremoris bacterium. In some embodiments, the Lactococcus lactis cremoris bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of Lactococcus lactis cremoris strain A (ATCC Designation No. PTA-125368). In some embodiments, the Lactococcus bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of Lactococcus lactis cremoris strain A (ATCC Designation No. PTA-125368). In some embodiments, the Lactococcus bacterium is Lactococcus lactis cremoris strain A (ATCC Designation No. PTA-125368).

[0109] In some embodiments, the bacterium is a Prevotella bacterium. In some embodiments, the Prevotella bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella bacterium is a Prevotella strain B 50329 (NRRL accession number B 50329).

[0110] In some embodiments, the bacterium is a Bifidobacterium bacterium. In some embodiments, the Bifidobacterium bacterium is from a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacterium deposited under ATCC Designation No. PTA-125097. In some embodiments, the Bifidobacterium bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacterium deposited under ATCC Designation No. PTA-125097. In some embodiments, the Bifidobacterium bacterium is the Bifidobacterium bacterium deposited under ATCC Designation No. PTA-125097.

[0111] In some embodiments, the bacterium is a Veillonella bacterium. In some embodiments, the Veillonella bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacterium deposited under ATCC Designation No. PTA-125691. In some embodiments, the Veillonella bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacterium deposited under ATCC Designation No. PTA-125691. In some embodiments, the Veillonella bacterium is a Veillonella bacterium deposited under ATCC Designation No. PTA-125691.

[0112] In some embodiments, the bacterium is derived from a Ruminococcus gnavus bacterium. In some embodiments, the Ruminococcus gnavus bacterium is a strain that contains at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacterium deposited under ATCC Designation No. PTA-126695. In some embodiments, the Ruminococcus gnavus bacterium is a strain that contains at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacterium deposited under ATCC Designation No. PTA-126695. In some embodiments, the Ruminococcus gnavus bacterium is the Ruminococcus gnavus bacterium deposited under ATCC Designation No. PTA-126695.

[0113] In some embodiments, the bacterium is a Megasphaera sp. bacterium. In some embodiments, the Megasphaera sp. bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacterium deposited under ATCC Designation No. PTA-126770. In some embodiments, the Megasphaera sp. bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacterium deposited under ATCC Designation No. PTA-126770. In some embodiments, the Megasphaera sp. bacterium is a Megasphaera sp. bacterium deposited under ATCC Designation No. PTA-126770.

[0114] In some embodiments, the bacterium is a Fournierella massiliensis bacterium. In some embodiments, the Fournierella massiliensis bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under ATCC Designation No. PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under ATCC Designation No. PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is the Fournierella massiliensis bacterium deposited under ATCC Designation No. PTA-126696.

[0115] In some embodiments, the bacterium is a Harryflintia acetispora bacterium. In some embodiments, the Harryflintia acetispora bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC Designation No. PTA-126694. In some embodiments, the Harryflintia acetispora bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC Designation No. PTA-126694. In some embodiments, the Harryflintia acetispora bacterium is the Harryflintia acetispora bacterium deposited under ATCC Designation No. PTA-126694.

[0116] In some embodiments, the bacteria is selected from the group consisting of Acidaminococcaceae, Alcaligenaceae, Akkermansiaceae, Bacteriodaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae, Clostridiaceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcaceae, Fusobacteriaceae, Lachnospiraceae, Listeriaceae, Mycobacteriaceae, Neisseriaceae, and the like. iaceae, Odoribacteraceae, Oscillospiraceae, Peptococcaceae, Peptostreptococcaceae, Porphyromonadaceae, Prevotellaceae, Propionibacteraceae, Rikenellaceae ellaceae, Ruminococcaceae, Selenomonadaceae, Sporomusaceae, Streptococcaceae, Streptomycetaceae, Sutterellaceae, Synergistaceae or Veillonellaceae.

[0117] In some embodiments, the bacterium is of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides, or Erysipelatoclostridium.

[0118] In some embodiments, the bacterium is selected from the group consisting of Blautia hydrogenotrophica, Blautia stercoris, Blautia wexlerae, Eubacterium faecium, Eubacterium contortum, Eubacterium rectale, Enterococcus faecalis, Enterococcus durans, Enterococcus villorum, Enterococcus gallinarum; Bifidobacterium lactis; lactis, Bifidobacterium bifidium, Bifidobacterium longum, Bifidobacterium animalis or Bifidobacterium breve bacteria.

[0119] In some embodiments, the bacteria is selected from the group consisting of BCG (bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum, Ruminococcus gnavus, Paraclostridium benzoelyticum, Turicibacter sanguinus, Burkholderia, Klebsiella quasipneumoniae ssp. similpneumoniae, Klebsiella oxytoca, Tyzzerela nexilis or Neisseria bacteria.

[0120] In some embodiments, the bacterium is a Blautia hydrogenotrophica bacterium.

[0121] In some embodiments, the bacterium is a Blautia stercoris bacterium.

[0122] In some embodiments, the bacterium is a Blautia wexlerae bacterium.

[0123] In some embodiments, the bacterium is an Enterococcus gallinarum bacterium.

[0124] In some embodiments, the bacterium is an Enterococcus faecium bacterium.

[0125] In some embodiments, the bacterium is a Bifidobacterium bifidum bacterium.

[0126] In some embodiments, the bacterium is a Bifidobacterium breve bacterium.

[0127] In some embodiments, the bacterium is a Bifidobacterium longum bacterium.

[0128] In some embodiments, the bacterium is a Roseburia hominis bacterium.

[0129] In some embodiments, the bacterium is a Bacteroides thetaiotaomicron bacterium.

[0130] In some embodiments, the bacterium is a Bacteroides coprocola bacterium.

[0131] In some embodiments, the bacterium is an Erysipelatoclostridium ramosum bacterium.

[0132] In some embodiments, the bacterium is a Megasphera massiliensis bacterium.

[0133] In some embodiments, the bacterium is a Eubacterium bacterium.

[0134] In some embodiments, the bacterium is a Parabacteroides distasonis bacterium.

[0135] In some embodiments, the bacterium is a Lactobacillus plantarum bacterium.

[0136] In some embodiments, the bacterium is a bacterium of the class Negativicutes.

[0137] In some embodiments, the bacterium is of the family Veillonellaceae.

[0138] In some embodiments, the bacterium is of the family Selenomonadaceae.

[0139] In some embodiments, the bacterium is of the family Acidaminococcaceae.

[0140] In some embodiments, the bacterium is of the family Sporomusaceae.

[0141] In some embodiments, the bacterium is of the genus Megasphaera.

[0142] In some embodiments, the bacteria is of the genus Selenomonas.

[0143] In some embodiments, the bacteria is of the genus Propionospora.

[0144] In some embodiments, the bacteria is of the genus Acidaminococcus.

[0145] In some embodiments, the bacterium is a Megasphaera sp. bacterium.

[0146] In some embodiments, the bacterium is a Selenomonas felix bacterium.

[0147] In some embodiments, the bacterium is an Acidaminococcus intestini bacterium.

[0148] In some embodiments, the bacterium is a Propionospora sp. bacterium.

[0149] In some embodiments, the bacterium is a bacterium of the class Clostridia.

[0150] In some embodiments, the bacterium is of the family Oscillospriraceae.

[0151] In some embodiments, the bacterium is of the genus Faecalibacterium.

[0152] In some embodiments, the bacteria is of the genus Fournierella.

[0153] In some embodiments, the bacterium is of the genus Harryflintia.

[0154] In some embodiments, the bacterium is of the genus Agathobaculum.

[0155] In some embodiments, the bacterium is a Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii strain A) bacterium.

[0156] In some embodiments, the bacterium is a Fournierella massiliensis (e.g., Fournierella massiliensis strain A) bacterium.

[0157] In some embodiments, the bacterium is a Harryflintia acetispora (e.g., Harryflintia acetispora strain A) bacterium.

[0158] In some embodiments, the bacterium is an Agathobaculum sp. (eg, Agathobaculum sp. strain A) bacterium.

[0159] In some embodiments, the bacterium is an Agathobaculum sp. strain. In some embodiments, the Agathobaculum sp. strain is a strain that comprises at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., genome sequence, 16S sequence, CRISPR sequence) of Agathobaculum sp. strain A (ATCC accession number PTA-125892). In some embodiments, the Agathobaculum sp. strain is Agathobaculum sp. strain A (ATCC Accession No. PTA-125892).

[0160] In some embodiments, the bacteria are of the class Bacteroidia (phylum Bacteroidota). In some embodiments, the bacteria are of the order Bacteroidales. In some embodiments, the bacteria are of the family Porphyromonoadaceae. In some embodiments, the bacteria are of the family Prevotellaceae. In some embodiments, the bacteria are of the class Bacteroidia, and the cell envelope structure of the bacteria is a diderm. In some embodiments, the bacteria are of the class Bacteroidia that stain gram-negative. In some embodiments, the bacteria are of the class Bacteroidia, the bacteria are diderm, and the bacteria stain gram-negative.

[0161] In some embodiments, the bacterium is of the class Clostridia (phylum Firmicutes). In some embodiments, the bacterium is of the order Eubacteriales. In some embodiments, the bacterium is of the family Oscillospiraceae. In some embodiments, the bacterium is of the family Lachnospiraceae. In some embodiments, the bacterium is of the family Peptostreptococcaceae. In some embodiments, the bacterium is of Clostridiaceae family XIII / Incertae sedis 41. In some embodiments, the bacterium is of the class Clostridia, and the cell envelope structure of the bacterium is monoderm. In some embodiments, the bacterium is of the class Clostridia that stains Gram-negative. In some embodiments, the bacteria are of the class Clostridia, which stain Gram-positive. In some embodiments, the bacteria are of the class Clostridia, the cell envelope structure of the bacteria is monoderm, and the bacteria stain Gram-negative. In some embodiments, the bacteria are of the class Clostridia, the cell envelope structure of the bacteria is monoderm, and the bacteria stain Gram-positive.

[0162] In some embodiments, the bacterium is of the class Negativicutes (phylum Firmicutes). In some embodiments, the bacterium is of the order Veillonellales. In some embodiments, the bacterium is of the family Veillonelloceae. In some embodiments, the bacterium is of the order Selenomonadales. In some embodiments, the bacterium is of the family Selenomonadaceae. In some embodiments, the bacterium is of the family Sporomusaceae. In some embodiments, the bacterium is of the class Negativicutes, and the bacterial cell envelope structure is a diderm. In some embodiments, the bacterium is of the class Negativicutes that stains Gram-negative. In some embodiments, the bacterium is of the class Negativicutes, the cell envelope structure of the bacterium is a diderm, and the bacterium stains Gram-negative.

[0163] In some embodiments, the bacterium is of the class Synergistia (phylum Synergistota). In some embodiments, the bacterium is of the order Synergistales. In some embodiments, the bacterium is of the family Synergistaceae. In some embodiments, the bacterium is of the class Synergistia and the cell envelope structure of the bacterium is a diderm. In some embodiments, the bacterium is of the class Synergistia that stains Gram-negative. In some embodiments, the bacterium is of the class Synergistia and the cell envelope structure of the bacterium is a diderm, and the bacterium stains Gram-negative.

[0164] In some embodiments, the bacterium is a metabolite-producing bacterium, for example, the bacterium produces butyrate, iosine, propionate, or tryptophan metabolites.

[0165] In some embodiments, the bacterium produces butyrate, hi some embodiments, the bacterium is from the genus Blautia, Christensella, Copracoccus, Eubacterium, Lachnosperacea, Megasphaera, or Roseburia.

[0166] In some embodiments, the bacterium produces iosine, hi some embodiments, the bacterium is from the genus Bifidobacterium, Lactobacillus, or Olsenella.

[0167] In some embodiments, the bacterium produces propionate, hi some embodiments, the bacterium is from the genus Akkermansia, Bacteriodes, Dialister, Eubacterium, Megasphaera, Parabacteroides, Prevotella, Ruminococcus, or Veillonella.

[0168] In some embodiments, the bacterium produces a tryptophan metabolite, hi some embodiments, the bacterium is from the genus Lactobacillus or Peptostreptococcus.

[0169] In some embodiments, the bacterium is a bacterium that produces an inhibitor of histone deacetylase 3 (HDAC3), hi some embodiments, the bacterium is from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphera massiliensis, or Roseburia intestinalis.

[0170] In some embodiments, the bacterium is of the genus Cutibacterium.

[0171] In some embodiments, the bacterium is Cutibacterium avidum.

[0172] In some embodiments, the bacteria is from the genus Lactobacillus.

[0173] In some embodiments, the bacteria is from the genus Lactobacillus gasseri.

[0174] In some embodiments, the bacteria is from the genus Dysosmobacter.

[0175] In some embodiments, the bacterium is from the species Dysosmobacter welbionis.

[0176] In some embodiments, the bacterium is of the genus Leuconostoc.

[0177] In some embodiments, the bacterium is of the genus Lactobacillus.

[0178] In some embodiments, the bacterium is a bacterium of the genus Akkermansia; Bacillus; Blautia; Cupriavidus; Enhydrobacter; Faecalibacterium; Lactobacillus; Lactococcus; Micrococcus; Morganella; Propionibacterium; Proteus; Rhizobium or Streptococcus.

[0179] In some embodiments, the bacterium is a Leuconostoc holzapfelii bacterium.

[0180] In some embodiments, the bacterium is Akkermansia muciniphila; Cupriavidus metallidurans; Faecalibacterium prausnitzii; Lactobacillus casei; Lactobacillus plantarum; Lactobacillus paracasei; Lactobacillus plantarum; Lactobacillus rhamnosus; Lactobacillus sakei; or Streptococcus pyogenes.

[0181] In some embodiments, the bacterium is a Lactobacillus casei; Lactobacillus plantarum; Lactobacillus paracasei; Lactobacillus plantarum; Lactobacillus rhamnosus; or Lactobacillus sakei bacterium.

[0182] In some embodiments, the bacterium is a Megasphaera sp. bacterium (e.g., from a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387).

[0183] In some embodiments, the bacterium is a Megasphaera massiliensis bacterium (e.g., from a strain having accession number NCIMB 42787, NCIMB 43388, or NCIMB 43389).

[0184] In some embodiments, the bacterium is a Megasphaera massiliensis bacterium (e.g., from the strain having accession number DSM 26228).

[0185] In some embodiments, the bacterium is a Bacillus amyloliquefaciens bacterium (e.g., from a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086).

[0186] In some embodiments, the bacterium is a Parabacteroides distasonis bacterium (e.g., from the strain having accession number NCIMB 42382).

[0187] In some embodiments, the bacterium is Megasphaera massiliensis bacterium (e.g., from a strain having accession number NCIMB 43388 or NCIMB 43389) or a derivative thereof. See, e.g., WO 2020 / 120714. In some embodiments, the Megasphaera massiliensis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genomic sequence, a 16S sequence, and / or a CRISPR sequence) of a Megasphaera massiliensis bacterium from a strain having accession number NCIMB 43388 or NCIMB 43389. In some embodiments, the Megasphaera massiliensis bacterium is a strain having accession number NCIMB 43388 or NCIMB 43389.

[0188] In some embodiments, the bacterium is the Megasphaera massiliensis bacterial strain deposited under accession number NCIMB 42787 or a derivative thereof. See, e.g., WO 2018 / 229216. In some embodiments, the Megasphaera massiliensis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genome sequence, 16S sequence, and / or CRISPR sequence) of the Megasphaera massiliensis bacterial strain deposited under accession number NCIMB 42787. In some embodiments, the Megasphaera massiliensis bacterium is the strain deposited under accession number NCIMB 42787.

[0189] In some embodiments, the bacterium is a Megasphaera spp. bacterium or a derivative thereof from a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387. See, e.g., WO 2020 / 120714. In some embodiments, the Megasphaera sp. bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genomic sequence, a 16S sequence, and / or a CRISPR sequence) of Megasphaera sp. from a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387. In some embodiments, the Megasphaera sp. bacterium is a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387.

[0190] In some embodiments, the bacterium is Parabacteroides distasonis, or a derivative thereof, deposited under accession number NCIMB 42382. See, e.g., WO 2018 / 229216. In some embodiments, the Parabacteroides distasonis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genome sequence, 16S sequence, and / or CRISPR sequence) of the Parabacteroides distasonis bacterium deposited under accession number NCIMB 42382. In some embodiments, the Parabacteroides distasonis bacterium is the strain deposited under accession number NCIMB 42382.

[0191] In some embodiments, the bacterium is the Megasphaera massiliensis bacterium deposited under accession number DSM 26228 or a derivative thereof. See, e.g., WO 2018 / 229216. In some embodiments, the Megasphaera massiliensis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genome sequence, a 16S sequence, and / or a CRISPR sequence) of the Megasphaera massiliensis bacterium deposited under accession number DSM 26228. In some embodiments, the Megasphaera massiliensis bacterium is a strain deposited under accession number DSM 26228.

[0192] In some embodiments, the bacterium is a Bacillus amyloliquefaciens bacterium (e.g., from a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086) or a derivative thereof. See, e.g., WO 2019 / 236806. In some embodiments, the Bacillus amyloliquefaciens bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genomic sequence, a 16S sequence, and / or a CRISPR sequence) of a Bacillus amyloliquefaciens bacterial strain from a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086. In some embodiments, the Bacillus amyloliquefaciens bacterium is a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086. In some embodiments, the Bacillus amyloliquefaciens bacterium is a strain having accession number NCIMB 43088.

[0193] In some embodiments, the medicament comprises bacteria, and the dose of bacteria is about 1×10 7 ~Approx. 2×10 12 (For example, about 3 × 10 10 , or approximately 1.5 × 10 11 , or approximately 1.5 × 10 12) cells (e.g., the cell number is determined by total cell count, which is determined by a Coulter counter), and the dose is per capsule or tablet or per total number of mini-tablets in a capsule. In some embodiments, the pharmaceutical product includes bacteria, and the dose of bacteria is about 1 x 10 10 ~Approx. 2×10 12 (For example, about 1.6 × 10 11 , or approximately 8 × 10 11 , or approximately 9.6 × 10 11 , about 12.8×10 11 or approximately 1.6 x 10 12 ) cells (e.g., cell number is determined by total cell count, which is determined by Coulter counter), and dose is per capsule or tablet or per total number of mini-tablets in a capsule.

[0194] In some embodiments, the medicament comprises bacteria, and the dose of bacteria is about 1×10 9 , about 3×10 9 , about 5×10 9 , about 1.5×10 10 , about 3×10 10 , about 5×10 10 , about 1.5×10 11 , about 1.5×10 12 or about 2 x 10 12 cells, and the dose is per capsule or tablet or per total number of mini-tablets within a capsule.

[0195] In some embodiments, the pharmaceutical product comprises a powder containing the bacteria, and the dosage of the pharmaceutical product (e.g., the powder containing the bacteria) is from about 10 mg to about 3500 mg, and the dosage is per capsule or tablet or per total number of mini-tablets within a capsule.

[0196] In some embodiments, the pharmaceutical product comprises a powder containing bacteria, and the dosage of the pharmaceutical product (e.g., the powder containing bacteria) is about 30 mg to about 1300 mg (by weight of the bacterial powder) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg), where the dosage is per capsule or tablet or per total number of mini-tablets within a capsule.

[0197] In some embodiments, the pharmaceutical agent comprises a bacterium, and the dose of the pharmaceutical agent (e.g., the bacterium) is about 2×10 6 ~Approx. 2×10 16 Particles (e.g., particle number determined by NTA (Nanoparticle Tracking Analysis)), dose per capsule or tablet or total number of mini-tablets within a capsule.

[0198] In some embodiments, the pharmaceutical comprises bacteria, and the dosage of the pharmaceutical (e.g., bacteria) is from about 5 mg to about 900 mg total protein (e.g., total protein determined by Bradford assay or BCA), and the dosage is per capsule or tablet or per total number of mini-tablets within a capsule.

[0199] In some embodiments, the solid dosage form further comprises one or more additional therapeutic agents.

[0200] In some aspects, the present disclosure provides a method of treating a subject (e.g., a human) (e.g., a subject in need of treatment), the method comprising administering to the subject a medicament, pharmaceutical composition, or solid dosage form provided herein. In some aspects, the present disclosure provides a use of a medicament, pharmaceutical composition, or solid dosage form provided herein for the preparation of a medicament for treating a subject (e.g., a human) (e.g., a subject in need of treatment).

[0201] In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered orally (eg, is intended for oral administration).

[0202] In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered to a subject in a fed or fasted state. In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered to a subject in a fasting state (e.g., 1 hour before a meal or 2 hours after a meal). In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered to a subject 1 hour before a meal. In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered to a subject 2 hours after a meal.

[0203] In some embodiments, the medicament, pharmaceutical composition or solid dosage form is administered (eg, is for administration) 1, 2, 3, or 4 times per day.

[0204] In some embodiments, the pharmaceutical composition or solid dosage form provides for release of the pharmaceutical agent in the small intestine, for example, release of the pharmaceutical agent contained in the solid dosage form in the upper small intestine.

[0205] In some embodiments, the pharmaceutical composition or solid dosage form delivers the pharmaceutical agent to the small intestine, where the pharmaceutical agent acts on immune cells and / or epithelial cells in the small intestine, e.g., the upper small intestine, e.g., to cause a body-wide effect (e.g., a systemic effect).

[0206] In some embodiments, the pharmaceutical agent provides one or more beneficial immune effects outside the gastrointestinal tract, for example, when a solid dosage form is administered orally.

[0207] In some embodiments, the pharmaceutical agent modulates immune effects outside the gastrointestinal tract of a subject, for example, when administered orally.

[0208] In some embodiments, the pharmaceutical agent causes a systemic effect (eg, a non-gastrointestinal effect) when administered, for example, orally.

[0209] In some embodiments, the pharmaceutical agent acts on immune cells and / or epithelial cells in the small intestine (e.g., the upper small intestine) (e.g., causes a systemic effect (e.g., an extra-gastrointestinal effect)), e.g., when administered orally.

[0210] In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered orally and has one or more beneficial immune effects outside the gastrointestinal tract (e.g., interactions between the agent and cells in the small intestine modulate the systemic immune response).

[0211] In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered orally to modulate an immune effect outside the gastrointestinal tract (e.g., interactions between the agent and cells in the small intestine (e.g., the upper small intestine) modulate a systemic immune response).

[0212] In some embodiments, the medicament, pharmaceutical composition, or solid dosage form is administered orally to activate natural antigen-presenting cells (eg, in the small intestine (eg, upper small intestine)).

[0213] In some embodiments, the subject is in need of treatment (and / or prevention) of cancer.

[0214] In some embodiments, the subject is in need of treatment (and / or prevention) of an autoimmune disease.

[0215] In some embodiments, the subject is in need of treatment (and / or prevention) of an inflammatory disease.

[0216] In some embodiments, the subject is in need of treatment (and / or prevention) of a metabolic disease.

[0217] In some embodiments, the subject is in need of treatment (and / or prevention) of a dysbiosis.

[0218] In some embodiments, the medicament, pharmaceutical composition or solid dosage form is administered in combination with a therapeutic agent (eg, another therapeutic agent).

[0219] In some aspects, the present disclosure provides cryoprotectant solutions for use in, e.g., preparing pharmaceutical products, e.g., comprising the bacteria described herein.

[0220] In some aspects, the present disclosure provides a method comprising combining bacteria (e.g., a pellet containing bacteria) with a cryoprotectant solution, thereby preparing a formulation paste. In some embodiments, the present disclosure provides a formulation paste prepared by this method.

[0221] In some embodiments, the method further comprises lyophilizing the formulation paste, thereby preparing a lyophilized product. In some embodiments, the lyophilization comprises primary drying. In some embodiments, the lyophilization comprises primary drying and secondary drying. In some embodiments, the disclosure provides a lyophilized product prepared by this method.

[0222] In some embodiments, the method further comprises grinding the lyophilized product, thereby preparing a lyophilized powder (e.g., a powder, e.g., a pharmaceutical product). In some embodiments, the disclosure provides a pharmaceutical product prepared by this method.

[0223] In some embodiments, the method further comprises combining the lyophilized powder with one or more excipients, thereby preparing a pharmaceutical composition. In some embodiments, the present disclosure provides a pharmaceutical composition prepared by this method.

[0224] In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.2 to about 0.5 grams (g) of cryoprotectant solution per gram of pellet; about 0.05 to about 0.25 grams (g) of cryoprotectant solution per gram of pellet; about 0.06 to about 0.1 grams (g) of cryoprotectant solution per gram of pellet; or about 0.15 to about 0.2 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.4 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.18 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.1 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets at a ratio of about 0.08 grams (g) of cryoprotectant solution per gram of pellets.

[0225] In some embodiments, the cryoprotectant solution is mixed with the pellet at a ratio of 4% to 10% (volume / volume), e.g., 5% to 8% (volume / volume). In some embodiments, the cryoprotectant solution is mixed with the pellet at a ratio of about 6.5% (volume / volume).

[0226] In some embodiments, the cryoprotectant solution comprises sucrose. In some embodiments, the cryoprotectant solution comprises dextran. In some embodiments, the cryoprotectant solution comprises sucrose and dextran. In some embodiments, the cryoprotectant solution comprises equal amounts (e.g., on a weight percent basis) of sucrose and dextran. In some embodiments, the cryoprotectant solution comprises sucrose, dextran, and L-cysteine ​​HCl. In some embodiments, the cryoprotectant solution does not include L-cysteine ​​HCl.

[0227] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) sucrose. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) sucrose. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) sucrose.

[0228] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) dextran.

[0229] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) sucrose and about 10% to about 30% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) sucrose and about 15% to about 35% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) sucrose and about 20% (wt / wt) dextran.

[0230] In some embodiments, the cryoprotectant solution comprises about 40% to about 80% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 50% to about 70% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 55% to about 65% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 60% (wt / wt) water.

[0231] In some embodiments, the cryoprotectant solution comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant solution comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant solution comprises about 0.15% to about 0.45% (wt / wt) L-cysteine ​​HCl.

[0232] In some embodiments, the cryoprotectant solution comprises about 0.2% (wt / wt) L-cysteine ​​HCl.

[0233] In some embodiments, the cryoprotectant solution comprises about 59.8% (wt / wt) water.

[0234] In some embodiments, the cryoprotectant solution comprises about 0.4% (wt / wt) L-cysteine ​​HCl.

[0235] In some embodiments, the cryoprotectant solution comprises about 59.6% (wt / wt) water.

[0236] In certain embodiments, the cryoprotectant solution provided herein comprises: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; (iii) about 0.4% (wt / wt) L-cysteine ​​HCl; and (iv) about 59.6% (wt / wt) water.

[0237] In certain embodiments, the cryoprotectant solution provided herein comprises: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; (iii) about 0.2% (wt / wt) L-cysteine ​​HCl; and (iv) about 59.8% (wt / wt) water.

[0238] In certain embodiments, the cryoprotectant solutions provided herein comprise: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; and (iii) about 60% (wt / wt) water.

[0239] In some embodiments, the cryoprotectant (e.g., a water-free dry composition) comprises about 40% to about 60% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) sucrose.

[0240] In some embodiments, the cryoprotectant comprises about 40% to about 60% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) dextran.

[0241] In some embodiments, the cryoprotectant comprises about 40% to about 60% (wt / wt) sucrose and 40% to about 60% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) sucrose and about 45% to about 55% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) sucrose and about 50% (wt / wt) dextran.

[0242] In some embodiments, the cryoprotectant comprises about 0.25% to about 5% (wt / wt) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant comprises about 0.5% to about 2.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.75% to about 1.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 1% (wt / wt) L-cysteine ​​HCl.

[0243] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 50% (wt / wt) sucrose; (ii) about 50% (wt / wt) dextran; and (iii) about 1% (wt / wt) L-cysteine ​​HCl.

[0244] In certain embodiments, the cryoprotectants provided herein comprise: (i) about 50% (wt / wt) sucrose; and (ii) about 50% (wt / wt) dextran.

[0245] In some embodiments, the lyophilized powder comprises about 6% to about 12% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 8% to about 12% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 11% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 6% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 8% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 11% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 6% to about 12% (wt / wt) sucrose and about 6% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 8% to about 12% (wt / wt) sucrose and about 8% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 11% (wt / wt) sucrose and about 11% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 0.01% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.1% to about 0.3% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.15% to about 0.25% (wt / wt) L-cysteine ​​HCl.

[0246] In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 15% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 15% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) sucrose and about 7% to about 21% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) sucrose and about 10% to about 19% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 15% (wt / wt) sucrose and about 15% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 0.01% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.1% to about 0.4% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.15% to about 0.35% (wt / wt) L-cysteine ​​HCl.

[0247] In some embodiments, the lyophilized powder comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the lyophilized powder comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the lyophilized powder comprises about 26% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the lyophilized powder comprises about 21% to about 29% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 23% to about 27% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 25% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 6% to about 11% (wt / wt) dextrose. In some embodiments, the lyophilized powder comprises about 7% to about 10% (wt / wt) dextrose. In some embodiments, the lyophilized powder comprises about 9% (wt / wt) dextrose. In some embodiments, the lyophilized powder comprises about 4% to about 10% (wt / wt) glutamate. In some embodiments, the lyophilized powder comprises about 5% to about 9% (wt / wt) glutamate. In some embodiments, the lyophilized powder comprises about 7% (wt / wt) glutamate.

[0248] In some embodiments, the lyophilized powder comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 21% to about 29% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 23% to about 27% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl. In some embodiments, the lyophilized powder comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl.

[0249] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (w / w) sucrose; about 6% to about 11% (w / w) dextrose; and about 4% to about 10% (w / w) glutamate. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 23% to about 27% (w / w) sucrose; and about 7% to about 10% (w / w) dextrose. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); 23% to about 27% (wt / wt) sucrose; and about 5% to about 9% (wt / wt) glutamate.In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex®), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex® 21); 23% to about 27% (w / w) sucrose; about 7% to about 1% (w / w) dextrose; and about 5% to about 9% (w / w) glutamate. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0250] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 26% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 21% to about 29% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 23% to about 27% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 25% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 7% to about 10% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 9% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical composition comprises about 5% to about 9% (wt / wt) glutamate. In some embodiments, the pharmaceutical composition comprises about 7% (wt / wt) glutamate.

[0251] In some embodiments, the pharmaceutical composition comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 21% to about 29% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 23% to about 27% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0252] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (w / w) sucrose; about 6% to about 11% (w / w) dextrose; and about 4% to about 10% (w / w) glutamate. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 23% to about 27% (w / w) sucrose; and about 7% to about 10% (w / w) dextrose. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); 23% to about 27% (wt / wt) sucrose; and about 5% to about 9% (wt / wt) glutamate.In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex®), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex® 21); 23% to about 27% (w / w) sucrose; about 7% to about 1% (w / w) dextrose; and about 5% to about 9% (w / w) glutamate. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0253] In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21). In some embodiments, the cryoprotectant comprises sucrose. In some embodiments, the cryoprotectant comprises dextrose (also called glucose). In some embodiments, the cryoprotectant comprises monosodium glutamate. In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises equal amounts (e.g., on a weight percent basis) of a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and dextrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, dextrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises dextrose and sodium glutamate in equal amounts (e.g., on a weight percent basis).In some embodiments, the cryoprotectant comprises dried (dehydrated) corn glucose syrup (e.g., Glucidex), such as dried corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), sucrose, dextrose, sodium glutamate, and L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant does not comprise L-cysteine ​​HCl.

[0254] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 37% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21).

[0255] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) sucrose.

[0256] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) dextrose.

[0257] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) monosodium glutamate.

[0258] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 37% (wt / wt) sucrose.

[0259] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; about 8% to about 18% (wt / wt) dextrose; and about 8% to about 18% (wt / wt) monosodium glutamate.

[0260] In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; about 11% to about 15% (wt / wt) dextrose; and about 11% to about 15% (wt / wt) monosodium glutamate.

[0261] In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 37% (wt / wt) sucrose; about 13% (wt / wt) dextrose; and about 13% (wt / wt) monosodium glutamate.

[0262] In some embodiments, the cryoprotectant comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.1% to about 0.25% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.2% (wt / wt) L-cysteine ​​HCl.

[0263] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; (iv) about 13% (wt / wt) monosodium glutamate; and (v) about 0.2% (wt / wt) L-cysteine ​​HCl.

[0264] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; and (iv) about 13% (wt / wt) monosodium glutamate.

[0265] In certain embodiments, the lyophilized powder comprises about 40% to about 70% (w / w) dried bacteria. In certain embodiments, the pharmaceutical product comprises about 35% to about 70% (w / w) bacteria (e.g., lyophilized bacteria).

[0266] In certain embodiments, the lyophilized powder comprises about 64% (w / w) dry bacteria.

[0267] In certain embodiments, the lyophilized powder comprises about 15% to about 35% (weight / weight) bacteria (e.g., lyophilized bacteria). In certain embodiments, the lyophilized powder comprises about 18% to about 30% (weight / weight) bacteria (e.g., lyophilized bacteria). In certain embodiments, the lyophilized powder comprises about 25% (weight / weight) bacteria (e.g., lyophilized bacteria).

[0268] In certain embodiments, the lyophilized powder comprises Prevotella bacteria.

[0269] In certain embodiments, the lyophilized powder comprises Veillonella bacteria. [Brief explanation of the drawings]

[0270] [Figure 1] Figure 1 shows the total cells / gram stability profile over time for Prevotella histicola strain batch 1 under long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C (abbreviated as 25°C)) storage conditions. The bottom trace on the graph provides the value for the accelerated (25°C) storage condition. The top trace on the graph provides the value for the long-term (2-8°C (abbreviated as 5°C)) storage condition. Total cell counts (TCC) were determined by Coulter counter. [Figure 2] Figure 1 shows the water content stability profile over time for long-term (2-8°C) and accelerated (25°C) storage conditions for Prevotella histicola strain B batch 1. Water content was determined by the Karl Fischer method. [Figure 3] This graph shows the total cells / gram stability profile over time for long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C (abbreviated as 25°C)) storage conditions for Prevotella histicola B strain batch 2. Total cell count (TCC) was determined by Coulter counter. [Figure 4] 1 is a graph showing the water content stability profile over time for Prevotella histicola strain B batch 2 under long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C) storage conditions. The top trace on the graph provides the values ​​for the accelerated (25°C) storage condition. The bottom trace on the graph provides the values ​​for the long-term (2-8°C (abbreviated as 5°C)) storage condition. Water content was determined by the Karl Fischer method. [Figure 5]This graph shows the total cells / gram stability profile over time for Veillonella parvula strain A, batch A, under long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C / 60% RH (abbreviated as 25°C)) storage conditions. The graph's trace out to 6 months provides the value for the accelerated (25°C) storage condition. The graph's trace out to 12 months provides the value for the long-term (2-8°C (abbreviated as 5°C)) storage condition. Total cell counts (TCC) were determined by Coulter counter. [Figure 6] Figure 1 shows the water content stability profile over time for Veillonella parvula strain A, batch A, under long-term (2-8°C) and accelerated (25°C) storage conditions. The graph's trace out to 6 months provides the value for accelerated (25°C) storage conditions. The graph's trace out to 12 months provides the value for long-term (2-8°C (abbreviated: 5°C)) storage conditions. Water content was determined by the Karl Fischer method. [Figure 7] Figure 1 shows the total cells / gram stability profile over time for Veillonella parvula strain A, batch D, for long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C / 60% RH (abbreviated as 25°C)) storage conditions. The bottom trace on the graph provides the value for the accelerated (25°C) storage condition. The top trace on the graph provides the value for the long-term (2-8°C (abbreviated as 5°C)) storage condition. Total cell counts (TCC) were determined by Coulter counter. [Figure 8] Figure 1 shows the water content stability profile over time for Veillonella parvula strain A batch D under long-term (2-8°C (abbreviated: 5°C)) and accelerated (25°C) storage conditions. Water content was determined by the Karl Fischer method. [Figure 9]Figure 1 shows the total cells / gram stability profile over time for Prevotella histicola strain batch 1 under long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C (abbreviated as 25°C)) storage conditions. The graph's trace out to 6 months provides the value for the accelerated (25°C) storage condition. The graph's trace out to 18 months provides the value for the long-term (2-8°C (abbreviated as 5°C)) storage condition. Total cell counts (TCC) were determined by Coulter counter. [Figure 10] Figure 1 shows the water content stability profile over time for long-term (2-8°C) and accelerated (25°C) storage conditions for Prevotella histicola strain B batch 1. Water content was determined by the Karl Fischer method. [Figure 11] Figure 1 shows the total cells / gram stability profile over time for Prevotella histicola strain batch 2 under long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C (abbreviated as 25°C)) storage conditions. The graph's trace out to 6 months provides the value for the accelerated (25°C) storage condition. The graph's trace out to 18 months provides the value for the long-term (2-8°C (abbreviated as 5°C)) storage condition. Total cell counts (TCC) were determined by Coulter counter. [Figure 12] Figure 1 shows the water content stability profile over time for long-term (2-8°C) and accelerated (25°C) storage conditions for Prevotella histicola strain B batch 2. Water content was determined by the Karl Fischer method. [Figure 13] Figure 1 shows the total cells / gram stability profile over time for long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C (abbreviated as 25°C)) storage conditions for Prevotella histicola strain batch 4. Total cell count (TCC) was determined by Coulter counter. [Figure 14]Figure 1 shows the water content stability profile over time for long-term (2-8°C) and accelerated (25°C) storage conditions for Prevotella histicola strain B batch 4. Water content was determined by the Karl Fischer method. [Figure 15] Figure 1 shows the total cells / gram stability profile over time for long-term (2-8°C (abbreviated as 5°C)) and accelerated (25°C (abbreviated as 25°C)) storage conditions for Prevotella histicola strain batch 5. Total cell count (TCC) was determined by Coulter counter. [Figure 16] Figure 1 shows the water content stability profile over time for long-term (2-8°C) and accelerated (25°C) storage conditions for Prevotella histicola strain B batch 5. Water content was determined by the Karl Fischer method. [Figure 17] This graph shows the total cells / gram stability profile over time for long-term (-20°C) and accelerated (2-8°C (abbreviated: 5°C)) storage conditions for Prevotella histicola strain batch i. The graph's trace out to 6 months provides the value for the accelerated (2-8°C (abbreviated: 5°C)) storage condition. The graph's trace out to 24 months provides the value for the long-term (-20°C) storage condition. Total cell counts (TCC) were determined by Coulter counter. [Figure 18] This graph shows the water content stability profile over time for Prevotella histicola strain B batch i under long-term (-20°C) and accelerated (2–8°C (abbreviated: 5°C)) storage conditions. Water content was determined by the Karl Fischer method. DETAILED DESCRIPTION OF THE INVENTION

[0271] In certain embodiments, provided herein are pharmaceutical preparations (such as powders) comprising bacteria (e.g., lyophilized bacteria), wherein the bacteria in the pharmaceutical preparation are present in an amount of at least 1 x 10 per gram of the pharmaceutical preparation. 11There are 100 total cell counts (TCC) of cells.

[0272] In certain aspects, provided herein are pharmaceutical preparations (e.g., powders) comprising bacteria. In certain embodiments, the pharmaceutical preparations maintain their stability, e.g., for 3, 6, 12, 18, and / or 24 months under long-term (2-8°C) and / or accelerated (23-27°C (optionally 60% relative humidity (RH))) storage conditions, as determined, e.g., by total cell count (TCC) (e.g., determined by Coulter counter and described herein). In certain embodiments, the pharmaceutical preparations maintain their stability, e.g., for 3, 6, 12, 18, and / or 24 months under long-term (-20°C) and / or accelerated (2-8°C) storage conditions, as determined, e.g., by total cell count (TCC) (e.g., determined by Coulter counter and described herein).

[0273] In certain aspects, provided herein are pharmaceutical preparations (e.g., powders) containing bacteria. In some embodiments, the water content of the pharmaceutical preparations described herein, as determined, for example, by the Karl Fischer method for water content analysis provided in European Pharmacopoeia (Ph.Eur.) method 2.5.12, is about 0.5% to about 9%, about 1% to about 8%, or about 1% to about 6% (e.g., about 1.7%, such as 1.8%, for example, about 2%, for example, about 2.2%, for example, about 2.3%, for example, about 2.4%, for example, about 2.8%, for example, about 2.9%, for example, about 3%, for example, about 3.1%, for example, about 3.2%, for example, about 3.3%, for example, about 3.5%, for example, about 3.6%, for example, about 4%, for example, about 4.5%, for example, about 5%, for example, about 5.3%, for example, about 5.4%, or for example, about 7.8%). In some embodiments, the pharmaceutical product maintains its water content for, e.g., 3, 6, 12, 18, and / or 24 months under long-term (2-8°C) and / or accelerated (25°C (optionally 60% RH)) storage conditions. In certain embodiments, the pharmaceutical product maintains its water content for, e.g., 3, 6, 12, 18, and / or 24 months under long-term (-20) and / or accelerated (2-8°C) storage conditions, as determined, e.g., by total cell count (TCC) (determined, e.g., by Coulter counter and described herein).

[0274] In certain aspects, provided herein are pharmaceutical preparations (e.g., powders) comprising bacteria and a cryoprotectant.

[0275] definition When used before a numerical value, the term "about" indicates that the value can vary within a reasonable range, such as ±10%, ±5%, or ±1% of the stated value.

[0276] "Adjuvant" or "adjuvant therapy" refers broadly to an agent that affects the immunological or physiological response of a subject (e.g., a human). For example, an adjuvant may increase the presence of an antigen over time or in an area of ​​interest such as a tumor, aid in antigen uptake by antigen-presenting cells, activate macrophages and lymphocytes, and support cytokine production. By altering the immune response, an adjuvant may allow a lower dose of an immunointeractive agent to enhance the efficacy or safety of a particular dose of an immunointeractive agent. For example, an adjuvant may prevent T-cell exhaustion, thus enhancing the efficacy or safety of a particular immunointeractive agent.

[0277] "Administration" refers broadly to the route of administration of a composition (e.g., a pharmaceutical composition, such as a solid dosage form of a pharmaceutical agent described herein) to a subject. Examples of routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal), or injection. Administration by injection includes intravenous (IV), intramuscular (IM), intratumoral (IT), and subcutaneous (SC) administration. The pharmaceutical compositions described herein can be administered in any form by any effective route, including, but not limited to, intratumor, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, intraocular, nasal (intranasal), topical, parenteral, e.g., aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, intravaginal, intraarterial and intrathecal, transmucosal (e.g., sublingual, lingual, (trans)buccal, (trans)urethral, ​​vaginal (e.g., intravaginal and perivaginal), implant, intravesical, intrapulmonary, intraduodenal, intragastric, and intrabronchial. In preferred embodiments, the pharmaceutical compositions described herein are administered orally, rectally, intratumorally, topically, intravesically, by injection into or near a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously. In another preferred embodiment, the pharmaceutical compositions described herein are administered orally, intratumorally, or subcutaneously. In another embodiment, the pharmaceutical compositions described herein are administered orally.

[0278] As used herein, the term "antibody" can refer to both intact antibodies and antigen-binding fragments thereof. An intact antibody is a glycoprotein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain contains a heavy chain variable region (heavy chain variable region, herein referred to as V H Each light chain comprises a light chain variable region (abbreviated herein as V) and a heavy chain constant region. L and the light chain constant region. H and V L The region can be further subdivided into regions of hypervariability, called complementarity-determining regions (CDRs), interspersed with more conserved regions, called framework regions (FRs). H and V L is composed of three CDRs and four FRs, arranged in the following order from the amino terminus to the carboxy terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with an antigen. The term "antibody" includes, for example, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies (e.g., bispecific antibodies), single-chain antibodies, and antigen-binding antibody fragments.

[0279] As used herein, the terms "antigen-binding fragment" and "antigen-binding portion" of an antibody refer to one or more fragments of an antibody that retain the ability to bind to an antigen. Examples of binding fragments encompassed by the term "antigen-binding fragment" of an antibody include Fab, Fab', F(ab')2, Fv, scFv, disulfide-linked Fv, Fd, diabodies, single-chain antibodies, NANOBODIES®, isolated CDRH3, and other antibody fragments that retain at least a portion of the variable region of an intact antibody. These antibody fragments can be obtained using conventional recombinant and / or enzymatic techniques and can be screened for antigen binding in the same manner as intact antibodies.

[0280] "Cancer" broadly refers to the uncontrolled, abnormal growth of a host's own cells, resulting in invasion of surrounding tissues and potentially tissues distal to the primary site of the host's abnormal cell growth. Major classes include carcinomas, which are cancers of epithelial tissues (e.g., skin, squamous cells); sarcomas, which are cancers of connective tissues (e.g., bone, cartilage, fat, muscle, blood vessels, etc.); leukemias, which are cancers of blood-forming tissues (e.g., bone marrow tissue); lymphomas and myelomas, which are cancers of immune cells; and central nervous system cancers, including cancers of brain and spinal cord tissue. "Cancer," "neoplasms," and "cancers" are used interchangeably herein. "Cancer," as used herein, refers to all types of cancers or neoplasms or malignant tumors, including leukemias, carcinomas, and sarcomas, whether primary or recurrent. Specific examples of cancers are carcinomas, sarcomas, myelomas, leukemias, lymphomas, and mixed tumors. Non-limiting examples of cancers include primary or recurrent cancers of the brain, melanoma, bladder, breast, cervix, colon, head and neck, kidney, lung, non-small cell lung, mesothelioma, ovary, prostate, sarcoma, stomach, uterus, and medulloblastoma. In some embodiments, the cancer comprises a solid tumor. In some embodiments, the cancer comprises a metastasis.

[0281] "Carbohydrate" refers to a sugar or a polymer of sugars. The terms "sugar," "polysaccharide," "carbohydrate," and "oligosaccharide" may be used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups (usually one on each carbon atom of the molecule). Carbohydrates generally have the molecular formula C n H 2n O nCarbohydrates can be monosaccharides, disaccharides, trisaccharides, oligosaccharides, or polysaccharides. The most basic carbohydrates are monosaccharides, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose. Disaccharides are two linked monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose. Typically, oligosaccharides contain 3 to 6 monosaccharide units (e.g., raffinose, stachyose), while polysaccharides contain 6 or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates can also include modified sugar units, such as 2'-deoxyribose, where the hydroxyl group has been removed; 2'-fluororibose, where the hydroxyl group has been replaced with fluorine; or N-acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2'-fluororibose, deoxyribose, and hexose). Carbohydrates can exist in many different forms, including conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers and isomers.

[0282] "Cell expansion" broadly refers to the influx or expansion of cells in an environment that are substantially absent from the environment prior to administration of the composition and that are not present in the composition itself. Cells that expand the environment include immune cells, stromal cells, bacterial cells, and fungal cells. Environments of particular interest are the microenvironments in which cancer cells reside or are located. In some cases, the microenvironment is the tumor microenvironment or tumor-draining lymph nodes. In other cases, the microenvironment is the site of precancerous tissue or the site of local administration of the composition, or the site where the composition accumulates after remote administration.

[0283] "Clade" refers to an OTU or tree member that is downstream of a statistically valid node in the phylogenetic tree. A clade comprises a set of terminal leaves in the phylogenetic tree that are distinct monophyletic evolutionary units and share some degree of sequence similarity.

[0284] A "combination" of bacteria from two or more strains includes the physical coexistence of bacteria either in the same material or product or in physically connected products, as well as the temporal co-administration or co-localization of bacteria from these two or more strains.

[0285] The terms "reduce" or "deplete" refer to a change that is at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 1 / 100, 1 / 1000, 1 / 100,000, 1 / 1000,000, or undetectable after treatment compared to the pre-treatment state, depending on the context. Characteristics that may be reduced include the number of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; cytokine levels; or another physical parameter (e.g., ear thickness or tumor size (e.g., in a DTH animal model)).

[0286] "Dysbiosis" refers to a state of the microbiota or microbiome (or any other microbiome niche) of the intestine or other body regions (e.g., including mucosal or skin surfaces) in which the normal diversity and / or function of the host's gut microbiome ecological network ("microbiome") is disrupted. A dysbiotic state may cause pathology or may be unhealthy only if present under certain conditions or over an extended period of time. Dysbiosis can result from a variety of factors, including environmental factors, infectious agents, host genotype, host diet, and / or stress. Dysbiosis can result in: a change (e.g., increase or decrease) in the prevalence (e.g., increase or decrease) of one or more bacterial types (e.g., anaerobic), species, and / or strains; a change (e.g., increase or decrease) in the diversity (e.g., increase or decrease) of the host's microbiome population composition, a change (e.g., increase or decrease) in one or more populations of symbionts resulting in a reduction or loss of one or more beneficial effects; an overgrowth of one or more populations of pathogens (e.g., disease-causing bacteria); and / or the presence and / or overgrowth of symbionts that cause disease only when certain conditions are present.

[0287] The term "ecological consortium" refers to a group of bacteria that exchange metabolites and actively co-regulate each other, as opposed to two bacteria that induce host synergy by activating complementary host pathways to improve efficacy.

[0288] The term "effective dose" or "effective amount" is the amount of a pharmaceutical agent that, for a particular pharmaceutical agent, composition, and mode of administration, is effective to achieve a desired therapeutic response in a subject.

[0289] As used herein, "engineered bacteria" refers to any bacteria that have been genetically altered from their natural state by human intervention, and any progeny of such bacteria. Engineered bacteria include, for example, the products of targeted genetic modification, random mutagenesis screening, and directed evolution.

[0290] The term "epitope" refers to a protein determinant capable of specific binding to an antibody or T-cell receptor. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. A particular epitope can be defined by the specific amino acid sequence to which an antibody can bind.

[0291] The term "gene" is used broadly to refer to a nucleic acid associated with a biological function. The term "gene" applies to a specific genomic sequence and to the cDNA or mRNA encoded by that genomic sequence.

[0292] "Identity" between the nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the "FASTA" program, using default parameters, for example, as in Pearson et al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al., Nucleic Acids Research 12(I):387(1984)), BLASTP, BLASTN, FASTA Atschul, S. F., et al., J. Molec. Biol 215:403(1990); Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo et al. (1988) SIAM J Applied Math 48:1073). For example, identity can be determined using the BLAST function of the National Center for Biotechnology Information database. Other commercially or publicly available programs include the DNAStar "MegAlign" program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) "Gap" program (Madison, Wis.).

[0293] As used herein, the term "immune disorder" refers to any disease, disorder, or disease condition caused by activity of the immune system, including autoimmune diseases, inflammatory diseases, and allergies. Immune disorders include, but are not limited to, autoimmune diseases (e.g., psoriasis, atopic dermatitis, lupus, scleroderma, hemolytic anemia, vasculitis, type 1 diabetes, Graves' disease, rheumatoid arthritis, multiple sclerosis, Goodpasture's syndrome, pernicious anemia, and / or myopathy), inflammatory diseases (e.g., acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and / or interstitial cystitis), and / or allergies (e.g., food allergies, drug allergies, and / or environmental allergies).

[0294] "Immunotherapy" refers to treatments that use a subject's immune system to treat a disease (e.g., an immune disease, an inflammatory disease, a metabolic disease, or cancer), and includes, for example, checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cell, and dendritic cell therapy.

[0295] The term "increase" refers to a difference of at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10 ... 3 double, 10 4 double, 10 5 double, 10 6 times and / or 10 7 "A change in the number of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; cytokine levels; or another physical parameter (e.g., ear thickness or tumor size (e.g., in a DTH animal model))" refers to a change that is greater than 1-fold. Properties that may be increased include the number of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; cytokine levels; or another physical parameter (e.g., ear thickness or tumor size (e.g., in a DTH animal model)).

[0296] "Innate immune agonists" or "immunoadjuvants" are small molecules, proteins, or other agents that specifically target innate immune receptors, including Toll-like receptors (TLRs), NOD receptors, RLRs, C-type lectin receptors, STING-cGAS pathway components, and inflammasome complexes. For example, LPS is a bacterially derived or synthetic TLR-4 agonist, and aluminum can be used as an immunostimulatory adjuvant. Immune adjuvants are a specific class of broader adjuvants or adjuvant therapies. Examples of STING agonists include, but are not limited to, 2'3'-cGAMP, 3'3'-cGAMP, c-di-AMP, c-di-GMP, 2'2'-cGAMP, and 2'3'-cGAM(PS)2(Rp / Sp) (the Rp,Sp-isomer of the bis-phosphorothioate analog of 2'3'-cGAMP). Examples of TLR agonists include, but are not limited to, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, and TLR1. Examples of NOD agonists include, but are not limited to, N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyl dipeptide (MDP)), γ-D-glutamyl-meso-diaminopimelic acid (iE-DAP), and desmuramyl peptide (DMP).

[0297] The "internal transcribed spacer" (ITS) is a non-functional segment of RNA located between structural ribosomal RNAs (rRNAs) on a common precursor transcript, often used to identify eukaryotic species in certain fungi. Fungal rRNAs, which form the core of the ribosome, are transcribed as signal genes and consist of the 8S, 5.8S, and 28S regions, with ITSs 4 and 5 located between the 8S and 5.8S regions and between the 5.8S and 28S regions, respectively. These two intercistronic segments, between the 18S and 5.8S regions and between the 5.8S and 28S regions, are removed by splicing and contain significant variation between species for barcoding purposes, as previously described (Schoch et al., Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi. PNAS 109:6241-6246, 2012). Although 18S rDNA is traditionally used for phylogenetic reconstruction, the ITS can serve this function because it contains hypervariable regions that are generally highly conserved but possess sufficient nucleotide diversity to distinguish most fungal genera and species.

[0298] The terms "isolated" or "enriched" include microorganisms (such as bacteria) or other entities or substances that are (1) separated from at least some of the components with which they were originally associated when produced (whether in nature or an experimental setting) and / or (2) produced, prepared, purified, and / or manufactured by the hand of man. An isolated microorganism can be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which it was originally associated. In some embodiments, an isolated microorganism is greater than about 80%, greater than about 85%, greater than about 90%, greater than about 91%, greater than about 92%, greater than about 93%, greater than about 94%, greater than about 95%, greater than about 96%, greater than about 97%, greater than about 98%, greater than about 99%, or greater than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components. The terms "purify," "purifying," and "purified" refer to a microorganism or other material that has been isolated from at least some of the components that were associated with it when it was originally produced or generated (e.g., in a natural or experimental setting) or any time after initial production. A microorganism or population of microorganisms can be considered purified from the material or environment containing the microorganism or population of microorganisms if it is isolated during or after production; a purified microorganism or population of microorganisms can contain up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than about 90% other materials and still be considered "isolated." In some embodiments, a purified microorganism or population of microorganisms is more than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. In the case of the microbial compositions provided herein, one or more microbial species present in the composition can be purified independently from one or more other microorganisms produced and / or present in the material or environment containing the microbial species. Microbial compositions and their microbial components are generally purified from residual habitat products.

[0299] As used herein, "lipid" includes fats, oils, triglycerides, cholesterol, phospholipids, and fatty acids in any form, including free fatty acids. Fats, oils, and fatty acids can be saturated, unsaturated (cis or trans), or partially unsaturated (cis or trans).

[0300] The term "LPS mutant or lipopolysaccharide mutant" generally refers to selected bacteria that contain a loss of LPS. The loss of LPS is thought to be due to mutations or disruptions in genes involved in lipid A biosynthesis, such as lpxA, lpxC, and lpxD. Bacteria containing LPS mutants can be resistant to aminoglycosides and polymyxins (polymyxin B and colistin).

[0301] "Metabolite," as used herein, refers to any molecular compound, composition, molecule, ion, cofactor, catalyst, or nutrient that is used as a substrate in any cellular or microbial metabolic reaction, or that is obtained as a product from any cellular or microbial metabolic reaction.

[0302] "Microorganism" refers to archaea, parasites, bacteria, fungi, microalgae, protozoa, and any naturally occurring or engineered organism characterized by the developmental or life cycle stages associated with such organisms (e.g., vegetative, sporulating (including sporulation, dormancy, and germination), latent, biofilm). Examples of gut microbes include: Actinomyces graevenitzii, Actinomyces odontolyticus, Akkermansia muciniphila, Bacteroides caccae, Bacteroides fragilis, Bacteroides putredinis, Bacteroides thetaiotaomicron, Bacteroides vultagus, Bifidobacterium adolescentis, and Bifidobacterium bifidum. bifidum, Bilophila wadsworthia, Blautia, Butyrivibrio, Campylobacter gracilis, Clostridia cluster III, Clostridia cluster IV, Clostridia cluster IX (Acidaminococcaceae group), Clostridia cluster XI, Clostridia cluster XIII (Peptostreptococcus group), Clostridia cluster XIVXIV, Clostridia cluster XV, Collinsella aerofaciens, Coprococcus, Corynebacterium sunsvallense, Desulfomonas pigra, Dorea formicigenerans, Dorea longicatena, Escherichia coli, Eubacterium hadrum, Eubacterium rectale, Faecalibacteria prausnitzii prausnitzii, Gemella, Lactococcus, Lachnospira, Mollicutes cluster XVI, Mollicutes cluster XVIII, Prevotella, Rothia mucilaginosa, Ruminococcus callidus, Ruminococcus gnavus, Ruminococcus torques, and Streptococcus.

[0303] "Microbiome" broadly refers to the microorganisms present on or in a body site of a subject or patient. Microorganisms of the microbiome can include bacteria, viruses, eukaryotic microorganisms, and / or viruses. Individual microorganisms of the microbiome can be metabolically active, dormant, latent, exist as spores, planktonic, or in biological membranes, or exist in the microbiome in a sustainable or transient manner. The microbiome can be a commensal or healthy microbiome or a pathological microbiome. The microbiome can be native to the subject or patient, or components of the microbiome can be modulated, introduced, or depleted due to changes in health (e.g., precancerous or cancerous) or treatment (e.g., antibiotic treatment, exposure to different microorganisms). In some embodiments, the microbiome resides on a mucosal surface. In some embodiments, the microbiome is a gut microbiome. In some embodiments, the microbiome is a tumor microbiome.

[0304] A "microbiome profile" or "microbiome signature" of a tissue or sample refers to at least a partial characteristic of the bacterial makeup of the microbiome. In some embodiments, the microbiome profile indicates the presence or absence of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more bacterial strains in the microbiome. In some embodiments, the microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more cancer-associated bacterial strains are present in the sample. In some embodiments, the microbiome profile indicates the relative or absolute abundance of each bacterial strain detected in the sample. In some embodiments, the microbiome profile is a cancer-associated microbiome profile. A cancer-associated microbiome profile is a microbiome profile that occurs more frequently in subjects with cancer than in the general population. In some embodiments, the cancer-associated microbiome profile contains a greater number or amount of cancer-associated bacteria than is typically present in the microbiome of an otherwise equivalent tissue or sample taken from an individual without cancer.

[0305] "Modified" with respect to bacteria broadly refers to bacteria that have undergone a change from the wild type. Bacterial modifications can result from manipulation of the bacteria. Examples of bacterial modifications include genetic modifications, gene expression modifications, phenotypic modifications, formulation modifications, chemical modifications, and dosage or concentration. Examples of improved properties are described throughout this specification and include, for example, attenuation, auxotrophy, homing, or antigenicity. Phenotypic modifications can include, for example, growing the bacteria in a medium that modifies the bacterial phenotype to increase or decrease virulence.

[0306] "Oncobiome," as used herein, includes a tumorigenic microbiome and / or a cancer-associated microbiome, where the microbiome comprises one or more viruses, bacteria, fungi, protozoa, parasites, or other microorganisms.

[0307] "Tumor-tropic" or "tumor-tropic" microorganisms and bacteria are microorganisms that are highly associated with or present in the cancer microenvironment, and may be preferentially selected within, grow in, or be honed to the cancer microenvironment.

[0308] "Operational Taxonomic Unit" and "OTU" refer to the terminal leaves in a phylogenetic tree and are defined by a nucleic acid sequence, e.g., a whole genome or a specific gene sequence, and all sequences that share sequence identity with this nucleic acid sequence at the species level. In some embodiments, the specific gene sequence can be a 16S sequence or a portion of a 16S sequence. In other embodiments, the whole genomes of two entities are sequenced and compared. In another embodiment, selected regions, such as multilocus sequence tags (MLST), specific genes or sets of genes, can be genetically compared. In the case of 16S, OTUs that share 97% or more average nucleotide identity in the variable regions of the entire 16S or a portion of the 16S are considered the same OTU. See, e.g., Claesson MJ, Wang Q, O'Sullivan O, Greene-Diniz R, Cole JR, Ross RP, and O'Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38:e200. Konstantinidis KT, Ramette A, and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361:1929-1940. For complete genomes, MLST, specific genes other than 16S, or gene sets sharing 95% or more average nucleotide identity are considered the same OTU.See, for example, Achtman M, and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol. 6:431-440. Konstantinidis KT, Ramette A, and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361:1929-1940. OTUs are often defined by comparing sequences between organisms. Generally, sequences with 95% or less sequence identity are not considered to form part of the same OTU. OTUs can also be characterized by any combination of nucleotide markers or genes, particularly highly conserved genes (e.g., "housekeeping" genes). Provided herein are operational taxonomic units (OTUs) that are taxonomically assigned to, for example, genera, species, and clades.

[0309] As used herein, a gene is "overexpressed" in a bacterium if it is expressed at a higher level in the engineered bacterium under at least some conditions than it is expressed by a wild-type bacterium of the same species under the same conditions. Similarly, a gene is "underexpressed" in a bacterium if it is expressed at a lower level in the engineered bacterium under at least some conditions than it is expressed by a wild-type bacterium of the same species under the same conditions.

[0310] As used herein, the term "pharmaceutical product" refers to a pharmaceutical product for therapeutic use. In some embodiments, the pharmaceutical product is a composition comprising bacteria that can be used to treat and / or prevent a disease and / or condition. In some embodiments, a pharmaceutical product, medical food, food, or dietary supplement comprises the pharmaceutical product. In some embodiments, the pharmaceutical product is a powder containing bacteria. The powder may include one or more additional ingredients in addition to the bacteria, such as a cryoprotectant.

[0311] The terms "polynucleotide" and "nucleic acid" are used interchangeably. They refer to polymeric forms of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides can have any three-dimensional structure and can perform any function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci defined from linkage analysis, exons, introns, messenger RNA (mRNA), microRNA (miRNA), silencing RNA (siRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, vectors, isolated DNA of any sequence, isolated RNA of any sequence, nucleic acid probes, and primers. Polynucleotides can contain modified nucleotides, such as methylated nucleotides and nucleotide analogs. If present, modifications to the nucleotide structure can be imparted before or after assembly of the polymer. Polynucleotides can be further modified, such as by conjugation with a labeling component. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides.

[0312] As used herein, the term "preventing" a disease or condition in a subject refers to administering pharmaceutical treatment to a subject (e.g., administering one or more agents (e.g., pharmaceutical compositions)) such that the onset of at least one symptom of the disease or condition is delayed or prevented.

[0313] As used herein, a substance is "pure" if it is substantially free of other components. The terms "purify," "purifying," and "purified" refer to a microbial preparation or other substance that has been separated from at least some of the components that accompanied it when it was either originally produced or generated (e.g., in nature or in an experimental setting), or that have been associated with it for any time after initial production. A microbial preparation or composition may be considered purified if it has been isolated from, for example, one or more other bacterial components during or after production; a purified microorganism or population of microorganisms may contain up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than about 90% of other substances and still be considered "purified." In some embodiments, purified microorganisms are greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. A microbial composition (or preparation) is, for example, purified from residual habitat products.

[0314] "Residual habitat products" refers to materials derived from the habitat of the microbial flora in or on a subject. For example, a fermentation culture of a microorganism may contain contaminants, such as other microbial strains or forms (e.g., bacteria, viruses, mycoplasma, and / or fungi). For example, microorganisms live in feces in the gastrointestinal tract, on the skin itself, in saliva, in the mucous membranes of the respiratory tract, or in secretions of the genitourinary tract (i.e., biological material associated with the microbial community). By substantially free of residual habitat products, it is meant that the bacterial composition no longer contains biological material associated with the culture or microbial environment on or in a human or animal subject, and is 100% free, 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological material associated with the microbial community. Remaining habitat products may include abiotic material (including undigested food) or may include unwanted microorganisms. Substantially free of residual habitat products can also mean that the microbial composition is free of contaminants or detectable cells of human or animal origin, and only microbial cells are detectable. In one embodiment, substantially free of residual habitat products can also mean that the microbial composition is free of detectable viral (including bacterial viruses (e.g., phage)), fungal, or mycoplasmal contaminants. In another embodiment, substantially free of residual habitat products means that the microbial composition is free of 1×10 viable cells in the microbial composition compared to microbial cells. -2 %, 1×10 -3 %, 1×10 -4 %, 1×10 -5 %, 1×10 -6 %, 1×10 -7 %, 1×10 -8 This means that less than % of the sample is human or animal. There are multiple ways to achieve this purity, none of which are limiting. Thus, contamination can be reduced by isolating the desired construct through multiple steps of streaking single colonies on solid media until repeated (e.g., but not limited to, twice) streaks from a series of single colonies show only single colony morphology. Alternatively, multiple serial dilutions (e.g., 10-fold serial dilutions) of a single desired cell can be performed. -8 or 10-9 Reduction of contamination can be achieved by dilution of the desired product (e.g., dilution of the desired product). This can be further supported by demonstrating that multiple isolated colonies have similar cell shape and Gram staining behavior. Other methods of confirming sufficient purity include the use of genetic analysis (e.g., PCR, DNA sequencing), serological and antigenic analysis, enzymatic and metabolic analysis, and instrumental tools such as flow cytometry with reagents that distinguish the desired component from contaminants.

[0315] As used herein, "specific binding" refers to the ability of an antibody to bind to a predetermined antigen or a polypeptide to bind to its predetermined binding partner. Typically, an antibody or polypeptide binds to a specific antigen within about 10 -7 K below M D specifically binds to its given antigen or binding partner with an affinity corresponding to , and is at least 10-fold less, at least 100-fold less, or at least 1000-fold less than the affinity for binding to a nonspecific and unrelated antigen / binding partner (e.g., BSA, casein). D Alternatively, specific binding applies more broadly to two-component systems in which one component is a protein, lipid, or carbohydrate, or a combination thereof, and specifically binds to a second component that is a protein, lipid, carbohydrate, or a combination thereof.

[0316] A "strain" refers to a member of a bacterial species that possesses genetic characteristics that allow it to be distinguished from closely related members of the same bacterial species. The genetic characteristics can be the deletion of all or part of at least one gene, the deletion of all or part of at least one regulatory region (e.g., promoter, terminator, riboswitch, ribosome binding site), the absence ("curing") of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene from another species), the presence of at least one mutated regulatory region (e.g., promoter, terminator, riboswitch, ribosome binding site), the presence of at least one non-native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof. Genetic characteristics between different strains can be identified by PCR amplification, optionally followed by DNA sequencing of the genomic region of interest or the entire genome. If a strain (relative to another strain of the same species) gains or loses antibiotic resistance or gains or loses biosynthetic capabilities (such as auxotrophic strains), the strains can be differentiated by selecting or counterselecting with antibiotics or nutrients / metabolites, respectively.

[0317] The term "subject" or "patient" refers to any animal. A subject or patient described as "in need thereof" refers to one who requires treatment (or prevention) of a disease. Mammals (i.e., mammals) include humans, laboratory animals (e.g., primates, rats, mice), farm animals (e.g., cows, sheep, goats, pigs), and pets (e.g., dogs, cats, rodents). The subject may be a human. The subject may be a non-human mammal, including, but not limited to, a dog, cat, cow, horse, pig, donkey, goat, camel, mouse, rat, guinea pig, sheep, llama, monkey, gorilla, or chimpanzee. The subject may be healthy or may be suffering from cancer at any stage of development, either caused by or opportunistically supported by a cancer-related or causative pathogen, or may be at risk of developing cancer or transmitting a cancer-related or causative pathogen to others. In some embodiments, the subject has lung cancer, bladder cancer, prostate cancer, plasmacytoma, colorectal cancer, rectal cancer, Merkel cell carcinoma, salivary gland cancer, ovarian cancer, and / or melanoma. The subject may have a tumor. The subject may have a tumor that exhibits enhanced macropinocytosis, with the genomics underlying this process involving Ras activation. In other embodiments, the subject may have another cancer. In some embodiments, the subject is undergoing cancer treatment.

[0318] As used herein, a "systemic effect" in a subject treated with a pharmaceutical composition comprising the bacteria of the present invention (e.g., a medicine comprising the bacteria) refers to a physiological effect that occurs at one or more sites other than the gastrointestinal tract. A systemic effect may be due to immunomodulation (e.g., by increasing and / or decreasing one or more immune cell types or subtypes (e.g., CD8+ T cells) and / or one or more cytokines). Such a systemic effect may be the result of modulation by the bacteria of the present invention on immune cells or other cells (e.g., epithelial cells) in the gastrointestinal tract, which directly or indirectly results in altered activity (activation and / or deactivation) of one or more biochemical pathways outside the gastrointestinal tract. A systemic effect may include treating or preventing a disease or condition in the subject.

[0319] As used herein, the term "treating" a subject with a disease or a subject suspected of having or having a disease refers to administering pharmaceutical therapy to the subject, e.g., administering one or more drugs, such that at least one symptom of the disease is alleviated or prevented from worsening. Thus, in one embodiment, "treating" refers to, inter alia, delaying progression, promoting remission, inducing remission, enhancing remission, accelerating recovery, increasing the effectiveness of or reducing resistance to an alternative therapeutic agent, or a combination thereof.

[0320] As used herein, a value is "greater than" another value if it is higher than the other value by any amount (e.g., 100, 50, 20, 12, 11, 10.6, 10.1, 10.01, and 10.001 are each at least 10). Similarly, as used herein, a value is "less than" another value if it is lower than the other value by any amount (e.g., 1, 2, 4, 6, 8, 9, 9.2, 9.4, 9.6, 9.8, 9.9, 9.99, and 9.999 are each less than or equal to 10). In contrast, as used herein, a test value "is" the anchor value if the test value rounds to the anchor value (e.g., if "a component mass is 10% of the total mass" (in which case 10% is the anchor value), then test values ​​of 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3, and 10.4 would also satisfy the characteristic "component mass is 10% of the total mass").

[0321] bacteria The pharmaceuticals disclosed herein (e.g., pharmaceutical compositions containing the same) may contain bacteria. For example, the pharmaceuticals disclosed herein may include a powder containing bacteria. Within the pharmaceuticals containing bacteria, the pharmaceuticals may contain bacteria from one or more strains.

[0322] In some embodiments, pharmaceutical bacteria are modified to reduce toxicity or other adverse effects, to enhance delivery (e.g., oral delivery) (e.g., by improving acid tolerance, mucoadhesion and / or penetration and / or resistance to bile acids, digestive enzymes, resistance to antimicrobial peptides and / or neutralizing antibodies), to target desired cell types (e.g., M cells, goblet cells, enterocytes, dendritic cells, macrophages), to enhance their immunomodulatory and / or therapeutic effects of the bacteria (e.g., either alone or in combination with another therapeutic agent), and / or to enhance bacterial immune activation or suppression (e.g., through modified production of polysaccharides, pili, fimbriae, adhesins). In some embodiments, the engineered bacteria described herein are modified to improve bacterial production (e.g., higher oxygen tolerance, stability, improved freeze-thaw resistance, shorter production time). For example, in some embodiments, the engineered bacteria described include bacteria carrying one or more genetic alterations, such as insertions, deletions, translocations, or substitutions of one or more nucleotides contained in the bacterial chromosome or endogenous plasmids and / or one or more exogenous plasmids, or any combination thereof, which may result in overexpression and / or underexpression of one or more genes. Engineered bacteria may be generated using any technique known in the art, including, but not limited to, site-directed mutagenesis, transposon mutagenesis, knockout, knockin, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet mutagenesis, transformation (chemical or by electroporation), phage transduction, directed evolution, or any combination thereof.

[0323] Examples of bacterial taxa (e.g., classes, orders, families, genera, species, or strains) that can be used as sources of bacteria for the pharmaceutical products described herein are provided herein (e.g., listed in Table 1, Table 2, Table 3, and / or Table 4 and / or elsewhere herein (e.g., Table J)). In some embodiments, the bacterial strain is a bacterial strain having a genome with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to a strain listed herein. In some embodiments, the pharmaceutical bacterium is an oncotrophic bacterium. In some embodiments, the pharmaceutical bacterium is an immunomodulatory bacterium. In some embodiments, the pharmaceutical bacterium is an immunostimulatory bacterium. In some embodiments, the medicinal bacterium is an immunosuppressive bacterium. In some embodiments, the medicinal bacterium is an immunomodulatory bacterium. In certain embodiments, the medicinal bacterium is produced from a combination of bacterial strains described herein. In some embodiments, the combination is a combination of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45, or 50 bacterial strains. In some embodiments, the combination includes pharmaceutical bacteria derived from a bacterial strain listed herein and / or a bacterial strain having a genome with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity to a bacterial strain listed herein (e.g., listed in Table 1, Table 2, Table 3, and / or Table 4 and / or elsewhere herein (e.g., Table J)). In certain embodiments, the pharmaceutical bacteria are produced from a bacterial strain described herein.In some embodiments, the bacterium of the pharmaceutical agent is derived from a bacterial strain listed herein (e.g., listed in Table 1, Table 2, Table 3, and / or Table 4 and / or elsewhere herein (e.g., Table J)) and / or a bacterial strain having a genome with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8% or 99.9% sequence identity to a strain listed herein (e.g., listed in Table 1, Table 2, Table 3, and / or Table 4 and / or elsewhere herein (e.g., Table J)).

[0324] In some embodiments, the pharmaceutical bacterium is a gram-negative bacterium.

[0325] In some embodiments, the Gram-negative bacteria belong to the class Negativicutes. Negativicutes represent a unique classification of microorganisms, as they are the only diderm members of the phylum Firmicutes. These anaerobic organisms can be found in the environment and are normal commensals of the human oral cavity and GI tract. Negativicutes includes the families Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, and Sporomusaceae. The class Negativicutes includes the genera Megasphaera, Selenomonas, Propionospora, and Acidaminococcus. Exemplary Negativicutes species include, but are not limited to, Megasphaera sp., Selenomonas felix, Acidaminococcus intestini, and Propionospora sp.

[0326] In some embodiments, the pharmaceutical bacterium is a gram-positive bacterium.

[0327] In some embodiments, the bacterium of the pharmaceutical agent is an aerobic bacterium.

[0328] In some embodiments, the bacterium of the pharmaceutical agent is an anaerobic bacterium. In some embodiments, the anaerobe comprises an obligate anaerobe. In some embodiments, the anaerobe comprises a facultative anaerobe.

[0329] In some embodiments, the pharmaceutical bacterium is an acidophilic bacterium.

[0330] In some embodiments, the pharmaceutical bacterium is an alkaliphilic bacterium.

[0331] In some embodiments, the pharmaceutical bacterium is a neutrophilic bacterium.

[0332] In some embodiments, the pharmaceutical bacterium is a fastidious bacterium.

[0333] In some embodiments, the bacterium of the pharmaceutical agent is a non-fastidious bacterium.

[0334] In some embodiments, the pharmaceutical bacteria is freeze-dried.

[0335] In some embodiments, the pharmaceutical bacteria are gamma irradiated (eg, 17.5 or 25 kGy).

[0336] In some embodiments, the pharmaceutical bacteria is UV irradiated.

[0337] In some embodiments, the bacteria in the pharmaceutical preparation are heat inactivated (eg, 50° C. for 2 hours or 90° C. for 2 hours).

[0338] In some embodiments, the pharmaceutical bacteria is acid-treated.

[0339] In some embodiments, the pharmaceutical bacteria are sparged with oxygen (eg, 0.1 vvm for 2 hours).

[0340] The growth phase can affect the quantity or characteristics of bacteria. For example, bacteria can be isolated at the beginning of the logarithmic growth phase, mid-logarithmic phase, and / or when the bacterial culture has reached the stationary growth phase.

[0341] In certain embodiments, the bacterium of the pharmaceutical agent is an obligate anaerobic bacterium. Examples of obligate anaerobic bacteria include gram-negative rods (including Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Bilophila and Sutterella spp.), gram-positive cocci (mainly Peptostreptococcus spp.), gram-positive spore-forming bacteria (Clostridium spp.), non-spore-forming rods (Actinomyces, Propionibacterium, Eubacterium, Lactobacillus and Bifidobacterium spp.). spp.) and Gram-negative cocci (mainly Veillonella spp.). In some embodiments, the obligately anaerobic bacteria are of a genus selected from the group consisting of Agathobaculum, Atopobium, Blautia, Burkholderia, Dielma, Longicatena, Paraclostridium, Turicibacter, and Tyzzerella.

[0342] The class Negativicutes includes the families Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, and Sporomusaceae. The class Negativicutes includes the genera Megasphaera, Selenomonas, Propionospora, and Acidaminococcus. Exemplary Negativicutes species include, but are not limited to, Megasphaera sp., Selenomonas felix, Acidaminococcus intestini, and Propionospora sp.

[0343] In some embodiments, the bacterium of the pharmaceutical agent is of the class Negativicutes.

[0344] In some embodiments, the bacterium of the pharmaceutical agent is of the family Veillonellaceae.

[0345] In some embodiments, the pharmaceutical bacterium is of the family Selenomonadaceae.

[0346] In some embodiments, the pharmaceutical bacterium is of the family Acidaminococcaceae.

[0347] In some embodiments, the medicinal bacterium is of the family Sporomusaceae.

[0348] In some embodiments, the pharmaceutical bacterium is of the genus Megasphaera.

[0349] In some embodiments, the pharmaceutical bacterium is of the genus Selenomonas.

[0350] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Propionospora.

[0351] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Acidaminococcus.

[0352] In some embodiments, the pharmaceutical bacterium is a Megasphaera species bacterium.

[0353] In some embodiments, the pharmaceutical bacterium is a Selenomonas felix bacterium.

[0354] In some embodiments, the pharmaceutical bacterium is Acidaminococcus intestini bacterium.

[0355] In some embodiments, the bacterium of the pharmaceutical agent is a Propionospora sp. bacterium.

[0356] Microorganisms of the family Oscillospriraceae within the class Clostridia are common commensals of vertebrates.

[0357] In some embodiments, the pharmaceutical bacterium is of the class Clostridia.

[0358] In some embodiments, the pharmaceutical bacterium is of the family Oscillospriraceae.

[0359] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Faecalibacterium.

[0360] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Fournierella.

[0361] In some embodiments, the pharmaceutical bacterium is of the genus Harryflintia.

[0362] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Agathobaculum.

[0363] In some embodiments, the pharmaceutical bacterium is a Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii strain A) bacterium.

[0364] In some embodiments, the bacterium of the pharmaceutical agent is Fournierella massiliensis (e.g., Fournierella massiliensis strain A) bacterium.

[0365] In some embodiments, the pharmaceutical bacterium is Harryflintia acetispora (e.g., Harryflintia acetispora strain A) bacterium.

[0366] In some embodiments, the bacterium of the pharmaceutical agent is an Agathobaculum sp. (eg, Agathobaculum sp. strain A) bacterium.

[0367] In some embodiments, the pharmaceutical bacterium is a bacterium of a genus selected from the group consisting of Escherichia, Klebsiella, Lactobacillus, Shigella, and Staphylococcus.

[0368] In some embodiments, the bacterium of the pharmaceutical agent is selected from the group consisting of Blautia massiliensis, Paraclostridium benzoelyticum, Dielma fastidiosa, Longicatena caecimuris, Lactococcus lactis cremoris, Tyzzerella nexilis, Hungatella effluvia, Klebsiella quasipneumoniae subsp. Similipneumoniae, Klebsiella oxytoca, and Veillonella tobetsuensis. tobetsuensis).

[0369] In some embodiments, the pharmaceutical bacterium is selected from the group consisting of Prevotella albensis, Prevotella amnii, Prevotella bergensis, Prevotella bivia, Prevotella brevis, Prevotella bryantii, Prevotella buccae, Prevotella buccalis, Prevotella copri, Prevotella dentalis, Prevotella denticola, Prevotella disiens, Prevotella histicola, and Prevotella intermedia. intermedia, Prevotella maculosa, Prevotella marshii, Prevotella melaninogenica, Prevotella micans, Prevotella multiformis, Prevotella nigrescens, Prevotella oralis, Prevotella oris, Prevotella oulorum, Prevotella pallens, Prevotella salivae, Prevotella stercorea, Prevotella tannellae tannerae), Prevotella timonensis, Prevotella jejunijejuni, Prevotella aurantiaca, Prevotella baroniae, Prevotella colorans, Prevotella corporis, Prevotella dentasini, Prevotella enoeca, Prevotella falsenii, Prevotella fusca, Prevotella heparinolytica, Prevotella loescheii, Prevotella multisaccharivorax, Prevotella nanseiensis The Prevotella bacterium is a Prevotella bacterium selected from the group consisting of Prevotella nanceiensis, Prevotella oryzae, Prevotella paludivivens, Prevotella pleuritidis, Prevotella ruminicola, Prevotella saccharolytica, Prevotella scopos, Prevotella shahii, Prevotella zoogleoformans, and Prevotella veroralis.

[0370] In some embodiments, the bacterium of the pharmaceutical agent is a strain of bacteria that comprises a genomic sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the genomic sequence of the strain of bacteria deposited under the ATCC accession number provided in Table 3. In some embodiments, the bacterium of the pharmaceutical agent is a strain of bacteria that comprises a 16S sequence that is at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the 16S sequence of the bacterial strain deposited under the ATCC accession number provided in Table 3.

[0371] The class Negativicutes includes the families Veillonellaceae, Selenomonadaceae, Acidaminococcaceae, and Sporomusaceae. The class Negativicutes includes the genera Megasphaera, Selenomonas, Propionospora, and Acidaminococcus. Exemplary Negativicutes species include, but are not limited to, Megasphaera sp., Selenomonas felix, Acidaminococcus intestini, and Propionospora sp.

[0372] In some embodiments, the pharmaceutical bacterium is of the class Negativicutes.

[0373] In some embodiments, the bacterium of the pharmaceutical agent is of the family Veillonellaceae.

[0374] In some embodiments, the pharmaceutical bacterium is of the family Selenomonadaceae.

[0375] In some embodiments, the pharmaceutical bacterium is of the family Acidaminococcaceae.

[0376] In some embodiments, the medicinal bacterium is of the family Sporomusaceae.

[0377] In some embodiments, the pharmaceutical bacterium is of the genus Megasphaera.

[0378] In some embodiments, the pharmaceutical bacterium is of the genus Selenomonas.

[0379] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Propionospora.

[0380] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Acidaminococcus.

[0381] In some embodiments, the pharmaceutical bacterium is a Megasphaera species bacterium.

[0382] In some embodiments, the pharmaceutical bacterium is a Selenomonas felix bacterium.

[0383] In some embodiments, the pharmaceutical bacterium is Acidaminococcus intestini bacterium.

[0384] In some embodiments, the bacterium of the pharmaceutical agent is a Propionospora sp. bacterium.

[0385] Microorganisms of the family Oscillospriraceae within the class Clostridia are common commensals of vertebrates.

[0386] In some embodiments, the pharmaceutical bacterium is of the class Clostridia.

[0387] In some embodiments, the pharmaceutical bacterium is of the family Oscillospriraceae.

[0388] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Faecalibacterium.

[0389] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Fournierella.

[0390] In some embodiments, the pharmaceutical bacterium is of the genus Harryflintia.

[0391] In some embodiments, the bacterium of the pharmaceutical agent is of the genus Agathobaculum.

[0392] In some embodiments, the pharmaceutical bacterium is a Faecalibacterium prausnitzii (e.g., Faecalibacterium prausnitzii strain A) bacterium.

[0393] In some embodiments, the bacterium of the pharmaceutical agent is Fournierella massiliensis (e.g., Fournierella massiliensis strain A) bacterium.

[0394] In some embodiments, the pharmaceutical bacterium is Harryflintia acetispora (e.g., Harryflintia acetispora strain A) bacterium.

[0395] In some embodiments, the bacterium of the pharmaceutical agent is an Agathobaculum sp. (eg, Agathobaculum sp. strain A) bacterium.

[0396] In some embodiments, the bacterium of the pharmaceutical agent is a strain of Agathobaculum sp. In some embodiments, the Agathobaculum sp. strain is a strain that comprises at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genome sequence, 16S sequence, CRISPR sequence) of Agathobaculum sp. strain A (ATCC Accession No. PTA-125892). In some embodiments, the Agathobaculum sp. strain is Agathobaculum sp. strain A (ATCC Accession No. PTA-125892).

[0397] In some embodiments, the therapeutic bacterium is of the class Bacteroidia (phylum Bacteroidota). In some embodiments, the therapeutic bacterium is of the order Bacteroidales. In some embodiments, the therapeutic bacterium is of the family Porphyromonoadaceae. In some embodiments, the therapeutic bacterium is of the family Prevotellaceae. In some embodiments, the therapeutic bacterium is of the class Bacteroidia, and the bacterial cell envelope structure is a diderm. In some embodiments, the therapeutic bacterium is of the class Bacteroidia, which stains gram-negative. In some embodiments, the therapeutic bacterium is of the class Bacteroidia, the bacterium is a diderm, and the bacterium stains gram-negative.

[0398] In some embodiments, the therapeutic bacterium is a bacterium of the class Clostridia (phylum Firmicutes). In some embodiments, the therapeutic bacterium is of the order Eubacteriales. In some embodiments, the therapeutic bacterium is of the family Oscillospiraceae. In some embodiments, the therapeutic bacterium is of the family Lachnospiraceae. In some embodiments, the therapeutic bacterium is of the family Peptostreptococcaceae. In some embodiments, the therapeutic bacterium is of Clostridiales family XIII / Incertae sedis 41. In some embodiments, the therapeutic bacterium is of the class Clostridia and the bacterial cell envelope structure is a monoderm. In some embodiments, the therapeutic bacterium is of the class Clostridia, which stains Gram-negative. In some embodiments, the therapeutic bacterium is of the class Clostridia, which stains Gram-positive. In some embodiments, the therapeutic bacterium is of the class Clostridia, the bacterial cell envelope structure is monoderm, and the bacterium stains Gram-negative. In some embodiments, the therapeutic bacterium is of the class Clostridia, the bacterial cell envelope structure is monoderm, and the bacterium stains Gram-positive.

[0399] In some embodiments, the therapeutic bacterium is of the class Negativicutes (phylum Firmicutes). In some embodiments, the therapeutic bacterium is of the order Veillonellales. In some embodiments, the therapeutic bacterium is of the family Veillonelloceae. In some embodiments, the therapeutic bacterium is of the order Selenomonadales. In some embodiments, the therapeutic bacterium is of the family Selenomonadaceae. In some embodiments, the therapeutic bacterium is of the family Sporomusaceae. In some embodiments, the therapeutic bacterium is of the class Negativicutes and the bacterial cell envelope structure is a diderm. In some embodiments, the pharmaceutical bacterium is from the class Negativicutes, the cell envelope structure of the bacterium is a diderm, and the bacterium stains gram-negative.

[0400] In some embodiments, the therapeutic bacterium is of the class Synergistia (phylum Synergistota). In some embodiments, the therapeutic bacterium is of the order Synergistales. In some embodiments, the therapeutic bacterium is of the family Synergistaceae. In some embodiments, the therapeutic bacterium is of the class Synergistia and the bacterial cell envelope structure is a diderm. In some embodiments, the therapeutic bacterium is of the class Synergistia that stains Gram-negative. In some embodiments, the therapeutic bacterium is of the class Synergistia and the bacterial cell envelope structure is a diderm, and the bacterium stains Gram-negative.

[0401] In some embodiments, the bacterium of the pharmaceutical agent is derived from one bacterial strain, such as a strain provided herein.

[0402] In some embodiments, the bacterium of the pharmaceutical agent is from one bacterial strain (e.g., a strain provided herein) or from two or more strains provided herein.

[0403] In some embodiments, the pharmaceutical bacterium is a Lactococcus lactis cremoris bacterium, such as a strain that contains at least 90% or at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of Lactococcus lactis cremoris strain A (ATCC Designation No. PTA-125368). In some embodiments, the pharmaceutical bacterium is a Lactococcus bacterium, such as Lactococcus lactis cremoris strain A (ATCC Designation No. PTA-125368).

[0404] In some embodiments, the bacterium of the pharmaceutical agent is a Prevotella bacterium, such as a strain that comprises at least 90% or at least 99% genomic, 16S and / or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL accession number B 50329). In some embodiments, the bacterium of the pharmaceutical agent is a Prevotella bacterium, such as Prevotella strain B 50329 (NRRL accession number B 50329).

[0405] In some embodiments, the bacterium of the pharmaceutical agent is a Bifidobacterium bacterium, such as a strain that comprises at least 90% or at least 99% genomic, 16S and / or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium bacterium deposited under ATCC Designation No. PTA- 125097. In some embodiments, the bacterium of the pharmaceutical agent is a Bifidobacterium bacterium, such as the Bifidobacterium bacterium deposited under ATCC Designation No. PTA-125097.

[0406] In some embodiments, the bacterium of the pharmaceutical agent is a Veillonella bacterium, such as a strain that comprises at least 90% or at least 99% genomic, 16S and / or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacterium deposited under ATCC Designation No. PTA- 125691. In some embodiments, the bacterium of the pharmaceutical agent is a Veillonella bacterium, such as a Veillonella bacterium deposited under ATCC Designation No. PTA-125691.

[0407] In some embodiments, the bacterium of the pharmaceutical agent is a Ruminococcus gnavus bacterium. In some embodiments, the Ruminococcus gnavus bacterium is a strain that contains at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacterium deposited under ATCC Designation No. PTA-126695. In some embodiments, the Ruminococcus gnavus bacterium is a strain that contains at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus gnavus bacterium deposited under ATCC Designation No. PTA-126695. In some embodiments, the Ruminococcus gnavus bacterium is the Ruminococcus gnavus bacterium deposited under ATCC Designation No. PTA-126695.

[0408] In some embodiments, the bacterium of the pharmaceutical agent is a Megasphaera bacterium. In some embodiments, the Megasphaera sp. bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacterium deposited under ATCC Designation No. PTA-126770. In some embodiments, the Megasphaera sp. bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Megasphaera sp. bacterium deposited under ATCC Designation No. PTA-126770. In some embodiments, the Megasphaera sp. bacterium is a Megasphaera sp. bacterium deposited under ATCC Designation No. PTA-126770.

[0409] In some embodiments, the bacterium of the pharmaceutical agent is a Fournierella massiliensis bacterium. In some embodiments, the Fournierella massiliensis bacterium is a strain that contains at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under ATCC Designation No. PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is a strain that contains at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under ATCC Designation No. PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is the Fournierella massiliensis bacterium deposited under ATCC Designation No. PTA-126696.

[0410] In some embodiments, the bacterium of the pharmaceutical agent is a Harryflintia acetispora bacterium. In some embodiments, the Harryflintia acetispora bacterium is a strain that comprises at least 90% (or at least 97%) genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC Designation No. PTA-126694. In some embodiments, the Harryflintia acetispora bacterium is a strain that comprises at least 99% genomic, 16S, and / or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC Designation No. PTA-126694. In some embodiments, the Harryflintia acetispora bacterium is the Harryflintia acetispora bacterium deposited under ATCC Designation No. PTA-126694.

[0411] In some embodiments, the pharmaceutical bacterium is a bacterium that produces a metabolite, for example, the bacterium produces butyrate, iosine, propionate, or a tryptophan metabolite.

[0412] In some embodiments, the bacterium produces butyrate, hi some embodiments, the bacterium is from the genus Blautia, Christensella, Copracoccus, Eubacterium, Lachnosperacea, Megasphaera, or Roseburia.

[0413] In some embodiments, the bacterium produces iosine, hi some embodiments, the bacterium is from the genus Bifidobacterium, Lactobacillus, or Olsenella.

[0414] In some embodiments, the bacterium produces propionate, hi some embodiments, the bacterium is from the genus Akkermansia, Bacteriodes, Dialister, Eubacterium, Megasphaera, Parabacteroides, Prevotella, Ruminococcus, or Veillonella.

[0415] In some embodiments, the bacterium produces a tryptophan metabolite, hi some embodiments, the bacterium is from the genus Lactobacillus or Peptostreptococcus.

[0416] In some embodiments, the pharmaceutical bacterium is a bacterium that produces an inhibitor of histone deacetylase 3 (HDAC3), hi some embodiments, the bacterium is from the species Bariatricus massiliensis, Faecalibacterium prausnitzii, Megasphaera massiliensis, or Roseburia intestinalis.

[0417] In some embodiments, the bacterium is of the genus Cutibacterium.

[0418] In some embodiments, the bacterium is Cutibacterium avidum.

[0419] In some embodiments, the bacteria is from the genus Lactobacillus.

[0420] In some embodiments, the bacteria is from the genus Lactobacillus gasseri.

[0421] In some embodiments, the bacteria is from the genus Dysosmobacter.

[0422] In some embodiments, the bacterium is from the species Dysosmobacter welbionis.

[0423] In some embodiments, the bacterium is of the genus Leuconostoc.

[0424] In some embodiments, the bacterium is of the genus Lactobacillus.

[0425] In some embodiments, the bacterium is a bacterium of the genus Akkermansia; Bacillus; Blautia; Cupriavidus; Enhydrobacter; Faecalibacterium; Lactobacillus; Lactococcus; Micrococcus; Morganella; Propionibacterium; Proteus; Rhizobium or Streptococcus.

[0426] In some embodiments, the bacterium is a Leuconostoc holzapfelii bacterium.

[0427] In some embodiments, the bacterium is Akkermansia muciniphila; Cupriavidus metallidurans; Faecalibacterium prausnitzii; Lactobacillus casei; Lactobacillus plantarum; Lactobacillus paracasei; Lactobacillus plantarum; Lactobacillus rhamnosus; Lactobacillus sakei; or Streptococcus pyogenes.

[0428] In some embodiments, the bacterium is a Lactobacillus casei; Lactobacillus plantarum; Lactobacillus paracasei; Lactobacillus plantarum; Lactobacillus rhamnosus; or Lactobacillus sakei bacterium.

[0429] In some embodiments, the bacterium is a Megasphaera sp. bacterium (e.g., from a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387).

[0430] In some embodiments, the bacterium is a Megasphaera massiliensis bacterium (e.g., from a strain having accession number NCIMB 42787, NCIMB 43388, or NCIMB 43389).

[0431] In some embodiments, the bacterium is a Megasphaera massiliensis bacterium (e.g., from the strain having accession number DSM 26228).

[0432] In some embodiments, the bacterium is a Bacillus amyloliquefaciens bacterium (e.g., from a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086).

[0433] In some embodiments, the bacterium is a Parabacteroides distasonis bacterium (e.g., from the strain having accession number NCIMB 42382).

[0434] In some embodiments, the bacterium is Megasphaera massiliensis bacterium (e.g., from a strain having accession number NCIMB 43388 or NCIMB 43389) or a derivative thereof. See, e.g., WO 2020 / 120714. In some embodiments, the Megasphaera massiliensis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genomic sequence, a 16S sequence, and / or a CRISPR sequence) of a Megasphaera massiliensis bacterium from a strain having accession number NCIMB 43388 or NCIMB 43389. In some embodiments, the Megasphaera massiliensis bacterium is a strain having accession number NCIMB 43388 or NCIMB 43389.

[0435] In some embodiments, the bacterium is the Megasphaera massiliensis bacterial strain deposited under accession number NCIMB 42787 or a derivative thereof. See, e.g., WO 2018 / 229216. In some embodiments, the Megasphaera massiliensis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genome sequence, 16S sequence, and / or CRISPR sequence) of the Megasphaera massiliensis bacterial strain deposited under accession number NCIMB 42787. In some embodiments, the Megasphaera massiliensis bacterium is the strain deposited under accession number NCIMB 42787.

[0436] In some embodiments, the bacterium is a Megasphaera spp. bacterium or a derivative thereof from a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387. See, e.g., WO 2020 / 120714. In some embodiments, the Megasphaera sp. bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genomic sequence, a 16S sequence, and / or a CRISPR sequence) of Megasphaera sp. from a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387. In some embodiments, the Megasphaera sp. bacterium is a strain having accession number NCIMB 43385, NCIMB 43386, or NCIMB 43387.

[0437] In some embodiments, the bacterium is Parabacteroides distasonis, or a derivative thereof, deposited under accession number NCIMB 42382. See, e.g., WO 2018 / 229216. In some embodiments, the Parabacteroides distasonis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genome sequence, 16S sequence, and / or CRISPR sequence) of the Parabacteroides distasonis bacterium deposited under accession number NCIMB 42382. In some embodiments, the Parabacteroides distasonis bacterium is the strain deposited under accession number NCIMB 42382.

[0438] In some embodiments, the bacterium is the Megasphaera massiliensis bacterium deposited under accession number DSM 26228 or a derivative thereof. See, e.g., WO 2018 / 229216. In some embodiments, the Megasphaera massiliensis bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genome sequence, a 16S sequence, and / or a CRISPR sequence) of the Megasphaera massiliensis bacterium deposited under accession number DSM 26228. In some embodiments, the Megasphaera massiliensis bacterium is a strain deposited under accession number DSM 26228.

[0439] In some embodiments, the bacterium is a Bacillus amyloliquefaciens bacterium (e.g., from a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086) or a derivative thereof. See, e.g., WO 2019 / 236806. In some embodiments, the Bacillus amyloliquefaciens bacterium is a strain that comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to a nucleotide sequence (e.g., a genomic sequence, a 16S sequence, and / or a CRISPR sequence) of a Bacillus amyloliquefaciens bacterial strain from a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086. In some embodiments, the Bacillus amyloliquefaciens bacterium is a strain having accession number NCIMB 43088, NCIMB 43087, or NCIMB 43086. In some embodiments, the Bacillus amyloliquefaciens bacterium is a strain having accession number NCIMB 43088.

[0440] [Table 1]

[0441] [Table 2]

[0442] [Table 3]

[0443]

Table 4

[0444]

Table 5

[0445]

Table 6

[0446]

Table 7

[0447]

Table 8

[0448]

Table 9

[0449]

Table 10

[0450]

Table 11

[0451]

Table 12

[0452]

Table 13

[0453]

Table 14

[0454]

Table 15

[0455] Table 16

[0456]

Table 17

[0457] Table 18

[0458] Table 19

[0459] Table 20

[0460] Table 21

[0461] Table 22

[0462] Table 23

[0463] Table 24

[0464] Table 25

[0465] Table 26

[0466] Table 27

[0467] Table 28

[0468] Table 29

[0469] Table 30

[0470] Table 31

[0471] Table 32

[0472]

Table 33

[0473] Table 34

[0474] [Table 35]

[0475] [Table 36]

[0476] Modified bacteria In some embodiments, the bacteria described herein are modified to include, be linked to, and / or be bound to a therapeutic moiety.

[0477] In some embodiments, the therapeutic moiety is a cancer-specific moiety. In some embodiments, the cancer-specific moiety has binding specificity for a cancer cell (e.g., has binding specificity for a cancer-specific antigen). In some embodiments, the cancer-specific moiety comprises an antibody or antigen-binding fragment thereof. In some embodiments, the cancer-specific moiety comprises a T-cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the cancer-specific moiety comprises a ligand for a receptor expressed on the surface of a cancer cell, or a receptor-binding fragment thereof. In some embodiments, the cancer-specific moiety is a bipartite fusion protein having two moieties: a first moiety that is bound to and / or linked to bacteria, and a second moiety that can bind to cancer cells (e.g., by having binding specificity for a cancer-specific antigen). In some embodiments, the first moiety is a full-length peptidoglycan recognition protein or a fragment thereof, such as PGRP. In some embodiments, the first moiety has binding specificity for bacteria (e.g., by having binding specificity for a bacterial antigen). In some embodiments, the first and / or second moiety comprise an antibody or antigen-binding fragment thereof. In some embodiments, the first and / or second moiety comprise a T-cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the first and / or second moiety comprises a ligand for a receptor expressed on the surface of a cancer cell, or a receptor-binding fragment thereof. In certain embodiments, co-administration of the cancer-specific moiety and the pharmaceutical agent (either administered in combination or separately) increases targeting of the pharmaceutical agent to the cancer cell.

[0478] In some embodiments, the bacteria described herein comprise, are linked to, and / or are modified to bind to a magnetic and / or paramagnetic moiety (e.g., a magnetic bead). In some embodiments, the magnetic and / or paramagnetic moiety is comprised in the bacterium and / or directly linked to the bacterium. In some embodiments, the magnetic and / or paramagnetic moiety is linked to and / or is part of a bacterium-binding moiety that binds to the bacterium. In some embodiments, the bacterium-binding moiety is a full-length peptidoglycan recognition protein, such as PGRP, or a fragment thereof. In some embodiments, the bacterium-binding moiety has binding specificity for the bacterium (e.g., by having binding specificity for a bacterial antigen). In some embodiments, the bacterium-binding moiety comprises an antibody or an antigen-binding fragment thereof. In some embodiments, the bacterium-binding moiety comprises a T-cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the bacterium-binding moiety comprises a ligand for a receptor expressed on the surface of a cancer cell, or a receptor-binding fragment thereof. In certain embodiments, co-administration (either combined or separate) of magnetic and / or paramagnetic moieties with bacteria may be used to increase targeting of the bacteria to, for example, cancer cells and / or areas where cancer cells are present in a subject.

[0479] Pharmaceuticals and Compositions In certain embodiments, provided herein are pharmaceutical compositions and / or solid dosage forms (e.g., pharmaceutical products having solid dosage forms) comprising pharmaceutical products containing bacteria. The bacteria can be live bacteria; non-viable (dead) bacteria; non-replicating bacteria; gamma-irradiated bacteria; and / or freeze-dried bacteria.

[0480] In certain embodiments, provided herein are pharmaceutical preparations containing bacteria. In some embodiments, the pharmaceutical preparations may optionally include one or more additional ingredients, such as a cryoprotectant. The pharmaceutical preparations may be lyophilized (e.g., to obtain a powder). The pharmaceutical preparations may be combined with one or more excipients (e.g., pharmaceutically acceptable excipients) in pharmaceutical compositions and / or solid dosage forms (e.g., solid dosage forms).

[0481] In some embodiments, the pharmaceutical agent has the appearance of a fine, smooth granular powder.

[0482] In some embodiments, the pharmaceutical agent has the appearance of a fine off-white to brown powder.

[0483] In certain embodiments, provided herein are pharmaceutical compositions and / or solid dosage forms comprising medicaments comprising bacteria. The bacteria can be live bacteria. The bacteria can be live bacteria; non-viable (dead) bacteria; non-replicating bacteria; gamma-irradiated bacteria; and / or freeze-dried bacteria.

[0484] In some embodiments, the pharmaceutical product comprises bacteria (e.g., whole bacteria) (e.g., live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the pharmaceutical product comprises bacteria from one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) of the bacterial strains or species or taxa listed herein. In some embodiments, the pharmaceutical product comprises bacteria from one of the bacterial strains or species or taxa listed herein. In some embodiments, the pharmaceutical product comprises freeze dried (e.g., lyophilized) bacteria. In some embodiments, the pharmaceutical product comprises gamma irradiated bacteria. In some embodiments, the pharmaceutical agent is a bacterial strain or species described herein, such as Lactococcus, Prevotella, Bifidobacterium, Veillonella, Fournierella, Harryflinti, Megasphaera; for example, Lactococcus lactis cremoris; Prevotella histicola; Bifidobacterium animalis lactis; Veillonella parvula; Fournierella massiliensis; Harryflintia acetispora; acetispora); or Megasphaera sp.

[0485] In some embodiments, electron microscopy (e.g., ultrathin cryosection EM) can be used to visualize and count bacteria relative to their number to quantify the number of bacteria present in a sample. Alternatively, nanoparticle tracking analysis (NTA), Coulter counting, or dynamic light scattering (DLS), or a combination of these techniques, can be used. NTA and Coulter counters count particles and indicate their size. DLS indicates particle size distribution but not concentration. Bacteria are often 1-2 microns in diameter, with the full range being 0.2-20 microns. Combining the results of Coulter counting and NTA can reveal the number of bacteria in a given sample. Coulter counting reveals the number of particles with diameters between 0.7-10 microns. For most bacterial samples, Coulter counters alone can reveal the number of bacteria in a sample. For NTA, Nanosight instruments are available from Malvern Pananlytical. For example, the NS300 can visualize and measure particles in suspension in the size range of 10-2000 nm. NTA can count particles with diameters of, for example, 50-1000 nm. DLS reveals the distribution of particles with various diameters in the range of approximately 1 nm to 3 μm.

[0486] In some embodiments, bacteria can be quantified based on total cell count (TCC), for example, by Coulter counter.

[0487] In some embodiments, bacteria can be quantified based on particle count, for example, the total particle count of a bacterial preparation can be measured using NTA.

[0488] In some embodiments, bacteria can be quantified based on the amount of protein, lipid, or carbohydrate, for example, the total protein content of bacteria and / or preparations can be measured using the Bradford assay or BCA.

[0489] In some embodiments, the bacteria is isolated from one or more other bacterial components of the original bacterial culture. In some embodiments, the pharmaceutical product further comprises other bacterial components.

[0490] In certain aspects, provided herein are medicaments, pharmaceutical compositions, and / or solid dosage forms comprising bacteria useful for the treatment and / or prevention of disease (e.g., cancer, autoimmune disease, inflammatory disease, metabolic disease, or dysbiosis), as well as methods of making and / or identifying such bacteria, and methods of using the medicaments, pharmaceutical compositions, and solid dosage forms (e.g., for the treatment of cancer, autoimmune disease, inflammatory disease, or metabolic disease, alone or in combination with another therapeutic agent). In some embodiments, the medicament comprises bacteria (e.g., whole bacteria) (e.g., live bacteria, dead (e.g., killed) bacteria, non-replicating bacteria, attenuated bacteria). In some embodiments, the medicament comprises bacteria from one or more of the bacterial strains or species or taxa listed herein. In some embodiments, the medicament is bacteria from one of the bacterial strains or species or taxa listed herein. In some embodiments, the pharmaceutical agent is a bacterial strain or species described herein, such as Lactococcus, Prevotella, Bifidobacterium, Veillonella, Fournierella, Harryflinti, Megasphaera; for example, Lactococcus lactis cremoris; Prevotella histicola; Bifidobacterium animalis lactis; Veillonella parvula; Fournierella massiliensis; Harryflintia acetispora; acetispora); or Megasphaera sp.

[0491] In certain aspects, medicaments, pharmaceutical compositions, and / or solid dosage forms are provided for administration to a subject (e.g., a human subject). In some embodiments, the medicaments, pharmaceutical compositions, and / or solid dosage forms are combined with additional active and / or inactive substances to produce a final product, which may be in a single-dose unit or multi-dose format. In some embodiments, the medicaments are combined with an adjuvant, such as an immune adjuvant (e.g., a STING agonist, a TLR agonist, a NOD agonist).

[0492] In some embodiments, the medicament, pharmaceutical composition and / or solid dosage form comprises at least one carbohydrate.

[0493] In some embodiments, the medicament, pharmaceutical composition, and / or solid dosage form comprises at least one lipid. In some embodiments, the lipid is selected from the group consisting of lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), margaric acid (17:0), heptadecenoic acid (17:1), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid ( The composition of the present invention comprises at least one fatty acid selected from the group consisting of 20:0), eicosenoic acid (20:1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosenoic acid (22:1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and tetracosanoic acid (24:0).

[0494] In some embodiments, the pharmaceutical product, pharmaceutical composition, and / or solid dosage form comprises at least one mineral or mineral source. Examples of minerals include, but are not limited to, chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the above minerals include soluble mineral salts, sparingly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals (e.g., carbonyl minerals), and reduced minerals, and combinations thereof.

[0495] In some embodiments, the medicament, pharmaceutical composition, and / or solid dosage form comprises at least one vitamin. The at least one vitamin can be a fat-soluble or water-soluble vitamin. Suitable vitamins include, but are not limited to, vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin. Suitable forms of any of the above include salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity as the vitamin, and metabolites of the vitamin.

[0496] In some embodiments, the medicament, pharmaceutical composition and / or solid dosage form comprises an excipient. Non-limiting examples of suitable excipients include buffering agents, preservatives, stabilizers, binders, compression agents, lubricants, dispersion enhancers, disintegrants, flavoring agents, sweeteners and coloring agents.

[0497] Suitable excipients that may be included in the medicament, pharmaceutical composition, and / or solid dosage form can be one or more pharmaceutically acceptable excipients known in the art, see, e.g., Rowe, Sheskey, and Quinn, eds., Handbook of Pharmaceutical Excipients, sixth ed.; 2009; Pharmaceutical Press and American Pharmacists Association.

[0498] solid dosage forms The pharmaceutical agent can be formulated into a solid dosage form. The solid dosage forms described herein can be, for example, tablets or mini-tablets. Furthermore, multiple mini-tablets can be placed in (e.g., filled into) a capsule.

[0499] In certain embodiments, the solid dosage form comprises a capsule. In some embodiments, the capsule is a size 00, 0, 1, 2, 3, 4, or 5 capsule. In some embodiments, the capsule is a size 0 capsule. As used herein, capsule size refers to the size of the tablet before enteric coating. In some embodiments, the capsule is banded after filling (and before enteric coating the capsule). In some embodiments, the capsule is banded with an HPMC-based banding solution.

[0500] In some embodiments, the solid dosage form comprises a tablet (>4 mm) (e.g., 5 mm to 17 mm). For example, the tablet is a 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablet. Size refers to the diameter of the tablet, as known in the art. As used herein, tablet size refers to the size of the tablet before application of an enteric coating.

[0501] In some embodiments, the solid dosage form comprises mini-tablets. The mini-tablets may range in size from 1 mm to 4 mm. For example, the mini-tablets may be 1 mm mini-tablets, 1.5 mm mini-tablets, 2 mm mini-tablets, 3 mm mini-tablets, or 4 mm mini-tablets. Size refers to the diameter of the mini-tablets, as known in the art. As used herein, mini-tablet size refers to the size of the mini-tablets before the application of an enteric coating.

[0502] The mini-tablets can be present in a capsule. The capsule can be a size 00, 0, 1, 2, 3, 4, or 5 capsule. The capsule containing the mini-tablets can comprise HPMC (hydroxypropyl methylcellulose) or gelatin. The mini-tablets can be present inside the capsule; the number of mini-tablets inside the capsule varies depending on the size of the capsule and the size of the mini-tablets. For example, a size 0 capsule can contain 31-35 mini-tablets (average, 33), which are 3mm mini-tablets. In some embodiments, the capsules are banded after filling. In some embodiments, the capsules are banded with an HPMC-based banding solution.

[0503] coating: The solid dosage forms (e.g., tablets or mini-tablets) described herein can be enterically coated, for example, with one enteric coating layer or two enteric coating layers, for example, an inner enteric coating and an outer enteric coating. The inner and outer enteric coatings are not identical (e.g., the inner and outer enteric coatings do not contain the same ingredients in the same amounts). The enteric coating, for example, enables release of the pharmaceutical agent in the small intestine, for example, the upper small intestine, for example, the duodenum and / or jejunum.

[0504] Release of a pharmaceutical agent into the small intestine, e.g., the upper small intestine, e.g., the duodenum or jejunum, allows the pharmaceutical agent to target and act on cells (e.g., epithelial cells and / or immune cells) located in these specific locations, which can cause a local effect within the small intestine and / or can cause a systemic effect (e.g., an effect outside the gastrointestinal tract).

[0505] EUDRAGIT is a brand name for a range of polymethacrylate copolymers, including anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic / acrylic acid esters or their derivatives.

[0506] Examples of other materials that can be used in the enteric coating (e.g., one enteric coating or the inner and / or outer enteric coating) include cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (esters of aryl acid), plastics, vegetable fibers, zein, Aqua-Zein® (an alcohol-free aqueous zein preparation), amylose starch, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, and / or sodium alginate.

[0507] The enteric coating (eg, one enteric coating or the inner and / or outer enteric coating) can include methacrylate ethyl acrylate (MAE) copolymer (1:1).

[0508] One enteric coating may include methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[0509] One enteric coating may comprise a Eudragit copolymer, such as Eudragit L (e.g., Eudragit L 100-55; Eudragit L30 D-55), Eudragit S, Eudragit RL, Eudragit RS, Eudragit E, or Eudragit FS (e.g., Eudragit FS 30 D).

[0510] Other examples of materials that can be used in enteric coatings (e.g., one enteric coating or inner and / or outer enteric coatings) include those described in, for example, U.S. Pat. Nos. 6,312,728; 6,623,759; 4,775,536; 5,047,258; 5,292,522; 6,555,124; 6,638,534; U.S. Patent Application Publication Nos. 2006 / 0210631; 2008 / 200482; 2005 / 0271778; 2004 / 0028737; and WO 2005 / 044240.

[0511] See also, e.g., U.S. Pat. No. 9,233,074, which provides pH-dependent enteric polymers that can be used with the solid dosage forms provided herein, including methacrylic acid copolymer, polyvinyl acetate phthalate, hydroxypropylmethylcellulose succinate, hydroxypropylmethylcellulose phthalate, and cellulose phthalate. Suitable methacrylic acid copolymers include poly(methacrylic acid, methyl methacrylate) 1:1, sold, for example, under the trade name Eudragit L100; poly(methacrylic acid, ethyl acrylate) 1:1, sold, for example, under the trade name Eudragit L100-55; partially neutralized poly(methacrylic acid, ethyl acrylate) 1:1, sold, for example, under the trade name Kollicoat MAE-100P; and poly(methacrylic acid, methyl methacrylate) 1:2, sold, for example, under the trade name Eudragit S100.

[0512] In certain aspects, the solid dosage forms (e.g., tablets or mini-tablets) described herein further comprise a subcoat. In some embodiments, the solid dosage form further comprises a subcoat, e.g., in addition to an enteric coating, e.g., the subcoat is beneath the enteric coating (e.g., between the solid dosage form and the enteric coating). In some embodiments, the subcoat comprises Opadry QX, e.g., Opadry QX Blue. The subcoat can be used, for example, to visually mask the appearance of the therapeutic agent.

[0513] dose A pharmaceutical dose (eg, for a human subject) is a dose per solid dosage form, such as per capsule or tablet, or per total number of mini-tablets used in a capsule.

[0514] In embodiments where the dose is determined by total cell number, the total cell number may be determined by a Coulter counter.

[0515] In some embodiments, the medicament comprises bacteria, and the dose of bacteria is about 1×10 7 ~Approx. 2×10 12 (For example, about 3 × 10 10 , or approximately 1.5 × 10 11 , or approximately 1.5 × 10 12 ) cells (e.g., the cell number is determined by total cell count, which is determined by a Coulter counter), and the dose is per capsule or tablet or per total number of mini-tablets in a capsule. In some embodiments, the pharmaceutical product includes bacteria, and the dose of bacteria is about 1 x 10 10 ~Approx. 2×10 12 (For example, about 1.6 × 10 11 , or approximately 8 × 10 11 , or approximately 9.6 × 10 11 , about 12.8×10 11 or approximately 1.6 x 10 12 ) cells (e.g., cell number is determined by total cell count, which is determined by Coulter counter), and dose is per capsule or tablet or per total number of mini-tablets in a capsule.

[0516] In some embodiments, the medicament comprises bacteria, and the dose of bacteria is about 1×10 9 , about 3×10 9 , about 5×10 9 , about 1.5×10 10 , about 3×10 10 , about 5×10 10 , about 1.5×10 11 , about 1.5×10 12 or about 2 x 10 12 cells, and the dose is per capsule or tablet or per total number of mini-tablets in a capsule.

[0517] In some embodiments, the pharmaceutical dose may be a milligram (mg) dose determined by the weight of the pharmaceutical (e.g., a powder containing bacteria). The pharmaceutical dose may be per capsule or tablet or per total number of mini-tablets, for example, within a capsule.

[0518] For example, to administer a single dose of about 400 mg of a drug, there would be about 200 mg of drug per capsule, and two capsules would be administered to provide a dose of about 400 mg. The two capsules could be administered, for example, once or twice daily.

[0519] For example, mini-tablets may contain about 0.1 to about 3.5 mg (0.1, 0.35, 1.0, 3.5 mg) of pharmaceutical agent per mini-tablet. Mini-tablets may be present inside a capsule; the number of mini-tablets inside a capsule varies depending on the capsule size and the size of the mini-tablets. For example, an average of 33 (range 31 to 35) 3 mm mini-tablets fit inside a size 0 capsule. As an example, with 0.1 to 3.5 mg of pharmaceutical agent per mini-tablet, the dosage range would be 3.3 mg to 115.5 mg per capsule (for 33 mini-tablets in a size 0 capsule), (3.1 mg to 108.5 mg for 31 mini-tablets in a size 0 capsule), (3.5 mg to 122.5 mg for 35 mini-tablets in a size 0 capsule). Multiple capsules and / or larger capsules can be administered to increase the dosage, and / or the dosage can be increased by administering more than once per day.

[0520] In some embodiments, the dose can be from about 3 mg to about 125 mg of pharmaceutical agent per capsule or tablet, or per total number of mini-tablets within a capsule, for example.

[0521] In some embodiments, the dose can be from about 35 mg to about 1200 mg (eg, about 35 mg, about 125 mg, about 350 mg, or about 1200 mg) of pharmaceutical agent.

[0522] In some embodiments, the dose of the pharmaceutical agent can be from about 30 mg to about 3500 mg (about 25, about 50, about 75, about 100, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 750, about 1000, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg).

[0523] Human doses can be appropriately calculated based on the allometric scaling of doses administered to model organisms (e.g., mice).

[0524] In some embodiments, one or two tablet capsules can be administered once or twice daily.

[0525] The pharmaceutical product contains bacteria or a powder containing bacteria, and may also contain one or more additional ingredients, such as a cryoprotectant.

[0526] In some embodiments, the mg (by weight) dose of the pharmaceutical agent is, for example, from about 1 mg to about 500 mg per capsule or per tablet or the total number of mini-tablets used in, for example, a capsule.

[0527] How to use The medicaments, pharmaceutical compositions and / or solid dosage forms described herein allow for, for example, oral administration of the pharmaceutical agent contained therein.

[0528] The pharmaceutical agent can be combined (eg, mixed) with a liquid (eg, a buffer, juice, or water), for example, for oral administration of the pharmaceutical agent contained therein.

[0529] The medicaments, pharmaceutical compositions and / or solid dosage forms described herein can be used for the treatment and / or prevention of cancer, inflammation, autoimmunity, metabolic disorders or microbial incompatibility.

[0530] Described herein are methods (eg, pharmaceutical uses) of using medicaments, pharmaceutical compositions and / or solid dosage forms (eg, for oral administration), wherein the medicament comprises bacteria.

[0531] The methods and administered medicaments, pharmaceutical compositions and / or solid dosage forms described herein allow, for example, oral administration of the medicament contained therein. The medicaments, pharmaceutical compositions and / or solid dosage forms can be administered to a subject in a fed or fasted state. The medicaments, pharmaceutical compositions and / or solid dosage forms can be administered, for example, in a fasting state (e.g., 1 hour before a meal or 2 hours after a meal). The medicaments, pharmaceutical compositions and / or solid dosage forms can be administered 1 hour before a meal. The medicaments, pharmaceutical compositions and / or solid dosage forms can be administered 2 hours after a meal.

[0532] Provided herein are medicaments, pharmaceutical compositions and / or solid dosage forms for use in the treatment and / or prevention of cancer, an inflammatory disease, an autoimmune disease, a metabolic condition or a dysbiosis.

[0533] Provided herein is the use of a pharmaceutical product, pharmaceutical composition and / or solid dosage form for the preparation of a medicament for the treatment and / or prevention of cancer, an inflammatory disease, an autoimmune disease, a metabolic condition or a dysbiosis.

[0534] How to make a medicine In some aspects, the present disclosure provides methods for preparing a pharmaceutical comprising bacteria (e.g., lyophilized bacteria). The pharmaceutical can be a powder, e.g., a lyophilized powder.

[0535] The method can include combining the bacteria (e.g., a pellet containing the bacteria) with a cryoprotectant solution, thereby preparing a formulation paste.

[0536] In some embodiments, the method further comprises lyophilizing the formulation paste, thereby preparing a lyophilized product. In some embodiments, the lyophilization comprises primary drying. In some embodiments, the lyophilization comprises primary drying and secondary drying.

[0537] In some embodiments, the method further comprises grinding the lyophilized product, thereby preparing a lyophilized powder (eg, a powder, eg, a pharmaceutical product).

[0538] In some embodiments, the cryoprotectant solution is mixed with the pellets in a ratio of about 0.2 to about 0.5 grams (g) of cryoprotectant solution per gram of pellet; about 0.05 to about 0.25 grams (g) of cryoprotectant solution per gram of pellet; about 0.06 to about 0.1 grams (g) of cryoprotectant solution per gram of pellet; or about 0.15 to about 0.2 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets in a ratio of about 0.4 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets in a ratio of about 0.18 grams (g) of cryoprotectant solution per gram of pellet. In some embodiments, the cryoprotectant solution is mixed with the pellets in a ratio of about 0.1 grams (g), such as 0.08 g, of cryoprotectant solution per gram of pellet.

[0539] In some embodiments, the cryoprotectant solution is mixed with the pellet at a ratio of 6.5% (volume / volume).

[0540] In some embodiments, the cryoprotectant solution comprises sucrose. In some embodiments, the cryoprotectant solution comprises dextran. In some embodiments, the cryoprotectant solution comprises sucrose and dextran. In some embodiments, the cryoprotectant solution comprises equal amounts (e.g., on a weight percent basis) of sucrose and dextran. In some embodiments, the cryoprotectant solution comprises sucrose, dextran, and L-cysteine ​​HCl. In some embodiments, the cryoprotectant solution does not include L-cysteine ​​HCl.

[0541] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) sucrose. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) sucrose. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) sucrose.

[0542] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) dextran.

[0543] In some embodiments, the cryoprotectant solution comprises about 10% to about 30% (wt / wt) sucrose and about 10% to about 30% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 15% to about 35% (wt / wt) sucrose and about 15% to about 35% (wt / wt) dextran. In some embodiments, the cryoprotectant solution comprises about 20% (wt / wt) sucrose and about 20% (wt / wt) dextran.

[0544] In some embodiments, the cryoprotectant solution comprises about 40% to about 80% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 50% to about 70% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 55% to about 65% (wt / wt) water. In some embodiments, the cryoprotectant solution comprises about 60% (wt / wt) water.

[0545] In some embodiments, the cryoprotectant solution comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant solution comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant solution comprises about 0.15% to about 0.45% (wt / wt) L-cysteine ​​HCl.

[0546] In some embodiments, the cryoprotectant solution comprises about 0.2% (wt / wt) L-cysteine ​​HCl.

[0547] In some embodiments, the cryoprotectant solution comprises about 59.8% (wt / wt) water.

[0548] In some embodiments, the cryoprotectant solution comprises about 0.4% (wt / wt) L-cysteine ​​HCl.

[0549] In some embodiments, the cryoprotectant solution comprises about 59.6% (wt / wt) water.

[0550] In certain embodiments, the cryoprotectant solution provided herein comprises: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; (iii) about 0.4% (wt / wt) L-cysteine ​​HCl; and (iv) about 59.6% (wt / wt) water.

[0551] In certain embodiments, the cryoprotectant solution provided herein comprises: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; (iii) about 0.2% (wt / wt) L-cysteine ​​HCl; and (iv) about 59.8% (wt / wt) water.

[0552] In certain embodiments, the cryoprotectant solutions provided herein comprise: (i) about 20% (wt / wt) sucrose; (ii) about 20% (wt / wt) dextran; and (iii) about 60% (wt / wt) water.

[0553] In some embodiments, the cryoprotectant (e.g., a water-free dry composition) comprises about 40% to about 60% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) sucrose.

[0554] In some embodiments, the cryoprotectant comprises about 40% to about 60% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) dextran.

[0555] In some embodiments, the cryoprotectant comprises about 40% to about 60% (wt / wt) sucrose and 40% to about 60% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 45% to about 55% (wt / wt) sucrose and about 45% to about 55% (wt / wt) dextran. In some embodiments, the cryoprotectant comprises about 50% (wt / wt) sucrose and about 50% (wt / wt) dextran.

[0556] In some embodiments, the cryoprotectant comprises about 0.25% to about 5% (wt / wt) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant comprises about 0.5% to about 2.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.75% to about 1.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 1% (wt / wt) L-cysteine ​​HCl.

[0557] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 50% (wt / wt) sucrose; (ii) about 50% (wt / wt) dextran; and (iii) about 1% (wt / wt) L-cysteine ​​HCl.

[0558] In certain embodiments, the cryoprotectants provided herein comprise: (i) about 50% (wt / wt) sucrose; and (ii) about 50% (wt / wt) dextran.

[0559] In some embodiments, the lyophilized powder comprises about 6% to about 12% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 8% to about 12% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 11% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 6% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 8% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 11% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 6% to about 12% (wt / wt) sucrose and about 6% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 8% to about 12% (wt / wt) sucrose and about 8% to about 12% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 11% (wt / wt) sucrose and about 11% (wt / wt) dextran. In some embodiments, the lyophilized powder comprises about 0.01% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.1% to about 0.3% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.15% to about 0.25% (wt / wt) L-cysteine ​​HCl.

[0560] In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 15% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 15% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 7% to about 21% (wt / wt) sucrose and about 7% to about 21% (wt / wt) dextran. In some embodiments, the pharmaceutical composition comprises about 10% to about 19% (wt / wt) sucrose and about 10% to about 19% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 15% (wt / wt) sucrose and about 15% (wt / wt) dextran. In some embodiments, the pharmaceutical preparation comprises about 0.01% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.1% to about 0.4% (wt / wt) L-cysteine ​​HCl. In some embodiments, the pharmaceutical preparation comprises about 0.15% to about 0.35% (wt / wt) L-cysteine ​​HCl.

[0561] In certain embodiments, the lyophilized powder comprises about 40% to about 70% (w / w) dried bacteria. In certain embodiments, the pharmaceutical product comprises about 35% to about 70% (w / w) bacteria (e.g., lyophilized bacteria).

[0562] In certain embodiments, the lyophilized powder comprises about 64% (w / w) dry bacteria.

[0563] In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21). In some embodiments, the cryoprotectant comprises sucrose. In some embodiments, the cryoprotectant comprises dextrose (also called glucose). In some embodiments, the cryoprotectant comprises monosodium glutamate. In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises equal amounts (e.g., on a weight percent basis) of a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and dextrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, dextrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises dextrose and sodium glutamate in equal amounts (e.g., on a weight percent basis).In some embodiments, the cryoprotectant comprises dried (dehydrated) corn glucose syrup (e.g., Glucidex), such as dried corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), sucrose, dextrose, sodium glutamate, and L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant does not comprise L-cysteine ​​HCl.

[0564] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 37% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21).

[0565] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) sucrose.

[0566] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) dextrose.

[0567] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) monosodium glutamate.

[0568] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 37% (wt / wt) sucrose.

[0569] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; about 8% to about 18% (wt / wt) dextrose; and about 8% to about 18% (wt / wt) monosodium glutamate.

[0570] In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; about 11% to about 15% (wt / wt) dextrose; and about 11% to about 15% (wt / wt) monosodium glutamate.

[0571] In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 37% (wt / wt) sucrose; about 13% (wt / wt) dextrose; and about 13% (wt / wt) monosodium glutamate.

[0572] In some embodiments, the cryoprotectant comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.1% to about 0.25% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.2% (wt / wt) L-cysteine ​​HCl.

[0573] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; (iv) about 13% (wt / wt) monosodium glutamate; and (v) about 0.2% (wt / wt) L-cysteine ​​HCl.

[0574] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; and (iv) about 13% (wt / wt) monosodium glutamate.

[0575] In some embodiments, the lyophilized powder comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the lyophilized powder comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the lyophilized powder comprises about 26% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the lyophilized powder comprises about 21% to about 29% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 23% to about 27% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 25% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 6% to about 11% (wt / wt) dextrose. In some embodiments, the lyophilized powder comprises about 7% to about 10% (wt / wt) dextrose. In some embodiments, the lyophilized powder comprises about 9% (wt / wt) dextrose. In some embodiments, the lyophilized powder comprises about 4% to about 10% (wt / wt) glutamate. In some embodiments, the lyophilized powder comprises about 5% to about 9% (wt / wt) glutamate. In some embodiments, the lyophilized powder comprises about 7% (wt / wt) glutamate.

[0576] In some embodiments, the lyophilized powder comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 21% to about 29% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 23% to about 27% (wt / wt) sucrose. In some embodiments, the lyophilized powder comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl. In some embodiments, the lyophilized powder comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl.

[0577] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (w / w) sucrose; about 6% to about 11% (w / w) dextrose; and about 4% to about 10% (w / w) glutamate. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 23% to about 27% (w / w) sucrose; and about 7% to about 10% (w / w) dextrose. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); 23% to about 27% (wt / wt) sucrose; and about 5% to about 9% (wt / wt) glutamate.In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex®), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex® 21); 23% to about 27% (w / w) sucrose; about 7% to about 1% (w / w) dextrose; and about 5% to about 9% (w / w) glutamate. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0578] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 26% (w / w) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the pharmaceutical product comprises about 21% to about 29% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 23% to about 27% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 25% (wt / wt) sucrose. In some embodiments, the pharmaceutical composition comprises about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 7% to about 10% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 9% (wt / wt) dextrose. In some embodiments, the pharmaceutical composition comprises about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical composition comprises about 5% to about 9% (wt / wt) glutamate. In some embodiments, the pharmaceutical composition comprises about 7% (wt / wt) glutamate.

[0579] In some embodiments, the pharmaceutical composition comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 21% to about 29% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 23% to about 27% (w / w) sucrose. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0580] In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 6% to about 11% (wt / wt) dextrose. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (wt / wt) sucrose; and about 4% to about 10% (wt / wt) glutamate. In some embodiments, the pharmaceutical product comprises about 23% to about 30% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 21% to about 29% (w / w) sucrose; about 6% to about 11% (w / w) dextrose; and about 4% to about 10% (w / w) glutamate. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 23% to about 27% (w / w) sucrose; and about 7% to about 10% (w / w) dextrose. In some embodiments, the pharmaceutical product comprises about 24% to about 28% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); 23% to about 27% (wt / wt) sucrose; and about 5% to about 9% (wt / wt) glutamate.In some embodiments, the pharmaceutical composition comprises about 24% to about 28% (w / w) dry (dehydrated) corn glucose syrup (e.g., Glucidex®), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex® 21); 23% to about 27% (w / w) sucrose; about 7% to about 1% (w / w) dextrose; and about 5% to about 9% (w / w) glutamate. In some embodiments, the pharmaceutical composition comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl. In some embodiments, the pharmaceutical composition comprises about 0.1% to about 0.5% (w / w) L-cysteine ​​HCl.

[0581] In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21). In some embodiments, the cryoprotectant comprises sucrose. In some embodiments, the cryoprotectant comprises dextrose (also called glucose). In some embodiments, the cryoprotectant comprises monosodium glutamate. In some embodiments, the cryoprotectant comprises a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises equal amounts (e.g., on a weight percent basis) of a dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), and sucrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and dextrose. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises a dried (dehydrated) corn glucose syrup (such as Glucidex), such as a dried corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21), sucrose, dextrose, and sodium glutamate. In some embodiments, the cryoprotectant comprises dextrose and sodium glutamate in equal amounts (e.g., on a weight percent basis).In some embodiments, the cryoprotectant comprises dried (dehydrated) corn glucose syrup (e.g., Glucidex), such as dried corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), sucrose, dextrose, sodium glutamate, and L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant does not comprise L-cysteine ​​HCl.

[0582] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21). In some embodiments, the cryoprotectant comprises about 37% (wt / wt) of a dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21).

[0583] In some embodiments, the cryoprotectant (e.g., a dry composition that does not contain water) comprises about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) sucrose.

[0584] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) dextrose.

[0585] In some embodiments, the cryoprotectant comprises about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 13% (wt / wt) monosodium glutamate.

[0586] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 27% to about 47% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 32% to about 42% (wt / wt) sucrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21), and about 37% (wt / wt) sucrose.

[0587] In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; and about 8% to about 18% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 27% to about 47% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 27% to about 47% (wt / wt) sucrose; about 8% to about 18% (wt / wt) dextrose; and about 8% to about 18% (wt / wt) monosodium glutamate.

[0588] In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; and about 11% to about 15% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 32% to about 42% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 32% to about 42% (wt / wt) sucrose; about 11% to about 15% (wt / wt) dextrose; and about 11% to about 15% (wt / wt) monosodium glutamate.

[0589] In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) dextrose. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (such as Glucidex), such as a dry corn glucose syrup with a dextrose equivalent (DE) of 21 (such as Glucidex 21); about 37% (wt / wt) sucrose; and about 13% (wt / wt) monosodium glutamate. In some embodiments, the cryoprotectant comprises about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as dry corn glucose syrup with a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); about 37% (wt / wt) sucrose; about 13% (wt / wt) dextrose; and about 13% (wt / wt) monosodium glutamate.

[0590] In some embodiments, the cryoprotectant comprises about 0.05% to about 0.6% (wt / wt) L-cysteine ​​HCl (e.g., a form of L-cysteine). In some embodiments, the cryoprotectant comprises about 0.1% to about 0.5% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.1% to about 0.25% (wt / wt) L-cysteine ​​HCl. In some embodiments, the cryoprotectant comprises about 0.2% (wt / wt) L-cysteine ​​HCl.

[0591] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; (iv) about 13% (wt / wt) monosodium glutamate; and (v) about 0.2% (wt / wt) L-cysteine ​​HCl.

[0592] In certain embodiments, the cryoprotectant provided herein comprises: (i) about 37% (wt / wt) dry (dehydrated) corn glucose syrup (e.g., Glucidex), such as a dry corn glucose syrup having a dextrose equivalent (DE) of 21 (e.g., Glucidex 21); (ii) about 37% (wt / wt) sucrose; (iii) about 13% (wt / wt) dextrose; and (iv) about 13% (wt / wt) monosodium glutamate.

[0593] In certain embodiments, the lyophilized powder comprises about 15% to about 35% (weight / weight) bacteria (e.g., lyophilized bacteria). In certain embodiments, the lyophilized powder comprises about 18% to about 30% (weight / weight) bacteria (e.g., lyophilized bacteria). In certain embodiments, the lyophilized powder comprises about 25% (weight / weight) bacteria (e.g., lyophilized bacteria).

[0594] In certain embodiments, the lyophilized powder comprises Prevotella bacteria.

[0595] In certain embodiments, the lyophilized powder comprises Veillonella bacteria.

[0596] As an example of a method for preparing a pharmaceutical product, the method may include one or more of the following steps: centrifuging a fermentation broth containing bacteria (e.g., using continuous centrifugation) to prepare a pellet containing the bacteria; combining a cryoprotectant solution with the pellet to prepare a formulation paste; and freeze-drying the formulation paste to prepare a freeze-dried product. The freeze-drying may include primary drying (e.g., at -5°C). The freeze-drying may include secondary drying (e.g., at 25°C). The total drying time may be, for example, at least 48 hours. The freeze-dried product may be pulverized (e.g., using a pulverizer) to prepare a freeze-dried powder, e.g., a pharmaceutical product. The freeze-dried powder may optionally be irradiated with gamma rays.

[0597] In some embodiments, the method may further include combining the lyophilized powder with one or more excipients to thereby prepare a pharmaceutical composition. The pharmaceutical composition may be used in the methods described herein. The pharmaceutical composition may be prepared as a solid dosage form (e.g., capsules, tablets, and / or mini-tablets) as described herein. The solid dosage form may be coated, e.g., enterically coated, e.g., as described herein.

[0598] In some embodiments, the present disclosure provides a pharmaceutical preparation prepared by the methods described herein.

[0599] Further aspects of solid dosage forms A solid dosage form, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises a bacterium, and the solid dosage form further comprises an excipient, can provide a therapeutically effective amount of the pharmaceutical agent to a subject, e.g., a human.

[0600] A solid dosage form, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises a bacterium, and the solid dosage form further comprises an excipient, can provide a subject, e.g., a human, with a non-naturally occurring amount of a therapeutically active ingredient (e.g., present in the pharmaceutical agent).

[0601] A solid dosage form, e.g., as described herein, comprising a pharmaceutical agent (e.g., a therapeutically effective amount thereof), wherein the pharmaceutical agent comprises a bacterium, and the solid dosage form further comprises an excipient, can provide an artificial amount of the therapeutically active ingredient (e.g., present in the pharmaceutical agent) to a subject, e.g., a human.

[0602] For example, a solid dosage form comprising a pharmaceutical agent described herein (e.g., a therapeutically effective amount thereof), where the pharmaceutical agent comprises a bacterium, and the solid dosage form further comprises an excipient, can effect one or more changes in a subject, e.g., a human, to, for example, treat or prevent a disease or health disorder.

[0603] For example, a solid dosage form comprising a pharmaceutical agent described herein (e.g., a therapeutically effective amount thereof), where the pharmaceutical agent comprises a bacterium, and the solid dosage form further comprises an excipient, has the potential for important utility to affect, e.g., a subject, e.g., a human, for, e.g., treating or preventing a disease or health disorder.

[0604] Additional medications In certain aspects, the methods provided herein comprise administering to a subject a medicament, pharmaceutical composition, and / or solid dosage form described herein, either alone or in combination with an additional therapeutic agent, hi some embodiments, the additional therapeutic agent is an immunosuppressant, an anti-inflammatory agent, a steroid, and / or a cancer therapeutic agent.

[0605] In some embodiments, the medicament, pharmaceutical composition and / or solid dosage form is administered to the subject prior to (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days before) administration of the additional therapeutic agent. In some embodiments, the medicament, pharmaceutical composition and / or solid dosage form is administered to the subject after administration of the additional therapeutic agent (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days). In some embodiments, the medicament, pharmaceutical composition and / or solid dosage form and the additional therapeutic agent are administered to the subject simultaneously or nearly simultaneously (e.g., within one hour of each other).

[0606] In some embodiments, the antibiotic is administered to the subject prior to (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days prior to) administering the medicament, pharmaceutical composition, and / or solid dosage form to the subject. In some embodiments, the antibiotic is administered to the subject after (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days after) the medicament, pharmaceutical composition, and / or solid dosage form is administered to the subject. In some embodiments, the medicament, pharmaceutical composition, and / or solid dosage form and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g., within one hour of each other).

[0607] In some embodiments, the additional therapeutic agent is a cancer therapeutic agent. In some embodiments, the cancer therapeutic agent is a chemotherapeutic agent. Examples of such chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclophosphamide; alkylsulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (particularly bullatacin and bullatacinone); camptothecins (including the synthetic analog topotecan); bryostatin; kallistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); cryptophycins (particularly cryptophycin 1 and cryptophycin 8); dolastatins; duocal mycins (including synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, colofosfamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembitine, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics such as enediyne antibiotics (e.g., calicheamicin, especially calicheamicin gamma 1 and calicheamicin omega 1; dynemicins, including dynemicin A); bisphosphonates such as clodronate; esperamicin;and neocarzinostatin chromophore and related chromoprotein enediyne antibiotic chromophores, aclacinomycin, actinomycin, authrarnycin, azaserine, bleomycin, cactinomycin, carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, and deoxydoxorubicin). serotin, including serotin, epirubicin, esorubicin, idarubicin, marcelomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, potfilomycin, puromycin, queramycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid analogues such as denopterin, methotrexate, pteropterin, trimetrexor Purine analogues, e.g., fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogues, e.g., ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, e.g., calsterone, dromostanolone propionate, epithiostanol, mepitiostane, testolactone; antiadrenal agents, e.g., aminoglutethimide, mitotane, trilostane; folic acid supplements, e.g., folinic acid; aceglatone; aldophosphamide glycosides Cide; Aminolevulinic acid; Eniluracil; Amsacrine; Bestravcil; Bisantrene; Edatraxate; Defofamine; Demecolcine; Diazicon; Elformitin; Elliptinium acetate; Epothilone; Etoglucide; Gallium nitrate; Hydroxyurea; Lentinan; Lonidynin; Maytansinoids, such as maytansine and ansamitocin; Mitoguazone; Mitoxantrone; Mopidanmol; Nitraerin; Pentostatin; Fenamet; Pirarubicin; Rosoxantrone; Podophyllic acid; 2-Ethylhydrazide; Procarbazine;PSK polysaccharide complex); razoxane; rhizoxin; schizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2''-trichlorotriethylamine; trichothecenes (especially T-2 toxin, veracrine A, roridin A, and anguidin); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoids, such as paclitaxel and doxeta Examples of suitable anti-inflammatory drugs include cisplatin, chlorambucil, gemcitabine, 6-thioguanine, mercaptopurine, methotrexate, platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin, vinblastine, platinum, etoposide (VP-16), ifosfamide, mitoxantrone, vincristine, vinorelbine, novantrone, teniposide, edatrexate, daunomycin, aminopterin, xeloda, ibandronate, irinotecan (e.g., CPT-11), the topoisomerase inhibitor RFS 2000, difluoromethylomitin (DMFO), retinoids such as retinoic acid, capecitabine, and pharmaceutically acceptable salts, acids, or derivatives of any of the above.

[0608] In some embodiments, the cancer therapeutic agent is a cancer immunotherapeutic agent. Immunotherapy refers to therapies that use a subject's immune system to treat cancer, such as checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cell, and dendritic cell therapy. Non-limiting examples of immunotherapies are checkpoint inhibitors, including nivolumab (BMS, anti-PD-1), pembrolizumab (Merck, anti-PD-1), ipilimumab (BMS, anti-CTLA-4), MEDI4736 (AstraZeneca, anti-PD-L1), and MPDL3280A (Roche, anti-PD-L1). Other immunotherapies may include tumor vaccines such as Gardasil, Cervarix, BCG, Sipuleucel-T, Gp100:209-217, AGS-003, DCVax-L, Algenpantucel-L, Tergenpantucel-L, TG4010, ProstAtak, Prostvac-V / R-TRICOM, Rindopepimul, E75 acetate peptide, IMA901, POL-103A, Belagenpumatucel-L, GSK1572932A, MDX-1279, GV1001, and Tecemotide. Immunotherapies may be administered by injection (e.g., intravenously, intratumorally, subcutaneously, or into a lymph node), but may also be administered orally, topically, or by aerosol. Immunotherapies may include adjuvants, such as cytokines.

[0609] In some embodiments, the immunotherapeutic agent is an immune checkpoint inhibitor. Immune checkpoint inhibition refers to the broad inhibition of checkpoints that cancer cells can produce to prevent or downregulate immune responses. Examples of immune checkpoint proteins include, but are not limited to, CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3, or VISTA. The immune checkpoint inhibitor may be an antibody or antigen-binding fragment thereof that binds to and inhibits an immune checkpoint protein. Examples of immune checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446, BMS-936559, MEDI-4736, MSB-0020718C, AUR-012, and STI-A1010.

[0610] In some embodiments, the methods provided herein include administering a medicament, pharmaceutical composition, and / or solid dosage form described herein in combination with one or more additional therapeutic agents. In some embodiments, the methods disclosed herein include administering two immunotherapeutic agents (e.g., immune checkpoint inhibitors). For example, the methods provided herein include administering a medicament, pharmaceutical composition, and / or solid dosage form described herein in combination with a PD-1 inhibitor (such as pembrolizumab, nivolumab, or pidilizumab) or a CLTA-4 inhibitor (such as ipilimumab) or a PD-L1 inhibitor.

[0611] In some embodiments, the immunotherapeutic agent is an antibody or antigen-binding fragment thereof that binds to a cancer-associated antigen, for example, including, but not limited to, adipophilin, AIM-2, ALDH1A1, α-actinin-4, α-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1, BCLX(L), BCR-ABL fusion protein b3a2, β-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, and CSNK1. A1, CTAG1, CTAG2, cyclin D1, cyclin A1, dek-can fusion protein, DKK1, EFTUD2, elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250 / MN / CAIX, GAGE-1, 2, 8, GAGE-3, 4, 5, 6, 7, GAS7, glypican-3, GnTV, gp100 / Pmel17, GPNMB, HAUS3, hepsin, HE R-2 / neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Ralpha2, intestinal carboxylesterase, K-ras, kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM-HN-1, KMHN1 also known as CCDC110, LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE-A12, MAGE-A2, MA GE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm-2, ME1, melan-A / MART-1, Meloe, midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, myosin, myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY-BR-1, NY-ESO-1 / LAGE-2, OA1, OGT,OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARalpha fusion protein, polymorphic epithelial mucin (“PEM”), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38 / NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, telomerase, TGF-βRII, TPBG, TRAG-3, triosephosphate isomerase, TRP-1 / gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-1b / GAGED2a. In some embodiments, the antigen is a neoantigen.

[0612] In some embodiments, the immunotherapeutic agent is a cancer vaccine and / or a component of a cancer vaccine (e.g., an antigenic peptide and / or protein). The cancer vaccine can be a protein vaccine, a nucleic acid vaccine, or a combination thereof. For example, in some embodiments, the cancer vaccine comprises a polypeptide comprising an epitope of a cancer-associated antigen. In some embodiments, the cancer vaccine comprises a nucleic acid (e.g., DNA or RNA such as mRNA) encoding an epitope of a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, α-actinin-4, α-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1, BCLX(L), BCR-ABL fusion protein b3a2, β-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen ("CEA"), CASP-5, CASP-8, CD274, CD45, Cdc27, CD K12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, cyclin-A1, dek-can fusion protein, DKK1, EFTUD2, elongation factor 2, ENAH (hMena), Ep-CAM, EpCAM, EphA3, epithelial tumor antigen ("ETA"), ETV6-AML1 fusion protein, EZH2, FGF5, FLT3-ITD, FN1, G250 / M N / CAIX, GAGE-1,2,8, GAGE-3,4,5,6,7, GAS7, glypican-3, GnTV, gp100 / Pmel17, GPNMB, HAUS3, hepsin, HER-2 / neu, HERV-K-MEL, HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Rα2, intestinal carboxylesterase, K-ras, kallikrein 4, KIF20A, KK-LC-1, KMHN1, also known as KKLC1, KM-HN-1, CCDC110, LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE-A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2,MATN, MC1R, MCSP, mdm-2, ME1, Melan-A / MART-1, Meloe, midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, myosin, myosin class I, N-raw, NA88-A, neo-PAP, NFYC, NY-BR-1, NY-ESO-1 / LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5, PBF, pml-RARα fusion protein, polymorphic epithelial mucin ("PEM"), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTPRK, RAB38 / NY Examples of antigens include MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, secernin 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, survivin, SYT-SSX1 or -SSX2 fusion proteins, TAG-1, TAG-2, telomerase, TGF-βRII, TPBG, TRAG-3, triosephosphate isomerase, TRP-1 / gp75, TRP-2, TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, and XAGE-1b / GAGED2a. In some embodiments, the antigen is a neoantigen. In some embodiments, the cancer vaccine is administered with an adjuvant. Examples of adjuvants include, but are not limited to, immunomodulatory proteins, adjuvant 65, α-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-glucan peptides, CpG ODN DNA, GPI-0100, lipid A, lipopolysaccharide, Lipovant, Montanide, N-acetyl-muramyl-L-alanyl-D-isoglutamine, Pam3CSK4, quilA, cholera toxin (CT) and heat-labile toxins from enterotoxigenic Escherichia coli (LT), such as their derivatives (CTB, mmCT, CTA1-DD, LTB, LTK63, LTR72, dmLT), and trehalose dimycolate.

[0613] In some embodiments, the immunotherapeutic agent is an immunomodulatory protein for the subject. In some embodiments, the immunomodulatory protein is a cytokine or a chemokine. Examples of immunomodulatory proteins include, but are not limited to, B lymphocyte chemoattractant ("BLC"), CC motif chemokine 11 ("eotaxin-1"), eosinophil chemotactic protein 2 ("eotaxin-2"), granulocyte colony-stimulating factor ("G-CSF"), granulocyte-macrophage colony-stimulating factor ("GM-CSF"), 1-309, intercellular adhesion molecule 1 ("ICAM-1"), interferon alpha ("IFN-α"), interferon beta ("IFN-β"), interferon gamma ("IFN-γ"), interleukin-1 alpha ("IL-1α"), interleukin-1 beta ("IL-1β"), interleukin-1 receptor antagonist ("IL-1"), and the like. ra"), interleukin-2 ("IL-2"), interleukin-4 ("IL-4"), interleukin-5 ("IL-5"), interleukin-6 ("IL-6"), interleukin-6 soluble receptor ("IL-6 sR"), interleukin-7 ("IL-7"), interleukin-8 ("IL-8"), interleukin-10 ("IL-10"), interleukin-11 ("IL-11"), interleukin-12 subunit beta ("IL-12 p40" or "IL-12 p40"), p70"), interleukin-13 ("IL-13"), interleukin-15 ("IL-15"), interleukin-16 ("IL-16"), interleukin-17A-F ("IL-17A-F"), interleukin-18 ("IL-18"), interleukin-21 ("IL-21"), interleukin-22 ("IL-22"), interleukin-23 ("IL-23"), interleukin-24 ("IL-24"), interleukin-25 ("IL-25"), interleukin-26 ("IL-26"), interleukin-27 ("IL-27"), interleukin-28 ("IL-28"), interleukin-29 ("IL-29"), interleukin-30 ("IL-30"), interleukin-31 ("IL-31"), interleukin-32 ("IL-32"), interleukin-33 ("IL-33"), interleukin-34 ("IL-34"), interleukin-35 ("IL-35"), interleukin-36 ("IL-36"), interleukin-37 ("IL-37"), interleukin-38 ("IL-38"), interleukin-39 ("IL-39"), interleukin-31 ("IL-39"), interleukin-31 ("IL-39"), interleukin-32 ("IL-39"), interleukin-33 ("IL-39"), interleukin-34 ("IL-39"), interleukin-35 ("IL-39"), interleukin-36 ("IL-39"), interleukin-37 ("IL-39"), interleukin-38 ("IL-39"), interleukin- kin-33 ("IL-33"), chemokine (CC motif) ligand 2 ("MCP-1"), macrophage colony-stimulating factor ("M-CSF"), monokine induced by gamma interferon ("MIG"), chemokine (CC motif) ligand 2 ("MIP-1α"), chemokine (CC motif) ligand 4 ("MIP-1β"), macrophage inflammatory protein-1-δ ("MIP-1δ");Platelet-derived growth factor subunit B ("PDGF-BB"), chemokine (CC motif) ligand 5, activation-regulated normal T cell expressed and secreted ("RANTES"), TIMP metallopeptidase inhibitor 1 ("TIMP-1"), TIMP metallopeptidase inhibitor 2 ("TIMP-2"), tumor necrosis factor, lymphotoxin-α ("TNFα"), tumor necrosis factor, lymphotoxin-β ("TNFα"). "TNFβ"), soluble TNF receptor type 1 ("sTNFRI"), sTNFRIIAR, brain-derived neurotrophic factor ("BDNF"), basic fibroblast growth factor ("bFGF"), bone morphogenetic protein 4 ("BMP-4"), bone morphogenetic protein 5 ("BMP-5"), bone morphogenetic protein 7 ("BMP-7"), nerve growth factor ("b-NGF"), epidermal growth factor ("EGF"), epidermal growth factor receptor ("EGF") R"), endocrine-derived vascular endothelial growth factor ("EGF-VEGF"), fibroblast growth factor 4 ("FGF-4"), keratinocyte growth factor ("FGF-7"), growth differentiation factor 15 ("GDF-15"), glial cell line-derived neurotrophic factor ("GDNF"), growth hormone, heparin-binding EGF-like growth factor ("HB-EGF"), hepatocyte growth factor ("HGF"), insulin-like growth factor binding protein 1 ("IGFBP-1"), insulin-like growth factor binding protein 2 ("IGFBP-2"), insulin-like growth factor binding protein 3 ("IGFBP-3"), insulin-like growth factor binding protein 4 ("IGFBP-4"), insulin-like growth factor binding protein 6 ("IGFBP-6"), insulin-like growth factor 1 ("IGF-1"), insulin, macrophage colony-stimulating factor ("M-CSF"). R"), nerve growth factor receptor ("NGF R"), neurotrophin-3 ("NT-3"), neurotrophin-4 ("NT-4"), osteoclastogenesis inhibitory factor ("osteoprotegerin"), platelet-derived growth factor receptor ("PDGF-AA"), phosphatidylinositol-glycan biosynthesis factor ("PIGF"), Skp, cullin, F-box-containing complex ("SCF"), stem cell factor receptor ("SCF R"), transforming growth factor alpha ("TGFα"), transforming growth factor beta-1 ("TGFβ1"), transforming growth factor beta-3 ("TGFβ3"), vascular endothelial growth factor ("VEGF");Vascular endothelial growth factor receptor 2 ("VEGFR2"), vascular endothelial growth factor receptor 3 ("VEGFR3"), VEGF-D 6Ckine, tyrosine-protein kinase receptor UFO ("Axl"), betacellulin ("BTC"), mucosal-associated epithelial chemokine ("CCL28"), chemokine (C-C motif) ligand 27 ("CTACK"), chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), chemokine (C-C motif) ligand 26 ("eotaxin-3"), granulocyte chemoattractant protein 2 ("GCP-2"), GRO, chemokine (C-C motif) ligand 14 ("HCC-1"), chemokine (C-C motif) ligand 16 ("HCC-4"), interleukin-9 ("IL-9"), interleukin-17F ("IL-17F"), interleukin-18 binding protein ("IL-18") BPa"), interleukin-28A ("IL-28A"), interleukin-29 ("IL-29"), interleukin-31 ("IL-31"), C-X-C motif chemokine 10 ("IP-10"), chemokine receptor CXCR3 ("I-TAC"), leukemia inhibitory factor ("LIF"), Light, chemokine (C motif) ligand ("lymphotactin"), monocyte chemoattractant protein 2 ("MCP-2"), monocyte chemoattractant protein 3 ("MCP-3"), monocyte chemoattractant protein 4 ("MCP-4"), macrophage-derived chemokine ("MDC"), macrophage migration inhibitory factor ("MIF"), chemokine (C-C motif) ligand ("Lymphotactin"). and 20 ("MIP-3α"), CC motif chemokine 19 ("MIP-3β"), chemokine (CC motif) ligand 23 ("MPIF-1"), macrophage-stimulating protein alpha chain ("MSPα"), nucleosome assembly protein 1-like 4 ("NAP-2"), secreted phosphoprotein 1 ("osteopontin"), lung and activation-regulated cytokine ("PARC"), platelet factor 4 ("PF4"), stromal cell-derived factor 1 alpha ("SDF-1α"), chemokine (CC motif) ligand 17 ("TARC"), thymus-expressed chemokine ("TECK"), thymic stromal lymphopoietin ("TSLP4-IBB"), CD166 antigen ("ALCAM").Cluster of differentiation 80 ("B7-1"), tumor necrosis factor receptor superfamily member 17 ("BCMA"), cluster of differentiation 14 ("CD14"), cluster of differentiation 30 ("CD30"), cluster of differentiation 40 ("CD40 ligand"), carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein) ("CEACAM-1"), death receptor 6 ("DR6"), deoxythymidine kinase ("Dtk"), type 1 membrane glycoprotein ("E"). endothelial-leukocyte adhesion molecule 1 ("E-selectin"), receptor tyrosine-protein kinase erbB-3 ("ErbB3"), endothelial-leukocyte adhesion molecule 1 ("E-selectin"), apoptosis antigen 1 ("Fas"), Fms-like tyrosine kinase 3 ("Flt-3L"), tumor necrosis factor receptor superfamily member 1 ("GITR"), tumor necrosis factor receptor superfamily member 14 ("HVEM"), intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rβ, IL-17R, IL-2Rγ, IL-21R, lysosomal membrane protein 2 ("LIMPII"), neutrophil gelatinase-associated lipocalin ("lipocalin-2"), CD62L ("L-selectin"), lymphatic endothelial ("LYVE-1"), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRGl-βl, beta-type platelet-derived growth factor receptor ("PDGF Rβ"), platelet endothelial cell adhesion molecule ("PECAM-1"), RAGE, hepatitis A virus cellular receptor 1 ("TIM-1"), tumor necrosis factor receptor superfamily member IOC ("TRAIL-1"), and R3), Trappin protein transglutaminase binding domain ("Trappin-2"), urokinase receptor ("uPAR"), vascular cell adhesion protein 1 ("VCAM-1"), XEDAR Activin A, Agouti-related protein ("AgRP"), ribonuclease 5 ("angiogenin"), angiopoietin 1, angiostatin, catheprin S, CD40, latency family protein IB ("Cripto-1"), DAN, Dickkopf-related protein 1 ("DKK-1"), E-cadherin, epithelial cell adhesion molecule ("EpCAM"), Fas ligand (FasL or CD95L), Fcg RIIB / C, follistatin,Galectin-7, intercellular adhesion molecule 2 ("ICAM-2"), IL-13R1, IL-13R2, IL-17B, IL-2Ra, IL-2Rb, IL-23, LAP, neural cell adhesion molecule ("NrCAM"), plasminogen activator inhibitor-1 ("PAI-1"), platelet-derived growth factor receptor ("PDGF-AB"), resistin, stromal cell-derived factor 1 ("SDF-1β"), sgpl30, secreted frizzled-related protein 2 ("ShhN"), sialic acid-binding immunoglobulin-type lectin ("Siglec-5"), ST2, transforming growth factor-β2 ("TGFβ2"), Tie-2, thrombopoietin ("TPO"), tumor necrosis factor receptor superfamily member 10D ("TRAIL-1"), and TRAIL-2 receptor agonists. R4), triggering receptor expressed on myeloid cells 1 ("TREM-1"), vascular endothelial growth factor C ("VEGF-C"), VEGFR1, adiponectin, adipsin ("AND"), alpha-fetoprotein ("AFP"), angiopoietin-like 4 ("ANGPTL4"), beta-2-microglobulin ("B2M"), basal cell adhesion molecule ("BCAM"), carbohydrate antigen 125 ("CA125"), cancer antigen 15-3 ("CA15-3"), carcinoembryonic antigen ("CEA"), cAMP receptor protein ("CRP"), human epidermal growth factor receptor 2 ("ErbB2"), follistatin, follicle-stimulating hormone ("FSH"), chemokine (C-X-C motif) ligand 1 ("GROα"), human chorionic gonadotropin ("βHCG"), insulin-like growth factor 1 receptor ("IGF-1") sR"), IL-1 sRII, IL-3, IL-18 Rb, IL-21, leptin, matrix metalloproteinase-1 ("MMP-1"), matrix metalloproteinase-2 ("MMP-2"), matrix metalloproteinase-3 ("MMP-3"), matrix metalloproteinase-8 ("MMP-8"), matrix metalloproteinase-9 ("MMP-9"), matrix metalloproteinase-10 ("MMP-10"), matrix metalloproteinase-13 ("MMP-13"), neural cell adhesion molecule ("NCAM-1"); Entactin ("Nidogen-1"), neuron-specific enolase ("NSE"), oncostatin M ("OSM"), procalcitonin, prolactin, prostate-specific antigen ("PSA"), sialic acid-binding Ig-like lectin 9 ("Siglec-9"), ADAM17 endopeptidase ("TACE"), thyroglobulin, inhibitor of metalloproteinase 4 ("TIMP-4"), TSH2B4, a disintegrin and metalloproteinase domain-containing protein 9 ("ADAM-9"), angiopoietin 2, tumor necrosis factor ligand superoxide dismutase (TNF-α), and thyroglobulin. - family member 13 / acidic leucine-rich nuclear phosphoprotein 32 family member B ("APRIL"), bone morphogenetic protein 2 ("BMP-2"), bone morphogenetic protein 9 ("BMP-9"), complement component 5a ("C5a"), cathepsin L, CD200, CD97, chemerin, tumor necrosis factor receptor superfamily member 6B ("DcR3"), fatty acid binding protein 2 ("FABP2"), fibroblast activation protein, alpha ("FAP"), fibroblast growth factor 19 ("FGF-19"), galectin 3, hepatocyte growth factor receptor ("HGF") R"), IFN-γα / βR2, insulin-like growth factor 2 ("IGF-2"), insulin-like growth factor 2 receptor ("IGF-2R"), interleukin-1 receptor 6 ("IL-1R6"), interleukin-24 ("IL-24"), interleukin-33 ("IL-33"), kallikrein 14, asparaginyl endopeptidase ("Legumain"), oxidized low-density lipoprotein receptor 1 ("LOX-1"), mannose-binding lectin ("MBL"), neprilysin ("NEP"), Notch homolog 1, translocation associated (Drosophila) ("Notch-1"), nephroblastoma overexpressed ("NOV"), osteoactivin, programmed cell death protein 1 ("PD-1"), N-acetylmuramoyl-L-alanine amidase ("PGRP-5"), serpin A4, secreted frizzled-related protein 3 ("sFRP-3"), thrombomodulin, Toll-like receptor 2 ("TLR2"), tumor necrosis factor receptor superfamily member 10A ("TRAIL"), and TRAIL-1 receptor 1 ("TRAIL-1").R1"), transferrin ("TRF"), WIF-1ACE-2, albumin, AMICA, angiopoietin 4, B-cell activating factor ("BAFF"), carbohydrate antigen 19-9 ("CA19-9"), CD163, clusterin, CRT AM, chemokine (C-X-C motif) ligand 14 ("CXCL14"), cystatin C, decorin ("DCN"), Dickkopf-related protein 3 ("Dkk-3"), delta-like protein 1 ("DLL1"), fetuin A, heparin-binding growth factor 1 ("aFGF"), folate receptor alpha ("FOLR1"), furin, GPCR-associated sorting protein 1 ("GASP-1"), GPCR-associated sorting protein 2 ("GASP-2"), granulocyte colony-stimulating factor receptor ("GCSF"). R"), serine protease hepsin ("HAI-2"), interleukin-17B receptor ("IL-17B R"), interleukin-27 ("IL-27"), lymphocyte activation gene 3 ("LAG-3"), apolipoprotein AV ("LDL R"), pepsinogen I, retinol binding protein 4 ("RBP4"), SOST, heparan sulfate proteoglycan ("syndecan-1"), tumor necrosis factor receptor superfamily member 13B ("TACI"), tissue factor pathway inhibitor ("TFPI"), TSP-1, tumor necrosis factor receptor superfamily member 10b ("TRAIL-1"), and TRAIL-2 receptor ("TRAIL-2"). R2), TRANCE, troponin I, urokinase-type plasminogen activator ("uPA"), cadherin 5, type 2 or VE-cadherin (vascular endothelial), also known as CD144 ("VE-cadherin"), WNT1-induced signaling pathway protein 1 ("WISP-1"), and receptor for activator of nuclear factor-κB ("RANK").

[0614] In some embodiments, the cancer therapeutic agent is an anti-cancer compound. Exemplary anti-cancer compounds include, but are not limited to, alemtuzumab (Campath®), alitretinoin (Panretin®), anastrozole (Arimidex®), bevacizumab (Avastin®), bexarotene (Targretin®), bortezomib (Velcade®), bosutinib (Bosulif®), brentuximab vedotin (Adcetris®), cabozantinib (Cometriq®), and rivaroxaban (Renavir®). (TM), carfilzomib (Kyprolis™), cetuximab (Erbitux®), crizotinib (Xalkori®), dasatinib (Sprycel®), denileukin diftitox (Ontak®), erlotinib hydrochloride (Tarceva®), everolimus (Afinitor®), exemestane (Aromasin®), fulvestrant (Faslodex®), gefitinib (Iressa®), ibrix Momab tiuxetan (Zevalin®), imatinib mesylate (Gleevec®), ipilimumab (Yervoy™), lapatinib tosylate (Tykerb®), letrozole (Femara®), nilotinib (Tasigna®), ofatumumab (Arzerra®), panitumumab (Vectibix®), pazopanib hydrochloride (Votrient®), pertuzumab (Perjeta™), pralatrexate (Folot yn®), regorafenib (Stivarga®), rituximab (Rituxan®), romidepsin (Istodax®), sorafenib tosylate (Nexavar®), sunitinib malate (Sutent®), tamoxifen, temsirolimus (Torisel®), toremifene (Fareston®), tositumomab and 131I-tositumomab (Bexxar®), trastuzumab (Herceptin®),Tretinoin (Vesanoid®), vandetanib (Caprelsa®), vemurafenib (Zelboraf®), vorinostat (Zolinza®), and Ziv-aflibercept (Zaltrap®).

[0615] Exemplary anti-cancer compounds (e.g., HDAC inhibitors, retinoid receptor ligands) that alter the function of proteins that regulate gene expression and other cellular functions are vorinostat (Zolinza®), bexarotene (Targretin®), and romidepsin (Istodax®), alitretinoin (Panretin®), and tretinoin (Vesanoid®).

[0616] Exemplary anti-cancer compounds that induce apoptosis (e.g., proteasome inhibitors, antifolates) are bortezomib (Velcade®), carfilzomib (Kyprolis™), and pralatrexate (Folotyn®).

[0617] Exemplary anti-cancer compounds (e.g., anti-CD20, anti-CD52; anti-cytotoxic T-lymphocyte-associated antigen-4) that increase anti-tumor immune responses are rituximab (Rituxan®), alemtuzumab (Campath®), ofatumumab (Arzerra®), and ipilimumab (Yervoy™).

[0618] Exemplary anti-cancer compounds that deliver toxins to cancer cells (e.g., anti-CD20-radionuclide fusions; IL-2-diphtheria toxin fusions; anti-CD30-monomethylauristasin E (MMAE)-fusions) are tositumomab and 131I-tositumomab (Bexxar®) and ibritumomab tiuxetan (Zevalin®), denileukin diftitox (Ontak®), and brentuximab vedotin (Adcetris®).

[0619] Other exemplary anti-cancer compounds are small molecule inhibitors and conjugates thereof, such as Janus kinases, ALK, Bcl-2, PARP, PI3K, VEGF receptors, Braf, MEK, CDK, and HSP90.

[0620] Exemplary platinum-based anticancer compounds include, for example, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, triplatin, and lipoplatin. Other metal-based agents suitable for treatment include, but are not limited to, ruthenium-based compounds, ferrocene derivatives, titanium-based compounds, and gallium-based compounds.

[0621] In some embodiments, the cancer therapeutic agent is a radioactive moiety comprising a radionuclide. Exemplary radionuclides include, but are not limited to, Cr-51, Cs-131, Ce-134, Se-75, Ru-97, I-125, Eu-149, Os-189m, Sb-119, I-123, Ho-161, Sb-117, Ce-139, In-111, Rh-103m, Ga-67, Tl-201, Pd-103, Au-195, Hg-197, Sr-87m, Pt-191, P-33, Er-169, Ru-103, Yb-169, Au-199, Sn-121, Tm-167, Yb-175, and In-113m. , Sn-113, Lu-177, Rh-105, Sn-117m, Cu-67, Sc-47, Pt-195m, Ce-141, I-131, Tb-161, As-77, Pt-197, Sm-153, Gd-159, Tm-173, Pr-143, Au-198, T Examples include m-170, Re-186, Ag-111, Pd-109, Ga-73, Dy-165, Pm-149, Sn-123, Sr-89, Ho-166, P-32, Re-188, Pr-142, Ir-194, In-114m / In-114 and Y-90.

[0622] In some embodiments, the additional therapeutic agent is an antibiotic. For example, if the presence of disease-associated bacteria and / or a disease-associated microbiome profile is detected, an antibiotic can be administered, e.g., to eliminate the disease-associated bacteria from the subject. In some embodiments, the cancer therapeutic agent is an antibiotic. For example, if the presence of cancer-associated bacteria and / or a cancer-associated microbiome profile is detected according to the methods provided herein, an antibiotic can be administered to eliminate the cancer-associated bacteria from the subject. "Antibiotic" broadly refers to a compound that can inhibit or prevent bacterial infection. Antibiotics can be classified in various ways, including by their use in specific infections, mechanism of action, bioavailability, or spectrum of target microorganisms (e.g., gram-negative and gram-positive bacteria, aerobic and anaerobic bacteria, etc.), and they can be used to kill specific bacteria in specific regions ("niches") of the host (Leekha, et al. 2011. General Principles of Antimicrobial Therapy. Mayo Clin Proc. 86(2):156-167). In certain embodiments, antibiotics can be used to selectively target bacteria in specific niches. In some embodiments, antibiotics known to treat specific infections that contain disease niches (including cancer) can be used to target disease-associated microorganisms, including disease-associated bacteria, within the niche. In other embodiments, the antibiotic is administered after the solid dosage form. In some embodiments, the antibiotic is administered before the solid dosage form.

[0623] In some aspects, antibiotics can be selected based on their bactericidal or bacteriostatic properties. Bactericidal antibiotics include those with a mechanism of action that disrupts cell walls (e.g., β-lactams), cell membranes (e.g., daptomycin), or bacterial DNA (e.g., fluoroquinolones). Bacteriostatic agents inhibit bacterial replication and include sulfonamides, tetracyclines, and macrolides, which act by inhibiting protein synthesis. Furthermore, while some drugs may be bactericidal in certain organisms and bacteriostatic in others, knowing the target organism allows one of skill in the art to select antibiotics with appropriate properties. In certain treatment conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and bacteriostatic antibiotics are not combined.

[0624] Antibiotics include, but are not limited to, aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolones, sulfonamides, tetracyclines, and antimycobacterial compounds, and combinations thereof.

[0625] Aminoglycosides include, but are not limited to, amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, and spectinomycin. Aminoglycosides are effective against Gram-negative bacteria, such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis, and against certain aerobic bacteria, but are less effective against obligate / facultative anaerobes. Aminoglycosides are thought to bind to the bacterial 30S or 50S ribosomal subunits, thereby inhibiting bacterial protein synthesis.

[0626] Ansamycins include, but are not limited to, geldanamycin, herbimycin, rifamycin, and streptovaricin. Geldanamycin and herbimycin are believed to inhibit or alter the function of heat shock protein 90.

[0627] Carbacephems include, but are not limited to, loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.

[0628] Carbapenems include, but are not limited to, ertapenem, doripenem, imipenem / cilastatin, and meropenem. As broad-spectrum antibiotics, carbapenems are bactericidal against both gram-positive and gram-negative bacteria. Carbapenems are thought to inhibit bacterial cell wall synthesis.

[0629] Cephalosporins include, but are not limited to, cefadroxil, cefazolin, cefalotin, cefalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, ceftaroline fosamil, and ceftobiprole. Selected cephalosporins are effective against gram-negative and gram-positive bacteria, including, for example, Pseudomonas, and certain cephalosporins are effective against methicillin-resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by interfering with the synthesis of the peptidoglycan layer of the bacterial cell wall.

[0630] Glycopeptides include, but are not limited to, teicoplanin, vancomycin, and telavancin. Glycopeptides are effective against aerobic and anaerobic Gram-positive bacteria, including, for example, MRSA and Clostridium difficile. Glycopeptides are thought to inhibit bacterial cell wall synthesis by interfering with the synthesis of the peptidoglycan layer of the bacterial cell wall.

[0631] Lincosamides include, but are not limited to, clindamycin and lincomycin. Lincosamides are effective against, for example, anaerobic bacteria, as well as Staphylococcus and Streptococcus. Lincosamides are thought to bind to the bacterial 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

[0632] Lipopeptides include, but are not limited to, daptomycin. Lipopeptides are effective against, for example, Gram-positive bacteria. Lipopeptides are thought to bind to bacterial membranes and cause rapid depolarization.

[0633] Macrolides include, but are not limited to, azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spiramycin. Macrolides are effective against, for example, Streptococcus and Mycoplasma. Macrolides are thought to bind to bacteria or the 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

[0634] Monobactams include, but are not limited to, aztreonam. Monobactams are effective against, for example, Gram-negative bacteria. Monobactams are believed to inhibit bacterial cell wall synthesis by interfering with the synthesis of the peptidoglycan layer of the bacterial cell wall.

[0635] Nitrofurans include, but are not limited to, furazolidone and nitrofurantoin.

[0636] Oxazolidnones include, but are not limited to, linezolid, pocizolid, radezolid, and torezolid. Oxazolidnones are believed to be protein synthesis inhibitors.

[0637] Penicillins include, but are not limited to, amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin. Penicillins are effective against, for example, gram-positive bacteria, facultative anaerobes such as Streptococcus, Borrelia, and Treponema. Penicillins are thought to inhibit bacterial cell wall synthesis by interfering with the synthesis of the peptidoglycan layer of the bacterial cell wall.

[0638] Penicillin combinations include, but are not limited to, amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanate.

[0639] Polypeptide antibiotics include, but are not limited to, bacitracin, colistin, and polymyxins B and E. Polypeptide antibiotics are effective against, for example, Gram-negative bacteria. Certain polypeptide antibiotics are thought to inhibit isoprenyl pyrophosphate, which is involved in the synthesis of the peptidoglycan layer of the bacterial cell wall, while others destabilize the bacterial outer membrane by displacing bacterial counterions.

[0640] Quinolones and fluoroquinolones include, but are not limited to, ciprofloxacin, enoxacin, gatifloxacin, gemifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin. Quinolones / fluoroquinolones are effective against, for example, Streptococcus and Neisseria. Quinolones / fluoroquinolones are thought to inhibit bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.

[0641] Sulfonamides include, but are not limited to, mafenide, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfadimethoxine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim-sulfamethoxazole (cotrimoxazole), and sulfonamide chrysoidine. Sulfonamides are believed to inhibit folate synthesis by competitive inhibition of dihydropteroate synthase, thereby inhibiting nucleic acid synthesis.

[0642] Tetracyclines include, but are not limited to, demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline. Tetracyclines are effective against, for example, Gram-negative bacteria. Tetracyclines are thought to bind to the bacterial 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

[0643] Antimycobacterial compounds include, but are not limited to, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, and streptomycin.

[0644] Suitable antibiotics include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin / dalfopristin, tigecycline, tinidazole, trimethoprim-amoxicillin / clavulanate, ampicillin / sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin P1, clarithromycin, erythromycin, furazolidone, fusidic acid, sodium fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazole, mikamycin, mutacin B-Ny266, mutacin B-JH1 140, mutacin J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreoglycin, piperacillin / tazobactam, pristinamycin, ramoplanin, ranalexin, reuterin, rifaximin, rosamycin, rosaramycin, spectinomycin, spiramycin, stafilomycin, streptogramin, streptogramin A, synergistin, taurolidine, teicoplanin, telithromycin, ticarcillin / clavulanic acid, triacetyloleandomycin, tylosin, tyrocidine, tyrothricin, vancomycin, vemamycin, and virginiamycin.

[0645] In some embodiments, the additional therapeutic agent is an immunosuppressant, a DMARD, a pain control agent, a steroid, a nonsteroidal anti-inflammatory drug (NSAID), or a cytokine antagonist, and combinations thereof. Representative drugs include, but are not limited to, cyclosporine, retinoids, corticosteroids, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprofen, choline magnesium salicylate, fenoprofen, salsalate, difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetominophen, celecoxib, diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfen enamic acid, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprofen, firocoxib, methotrexate (MTX), antimalarials (e.g., hydroxychloroquine and chloroquine), sulfasalazine, leflunomide, azathioprine, cyclosporine, gold salts, minocycline, cyclophosphamide, D-penicillamine, minocycline, auranofin, tacrolimus, myocrisin, chlorambucil, TNFα antagonists (e.g., TNFα antagonists or TNFα receptor antagonists), such as adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®; TA-650), certolizumab pegol (Cimzia®; CDP870), golimumab (Simpom®; CNTO148), anakinra (Kineret®), rituximab (Rituxan®; MabThera®), abatacept (Orencia®), tocilizumab (RoActemra / Actemra®), integrin antagonists (TYSABRI® (natalizumab)), IL-1 antagonists (ACZ885 (Ilaris)), anakinra (Kineret®), CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (e.g., atacicept, Benlysta® / LymphoStat-B® (belimumab)), p38 inhibitors, CD20 antagonists (ocrelizumab, ofatumumab (Arzerra®)) ), interferon-gamma antagonist (fontolizumab), prednisolone, prednisone, dexamethasone, cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone, triamcinolone, beclomethasone, fludrocortisone, deoxycorticosterone, aldosterone, doxycycline, vancomycin, pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin+Viusid, TwHF, methoxsalen, vitamin D-ergocalciferol, milnacipran, paclitaxel, losanthazone, tacrolimus (Prograf®), RADOOl, rapamune, rapamycin, fostamatinib, fentanyl, XOMA052, fostamatinib disodium, rosiglitazone, curcumin (Longvida™), rosuvastatin, maraviroc, ramipinil (ramipnl), milnacipran, cobiprostone, somatropin, tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazole, everolimus, trastuzumab, JAK1 inhibitors and JAK2 inhibitors, pan-JAK inhibitors, such as tetracyclic pyridone 6( P6), 325, PF-956980, denosumab, IL-6 antagonists, CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, IL-21 antagonists, IL-22 antagonists, integrin antagonists (Tysarbri® (natalizumab)), VEGF antagonists, CXCL antagonists, MMP antagonists, defensin antagonists, IL-1 antagonists (e.g., IL-1β antagonists), and IL-23 antagonists (e.g., receptor decoys, antagonistic antibodies, etc.).

[0646] In some embodiments, the additional therapeutic agent is an immunosuppressant. Examples of immunosuppressants include, but are not limited to, corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressants, cyclosporine A, mercaptopurine, azathioprine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, sodium cromoglycate, anti-leukotrienes, anticholinergics for rhinitis, TLR antagonists, inflammasome inhibitors, anticholinergic decongestants, mast cell stabilizers, monoclonal anti-IgE antibodies, vaccines (e.g., vaccines used in vaccinations with gradually increasing amounts of allergens), cytokine inhibitors such as anti-IL-6 antibodies, TNF inhibitors such as infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept, and combinations thereof.

[0647] In some embodiments, the additional therapeutic agent is an RNA molecule, eg, double-stranded RNA.

[0648] In some embodiments, the additional therapeutic agent is an antisense oligonucleotide.

[0649] Administration In certain aspects, provided herein a...

Claims

1. A pharmaceutical product comprising bacteria, wherein the bacteria in the pharmaceutical product is at least 1×10 per gram of the pharmaceutical product. １１ A drug present in a total cell count (TCC) of cells.

2. The bacteria may be present in a concentration of about 1×10 per gram of the drug product. １１ cells to about 2.5 x 10 １２ 2. The pharmaceutical product of claim 1, wherein the total cell count (TCC) of cells is present in the pharmaceutical product.

3. A pharmaceutical product (e.g., powder) containing bacteria and a cryoprotectant.

4. 4. The pharmaceutical product of claim 3, wherein the cryoprotectant comprises sucrose, dextran or a combination thereof, optionally wherein the cryoprotectant comprises equal amounts of sucrose and dextran.

5. The pharmaceutical product of claim 3, wherein the cryoprotectant comprises sucrose, dextran and L-cysteine ​​HCl.

6. The pharmaceutical product of claim 3 , wherein the cryoprotectant does not include L-cysteine ​​HCl.

7. from about 6% to about 12% (w / w) or from about 7% to about 21% (w / w) sucrose; about 6% to about 12% (w / w) or about 7% to about 21% (w / w) dextran; or About 6% to about 12% (wt / wt) sucrose and about 6% to about 12% (wt / wt) dextran or about 7% to about 21% (wt / wt) sucrose and about 7% to about 21% (wt / wt) dextran The pharmaceutical product of claim 3 .

8. 4. The pharmaceutical product of claim 3, comprising about 0.10% to about 0.25% (w / w) or about 0.15% to about 0.35% (w / w) of L-cysteine ​​HCl.

9. A pharmaceutical composition comprising the pharmaceutical agent according to any one of claims 1 to 8 and one or more excipients.

10. A method of making a formulation paste, comprising combining bacteria with a cryoprotectant, optionally a cryoprotectant solution, thereby preparing a formulation paste.

11. 1. A method for preparing a pharmaceutical composition comprising the steps of: (a) carrying out the method of claim 10 to produce a formulation paste; (b) lyophilizing the formulation paste to form a lyophilized product; (c) grinding the lyophilized product to prepare a lyophilized powder; (d) combining the lyophilized powder with one or more excipients to prepare a pharmaceutical composition. The method includes:

12. 12. The method of claim 10 or 11, wherein the cryoprotectant is mixed with the pellet in a ratio of 0.1 to 0.25 grams (g) of cryoprotectant per gram of pellet; or 4% to 10% (volume / volume).

13. 11. The method of claim 10, wherein the cryoprotectant comprises sucrose, dextran, or a combination thereof, optionally wherein the cryoprotectant comprises equal amounts of sucrose and dextran.

14. The method of claim 10, wherein the cryoprotectant comprises sucrose, dextran and L-cysteine ​​HCl.

15. The method of claim 10, wherein the cryoprotectant does not include L-cysteine ​​HCl.

16. The cryoprotectant comprises about 10% to about 30% (w / w) sucrose; about 10% to about 30% (w / w) dextran; or about 10% to about 30% (w / w) sucrose and about 10% to about 30% (w / w) dextran The method of claim 10, comprising:

17. The method of claim 10, wherein the cryoprotectant comprises about 40% to about 80% (w / w) water.

18. 11. The method of claim 10, wherein the cryoprotectant comprises about 0.05% to about 0.6% (w / w) L-cysteine ​​HCl.

19. 11. The method of claim 10, wherein the cryoprotectant comprises about 0.25% to about 5% (w / w) L-cysteine ​​HCl.

20. A medicine that contains bacteria and maintains its stability.

21. 21. The pharmaceutical product of claim 20, wherein the water content of the pharmaceutical product is from about 0.5% to about 9%.

22. 22. A pharmaceutical product according to claim 20 or 21, which maintains its water content.

23. is of bacterial origin; a powder containing said bacteria and / or components thereof; containing an additional agent; and / or 21. The pharmaceutical product of claim 20, which is a lyophilized powder of the bacteria and / or components thereof, optionally further comprising additional agents.

24. 13. A solid dosage form comprising the pharmaceutical agent of claim 1.

25. Enteric coated; Optionally, the capsule comprises a capsule; optionally, the capsule is a size 00, 0, 1, 2, 3, 4, or 5 capsule; optionally, the capsule comprises HPMC (hydroxylpropylmethylcellulose) or gelatin; Optionally, the solid dosage form comprises a tablet, optionally wherein the tablet is a 5 mm, 6 mm, 7 mm, 8 mm, 9 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablet; Optionally, the solid dosage form comprises a mini-tablet, optionally wherein the mini-tablet is between about 1 mm mini-tablet and 4 mm mini-tablet; and / or 25. The solid dosage form of claim 24, optionally comprising a plurality of enteric coated mini-tablets contained within a capsule, optionally wherein the mini-tablets are 3 mm in size, and optionally wherein the capsule comprises HPMC (hydroxylpropylmethylcellulose) or gelatin.

26. The enteric coating comprises one enteric coating; The enteric coating comprises an inner enteric coating and an outer enteric coating; The enteric coating includes an inner enteric coating and an outer enteric coating, wherein the inner and outer enteric coatings are not identical; The enteric coating comprises a polymethacrylate-based copolymer; The enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1); The one enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1); said one enteric coating comprising a Eudragit copolymer; the enteric coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (esters of aryl acids), plastics, vegetable fibres, zein, aquazein (an alcohol-free aqueous zein preparation), amylose starch, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, hydroxypropyl methylcellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer or sodium alginate; and / or 26. The solid dosage form of claim 25, wherein the enteric coating comprises an anionic polymeric material.

27. 25. The solid dosage form of claim 24, wherein the bacteria is of the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

28. The bacterium is of the species Lactococcus lactis cremoris, optionally wherein the Lactococcus lactis cremoris is Lactococcus lactis cremoris strain A (ATCC Designation No. PTA-125368); the bacterium is of the species Veillonella parvula, optionally wherein the Veillonella parvula is Veillonella parvula. said bacterium being of the species Prevotella histicola, optionally wherein said Prevotella histicola is Prevotella histicola strain B 50329 (NRRL Accession No. B 50329); or said bacterium being of the species Bifidobacterium animalis, optionally wherein said Bifidobacterium animalis is 25. The solid dosage form of claim 24, wherein the Bifidobacterium animalis is Bifidobacterium animalis ssp. lactis (ATCC Designation No. PTA-125097).

29. the lyophilized powder comprises Prevotella or Veillonella bacteria; the bacterium is a species listed in Table 1, Table 2, Table 3 or Table 4, and optionally the bacterium is a bacterial strain having at least 95% genomic, 16S ribosomal ribonucleic acid or clustered regularly interspaced short palindromic repeats sequence identity with a strain listed in Table 1 or Table 3; the bacterium is of a taxonomic group listed in Table 1, Table 2, Table 3 or Table 4; the bacterium is a bacterial strain listed in Table 1, Table 2, Table 3 or Table 4; the bacterium is of a taxonomic group listed in Table J; and / or 25. The solid dosage form of claim 24, wherein the bacteria is a bacterial strain listed in Table J.

30. 25. A method of preventing or treating a disease in a subject, comprising administering to the subject the solid dosage form of claim 24.

31. 13. Use of the pharmaceutical agent according to claim 1 for the treatment or prevention of a disease in a subject.

32. 13. Use of the pharmaceutical agent according to claim 1 for the preparation of a medicament for treating or preventing a disease in a subject.

33. 10. A pharmaceutical composition according to claim 1 for use in the treatment or prevention of a disease in a subject.

34. 1. A cryoprotectant for use in the preparation of a medicine comprising bacteria, the cryoprotectant optionally being a cryoprotectant solution.

35. A method of preparing a pharmaceutical product, comprising combining bacteria with a cryoprotectant, optionally a cryoprotectant solution, thereby preparing a formulation paste.

36. The cryoprotectant comprises sucrose; the cryoprotectant comprises dextran; the cryoprotectant comprises sucrose and dextran, optionally, the cryoprotectant comprises equal amounts of sucrose and dextran; The cryoprotectant comprises sucrose, dextran and L-cysteine ​​HCl; and / or The cryoprotectant of claim 34 or the method of claim 35, wherein the cryoprotectant does not include L-cysteine ​​HCl.

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