TREM compositions and uses thereof

Abstract

To provide TREM compositions and uses thereof.SOLUTION: The invention relates generally to tRNA-based effector molecules and methods relating thereto. In one aspect, the present disclosure provides a method for making a purified tRNA effector molecule (TREM) pharmaceutical composition, the method comprising: providing a mammalian host cell comprising exogenous nucleic acid, such as DNA or RNA, encoding a TREM; maintaining the mammalian host cell under conditions sufficient to express the TREM; purifying the TREM from the mammalian host cell, for example, according to a method described herein; and formulating the purified TREM as a pharmaceutical composition, for example, by combining the TREM with a pharmaceutical excipient, thereby making the TREM pharmaceutical composition.SELECTED DRAWING: None

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 794,342, filed January 18, 2019, and U.S. Provisional Patent Application No. 62 / 855,547, filed May 31, 2019, the entire contents of each of which are incorporated herein by reference.

[0002] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy created on January 8, 2020, is named F2099-7000WO_SL.txt and is 228,808 bytes in size. [Background technology]

[0003] tRNAs are complex RNA molecules that have several functions, including protein initiation and elongation. Summary of the Invention [Means for solving the problem]

[0004] In one aspect, the disclosure provides a method of making a purified tRNA effector molecule (TREM) pharmaceutical composition, comprising: providing a mammalian host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining mammalian cells under conditions sufficient to express TREM; purifying the TREM from mammalian host cells, for example, according to the methods described herein; and The purified TREM is formulated as a pharmaceutical composition, for example, by combining the TREM with pharmaceutical excipients; thereby producing a TREM pharmaceutical composition. The present invention provides a method comprising:

[0005] In certain embodiments, the nucleic acid comprises RNA that, upon reverse transcription, results in DNA that can be transcribed into a TREM.

[0006] In certain embodiments, the nucleic acid comprises an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.

[0007] In certain embodiments, the nucleic acid may be, for example, a consensus sequence as provided herein, e.g., Formula I ZZZ , formula II ZZZ or formula III ZZZ The consensus sequence of ( ZZZ comprises an RNA sequence containing any of the 20 amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0008] In certain embodiments, the mammalian host cell is selected from a non-human cell or cell line, or a human cell or cell line, such as HEK293T cells (e.g., Freestyle 293-F cells), HT-1080 cells, PER.C6 cells, HKB-11 cells, CAP cells, HuH-7 cells, BHK 21 cells, MRC-S cells, MDCK cells, VERO cells, WI-38 cells, Chinese hamster ovary (CHO) cells, or MCF7 cells.

[0009] In some embodiments, the purification steps include, for example, the following steps, in the order listed: (i) isolating nucleic acids from cellular debris to provide an RNA preparation; (ii) separating RNAs with less than a threshold number of nucleotides, e.g., less than 500 nt, less than 400 nt, less than 300 nt, less than 250 nt, less than 200 nt, less than 150 nt, from larger RNA species in the RNA preparation to produce a small RNA preparation; or / and (iii) Separating TREMs from other RNA species in small RNA preparations by affinity-based separation, e.g., sequence affinity-based separation. Includes one, two or all of the following:

[0010] In one aspect, the invention provides a method of making a tRNA effector molecule (TREM) composition, comprising: (a) providing a host cell containing an exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM under conditions sufficient to express the TREM; and (b) purifying the expressed TREMs from the host cell culture to produce a TREMs composition; thereby producing a TREM composition. The present invention is characterized by a method comprising:

[0011] In certain embodiments, the TREM composition is a pharmaceutically acceptable composition.

[0012] In another aspect, the present invention provides a method of making a pharmaceutical TREM composition, comprising: a) providing a purified TREM composition, e.g., a purified TREM composition made by culturing mammalian host cells containing DNA or RNA encoding a TREM under conditions sufficient to express the TREM, and purifying the expressed TREM from the host cell culture to produce a purified TREM composition; b) providing a value, for example, by assessing or testing for a characteristic described herein (e.g., characteristics relating to identity (e.g., sequence), purity (e.g., process impurities such as TREM fragments, host cell proteins or host cell DNA), activity (e.g., adapter activity)); c) optionally, formulating the purified TREMs composition as a pharmaceutical formulation (e.g., combining the TREMs composition with pharmaceutical excipients) if the reference criteria for one or more characteristics are met; thereby producing a pharmaceutical TREM composition. The present invention is characterized by a method comprising:

[0013] In another aspect, the present invention provides a method of making a pharmaceutical TREM composition, comprising: a) TREMs, e.g., purified TREM compositions, e.g., TREM compositions made by the methods described herein; and b) combining pharmaceutically acceptable ingredients, e.g., excipients; thereby producing a pharmaceutical TREM composition. The present invention is characterized by a method comprising:

[0014] In another aspect, the present disclosure provides a composition comprising a purified tRNA effector molecule (TREM) (e.g., a purified TREM composition produced according to the methods described herein) comprising an RNA sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.

[0015] In some aspects, the present disclosure provides a consensus sequence provided herein, e.g., Formula I ZZZ , formula II ZZZ or formula III ZZZ The consensus sequence of ( ZZZprovides compositions comprising purified tRNA effector molecules (TREMs) (e.g., purified TREM compositions produced according to the methods described herein) that include an RNA sequence that includes any of the 20 amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0016] In another aspect, the invention features a GMP-grade recombinant TREM composition (e.g., a TREM composition made in accordance with cGMP and / or similar requirements) comprising an RNA sequence at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.

[0017] In another aspect, the invention features a GMP-grade recombinant TREM composition (e.g., a TREM composition made in accordance with cGMP and / or similar requirements) comprising an RNA sequence comprising a consensus sequence provided herein.

[0018] In one aspect, the invention features a TREM that includes a consensus sequence provided herein.

[0019] In one aspect, the present invention provides a compound of formula I ZZZ The consensus sequence of ( ZZZ represents any of the 20 amino acids, and Formula I corresponds to all species).

[0020] In one aspect, the present invention provides a compound of formula II ZZZ The consensus sequence of ( ZZZ represents any of the 20 amino acids, and Formula II corresponds to mammals).

[0021] In one aspect, the present invention provides a compound of formula III ZZZ The consensus sequence of ( ZZZ represents any of the 20 amino acids, and Formula III corresponds to the human form.

[0022] In one embodiment, ZZZ represents any of the amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0023] In one aspect, the invention features a GMP-grade recombinant TREM composition comprising an RNA sequence that includes a consensus sequence provided herein.

[0024] In embodiments of any of the TREM compositions or pharmaceutical TREM compositions provided herein, the composition comprises one or more, eg, a plurality of, TREMs.

[0025] In embodiments of any of the TREM compositions or pharmaceutical TREM compositions provided herein, the composition comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 TREMs.

[0026] In embodiments of any of the TREM compositions or pharmaceutical TREM compositions provided herein, the TREM composition (or an intermediate in the production of a TREM composition) has the following characteristics: (i) at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure; (ii) less than 0.1 ng / ml, 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of host cell protein (HCP) contamination; (iii) less than 0.1 ng, 1 ng, 5 ng, 10 ng, 15 ng, 20 ng, 25 ng, 30 ng, 35 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng of host cell protein (HCP) contamination per milligram (mg) of the TREM composition; (iv) less than 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of DNA, e.g., host cell DNA; (v) less than 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% fragments; (vi) low levels or absence of endotoxin, e.g., a negative result as measured by the Limulus amebocyte lysate (LAL) test; (vii) in vitro translation activity, for example, as measured by the assay described in Example 15; (viii) At least 0.1ng / mL, 0.5ng / mL, 1ng / mL, 5ng / mL, 10ng / mL, 50ng / mL, 0.1ug / mL, 0.5ug / mL, 1ug / mL, 2ug / mL, 5ug / mL, 10ug / mL, 20ug / mL, 30ug / mL, 40ug / mL, 50ug / mL, 60ug / mL, 70ug / mL, 80ug / mL, 100ug / mL, 200ug / mL, 300ug / mL, 500ug / mL, 1000ug / mL, 5000ug / mL, 10,000ug / mL, or 100,000ug / mL TREM concentration; (ix) Sterility, e.g., according to cGMP guidelines for sterile preparations, e.g., the composition or preparation supports the growth of less than 100 viable microorganisms when tested under sterile conditions, and the composition or preparation meets USP <71> and / or the composition or preparation meets the specifications of the U.S.P. <85> meets the standards for sterility; or (x) For example, the composition or preparation comprises one or more of the following viral contaminations: a lack of viral contamination, or an undetectable level of viral contamination.

[0027] In another aspect, the invention provides a cell comprising an exogenous nucleic acid comprising a nucleic acid sequence, e.g., DNA or RNA, encoding a TREM, wherein the nucleic acid sequence is (i) control region sequences; (ii) a sequence encoding a modified TREM; (iii) a sequence encoding two or more TREMs; (iv) tRNA Met a sequence other than a sequence; or (v) a promoter sequence containing a Pol III recognition site, such as a U6 promoter, a 7SK promoter, or an H1 promoter, or a fragment thereof The present invention is characterized in that the cell comprises:

[0028] In one aspect, the invention provides a method for modulating a tRNA pool in a cell, comprising: providing a purified TREM composition and contacting cells with the TREM composition; thereby regulating the tRNA pool in the cell The present invention is characterized by a method comprising:

[0029] In another aspect, the present invention provides a method for delivering TREM to a cell, tissue, or subject, comprising: Providing a cell, tissue, or subject and contacting the cell, tissue, or subject with a TREM composition comprising a TREM, e.g., a pharmaceutical TREM composition comprising a TREM. The present invention is characterized by a method comprising:

[0030] In another aspect, the invention provides a method of treating a subject, e.g., modulating the metabolism, e.g., translation capacity, of a cell in a subject, comprising: providing an exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM, e.g., administering it to a subject, thereby treating the subject; The present invention is characterized by a method comprising:

[0031] In any of the embodiments of the methods disclosed herein, the TREM composition comprises: providing a mammalian host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining the mammalian cells under conditions sufficient to express a TREM; and / or Purifying TREMs from mammalian host cells, for example, according to the methods described herein. It is made by

[0032] In embodiments of any of the methods disclosed herein, the mammalian host cell is a non-human cell or cell line selected from HEK293T cells (e.g., Freestyle 293-F cells), HT-1080 cells, PER.C6 cells, HKB-11 cells, CAP cells, HuH-7 cells, BHK 21 cells, MRC-S cells, MDCK cells, VERO cells, WI-38 cells, Chinese hamster ovary (CHO) cells, or MCF7 cells, or a human cell or cell line.

[0033] In any embodiment of the methods disclosed herein, the purification steps may include, for example, the following steps, in the order listed: (i) isolating nucleic acids from cellular debris to provide an RNA preparation; (ii) separating RNAs with less than a threshold number of nucleotides, e.g., less than 500 nt, less than 400 nt, less than 300 nt, less than 250 nt, less than 200 nt, less than 150 nt, from larger RNA species in the RNA preparation to produce a small RNA preparation; and / or (iii) separating TREM from other RNA species by affinity-based separation, e.g., sequence affinity-based separation; Includes one, two or all of the following:

[0034] In any of the embodiments of the methods disclosed herein, the TREM comprises: (i) an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof; or (ii) an RNA sequence comprising the consensus sequence provided herein; Includes.

[0035] In one aspect, the disclosure provides a method of making a purified tRNA effector molecule (TREM) pharmaceutical composition, comprising: providing an insect host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining insect host cells under conditions sufficient to express TREM; purifying the TREM from the insect host cells, for example, according to the methods described herein; and The purified TREM is formulated as a pharmaceutical composition, for example, by combining the TREM with pharmaceutical excipients; thereby producing a TREM pharmaceutical composition. The present invention provides a method comprising:

[0036] In certain embodiments, the insect host cell is selected from an insect cell or cell line, such as an Sf9 cell or cell line.

[0037] In some embodiments, the purification steps include, for example, the following steps, in the order listed: (i) separating nucleic acids from proteins to provide an RNA preparation; (ii) separating RNAs with less than a threshold number of nucleotides, e.g., less than 500 nt, less than 400 nt, less than 300 nt, less than 250 nt, less than 200 nt, less than 150 nt, from larger RNA species in the RNA preparation to produce a small RNA preparation; and / or (iii) Affinity-based separation of TREMs from other RNA species in small RNA preparations, e.g., by sequence affinity. Includes one, two or all of the following:

[0038] In one aspect, the disclosure provides a method of making a purified tRNA effector molecule (TREM) pharmaceutical composition, comprising: providing a yeast host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining yeast host cells under conditions sufficient to express TREM; Purifying the TREM from the yeast host cell, for example, according to the methods described herein; and The purified TREM is formulated as a pharmaceutical composition, for example, by combining the TREM with pharmaceutical excipients; thereby producing a TREM pharmaceutical composition. The present invention provides a method comprising:

[0039] In certain embodiments, the yeast host cell is selected from a yeast cell or cell line, such as a S. cerevisiae or S. pombe cell or cell line.

[0040] In some embodiments, the purification steps include, for example, the following steps, in the order listed: (i) separating nucleic acids from proteins to provide an RNA preparation; (ii) separating RNAs with less than a threshold number of nucleotides, e.g., less than 500 nt, less than 400 nt, less than 300 nt, less than 250 nt, less than 200 nt, less than 150 nt, from larger RNA species in the RNA preparation to produce a small RNA preparation; and / or (iii) Affinity-based separation of TREMs from other RNA species in small RNA preparations, e.g., by sequence affinity. Includes one, two or all of the following:

[0041] As disclosed herein, tRNA-based effector molecules (TREMs) are complex molecules that can mediate a variety of cellular processes. Pharmaceutical TREM compositions can be administered to cells, tissues, or subjects to modulate their function, for example, in vitro or in vivo. Disclosed herein are TREM compositions, preparations, methods of making the TREM compositions and preparations, and methods of using the TREM compositions and preparations.

[0042] Additional features of any of the foregoing TREM compositions, preparations, methods of making the TREM compositions and preparations, and methods of using the TREM compositions and preparations include one or more of the embodiments listed below.

[0043] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein which equivalents are intended to be encompassed by the embodiments recited below.

[0044] Enumerated Embodiments 1. A method for producing a purified tRNA effector molecule (TREM) pharmaceutical composition, comprising: providing a mammalian host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining the mammalian host cells under conditions sufficient to express the TREM; purifying the TREM from mammalian host cells, for example, according to the methods described herein; and The purified TREM is formulated as a pharmaceutical composition, for example, by combining the TREM with pharmaceutical excipients; thereby producing a TREM pharmaceutical composition. A method comprising:

[0045] 2. A method of making a tRNA effector molecule (TREM) composition, comprising: (a) providing a mammalian host cell containing an exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM under conditions sufficient to express the TREM; and (b) purifying the expressed TREMs from the mammalian host cells to produce a TREM composition; thereby producing a TREM composition. A method comprising:

[0046] 3. The method of embodiment 2, wherein the TREM composition is formulated as a pharmaceutical composition, for example, by combining the TREM with a pharmaceutical excipient.

[0047] 4. A method of making a pharmaceutical TREM composition, comprising: a) TREMs, e.g., purified TREM compositions, e.g., TREM compositions made by the methods described herein; and b) combining pharmaceutically acceptable ingredients, e.g., excipients; thereby producing a pharmaceutical TREM composition. A method comprising:

[0048] 5. The method of claim 4, wherein the TREM is purified from mammalian host cells, for example, according to the methods described herein.

[0049] 6. A method for producing a purified tRNA effector molecule (TREM) pharmaceutical composition, comprising: purifying TREMs from mammalian host cells; The purified TREM is formulated as a pharmaceutical composition, for example, by combining the TREM with pharmaceutical excipients; thereby producing a TREM pharmaceutical composition. A method comprising:

[0050] 7. The method of claim 5 or 6, wherein the mammalian host cell comprises an exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM.

[0051] 8. Purification steps include, for example, the following steps in the order listed: (i) separating nucleic acids from proteins to provide an RNA preparation; (ii) separating RNAs that are less than a threshold number of nucleotides, e.g., less than 500 nt, less than 400 nt, less than 300 nt, less than 250 nt, less than 200 nt, less than 150 nt, from larger RNA species in the RNA preparation to produce a small RNA preparation; (iii) Affinity-based separation of TREMs from other RNA species in small RNA preparations, e.g., by sequence affinity. The method of any one of embodiments 1 to 7, comprising one, two or all of:

[0052] 9. The method of embodiment 8, comprising step (i).

[0053] 10. The method of embodiment 8 or 9, comprising step (ii).

[0054] 11. The method of any one of embodiments 8 to 10, comprising step (iii).

[0055] 12. The method of any one of embodiments 8 or 10-11, comprising performing step (i) before step (ii).

[0056] 13. The method of any one of embodiments 8 or 11-12, comprising performing step (ii) before step (iii).

[0057] 14. The method of any one of embodiments 8-13, wherein (i) comprises extracting nucleic acids from proteins.

[0058] 15. The method of any one of embodiments 8-14, wherein (i) comprises phenol / chloroform extraction.

[0059] 16. The method of any one of embodiments 8-10 or 12-15, wherein (ii) comprises separating RNA of a first smaller size class from RNA of a second larger size class.

[0060] 17. The method of embodiment 16, wherein the first size class is less than 200 nt.

[0061] 18. The method of any one of embodiments 8 or 9-16, wherein (ii) comprises performing salt precipitation to enrich for RNAs less than 200 nt.

[0062] 19. The method of embodiment 18, wherein the salt comprises LiCl.

[0063] 20. The method of any one of embodiments 8-10 or 12-19, wherein (ii) further comprises performing a desalting or buffer exchange step.

[0064] 21. The method of any one of embodiments 8 or 11-20, wherein (iii) comprises performing an affinity-based separation to enrich for TREM.

[0065] 22. The method of embodiment 21, wherein the affinity-based separation comprises sequence-based separation, for example, using a probe comprising a sequence that binds to TREM.

[0066] 23. The method of any one of embodiments 1-22, wherein the TREM composition is a pharmaceutically acceptable composition.

[0067] 24. The method of any one of embodiments 1-3 or 7-23, comprising introducing exogenous DNA or RNA into a mammalian host cell.

[0068] 25. The method of any one of embodiments 1-3 or 7-24, wherein the nucleic acid comprises DNA that, upon transcription, expresses TREM.

[0069] 26. The method of any one of embodiments 1-3 or 7-25, wherein the nucleic acid comprises RNA that, upon reverse transcription, results in DNA that can be transcribed to provide TREM.

[0070] 27. The method of any one of embodiments 1-26, wherein the TREM recognizes a stop codon.

[0071] 28. The method of claim 27, wherein TREM mediates amino acid acceptance and uptake.

[0072] 29. The method of any one of embodiments 1-27, wherein TREM does not recognize a stop codon.

[0073] 30. TREM (i) an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof; or (ii) an RNA sequence comprising the consensus sequence provided herein; 30. The method of any one of embodiments 1-29, comprising:

[0074] 31. The method of any one of embodiments 1 to 30, wherein the TREM composition comprises a TREM fragment, for example as described herein, and optionally the TREM fragment is produced in vivo in a host cell.

[0075] 32. The method of embodiment 31, wherein the TREM fragment is produced by fragmenting expressed TREM after production of the TREM by the cell, for example, TREM produced by the host cell is fragmented after release or purification from the host cell, for example, the TREM is fragmented ex vivo.

[0076] 33. The method of any one of embodiments 1-32, wherein the method results in an increase, e.g., at least a 2.2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, or 20-fold increase (e.g., as measured by an assay described in any of Examples 7-11), in the production of total endogenous tRNA and TREM in the host cell, e.g., compared to a reference cell, e.g., a similar cell that has not been engineered or modified to express TREM.

[0077] 34. The method of embodiment 33, wherein the method results in a 2.2-20 fold, 2.2-15 fold, 2.2-10 fold, 2.2-9 fold, 2.2-8 fold, 2.2-7 fold, 2.2-6 fold, 2.2-5 fold, 2.2-4 fold, 2.2-3 fold, 2.2-2.5 fold, 2.5-20 fold, 3-20 fold, 4-20 fold, 5-20 fold, 6-20 fold, 7-20 fold, 8-20 fold, 9-20 fold, 10-20 fold, or 15-20 fold increase in TREM production and / or tRNA production.

[0078] 35. The method of any one of embodiments 1-34, wherein the method results in a detectable level of TREM in the host cell, for example, as measured by an assay described in any of Examples 7-11.

[0079] 36. The method of any one of embodiments 1-35, wherein the host cell is capable of post-transcriptional modification of TREM.

[0080] 37. The method of any one of embodiments 1-36, wherein the host cell is capable of a post-transcriptional modification of a TREM, e.g., a post-transcriptional modification selected from Table 2.

[0081] 38. The method of any one of embodiments 1-37, wherein the host cell has been modified to modulate, e.g., increase, its ability to effect a post-transcriptional modification of a TREM, e.g., a post-transcriptional modification selected from Table 2, e.g., the host cell has been modified to allow increased or decreased expression of a gene, e.g., a gene encoding an enzyme from Table 2, or a gene encoding an enzyme having nuclease activity (e.g., endonuclease activity or ribonuclease activity), such as, or one or more of Dicer, angiogenin, RNaseA, RNaseP, RNaseZ, Rny1, or PrrC.

[0082] 39. The method of any one of embodiments 1-38, wherein the host cell is a mammalian cell capable of post-transcriptional modification of a TREM, e.g., a post-transcriptional modification selected from Table 2.

[0083] 40. The method of any one of embodiments 1-39, wherein the host cell comprises a cell selected from a HEK293T cell (e.g., a Freestyle 293-F cell), an HT-1080 cell, a PER.C6 cell, an HKB-11 cell, a CAP cell, a HuH-7 cell, a BHK 21 cell, an MRC-S cell, an MDCK cell, a VERO cell, a WI-38 cell, a Chinese hamster ovary (CHO) cell, or an MCF7 cell.

[0084] 41. The method of any one of embodiments 1-40, wherein the host cells comprise HeLa cells, HEK293 cells, HT-1080 cells, PER.C6 cells, HKB-11 cells, CAP cells, or HuH-7 cells.

[0085] 42. The method of any one of embodiments 1-41, wherein the host cell has increased expression of an oncogene, such as Ras, c-myc, or c-jun.

[0086] 43. The method of any one of embodiments 1-42, wherein the host cell has reduced expression of a tumor suppressor, for example, p53 or Rb.

[0087] 44. The method of any one of embodiments 1-43, wherein the host cell has increased expression of RNA polymerase III (RNA Pol III).

[0088] 45. The host cell Met , e.g., tRNA iMet or tRNA eMet 45. The method of any one of embodiments 1-44, having increased expression of:

[0089] 46. The method of any one of embodiments 1-45, comprising culturing the host cells in a medium that promotes cellular hyperproliferation (e.g., promotes a signal pathway that is amplified in cancer cells).

[0090] 47. The method of any one of embodiments 1-46, comprising culturing the host cells in a growth-promoting medium, e.g., medium comprising or supplemented with one or a combination of growth factors, cytokines, or hormones, e.g., serum (e.g., fetal bovine serum (FBS)), fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor beta (TGFb), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), or tumor necrosis factor (TNF).

[0091] 48. The method of any one of embodiments 1-47, comprising, for example, culturing the host cell in a medium that promotes post-transcriptional processing of the TREM.

[0092] 49. Conditions, e.g., media that promote overexpression or overactivation of enzymes involved in post-transcriptional processing, e.g., a) removal of the 5' leader sequence, for example by RNase P; b) 3' trailer sequence exonuclease activity, e.g., RNase II, PNPase, RNase PH, or RNase T activity; c) CCA addition at the 3' end, for example, by nucleotidyl transferase; d) intron splicing, for example, by one or more (e.g., all) of a splicing endonuclease, a cyclic phosphodiesterase, an adenylyltransferase, a ligase, or a 2' phosphotransferase; e) For example, modifying enzymes, for example the following enzymatic activities: (i) Adenosine A 34 Inosine I 34 deamination to; (ii) adenosine m 1 A 58 methylation of; (iii) NCM 5 Um 34 or ncm 5 s 2 U 34 Modification generation; (iv)ct 6 A modification; isopentylation 6 A 37 Modification;A 37 From i 6 A 37 generating modifications to; or (v) enzymatic modification having one or more of the modifications listed in Table 2; or The method of any one of embodiments 1 to 48, comprising: f) culturing the host cell under conditions that promote the synthetases involved in amino acid loading.

[0093] 50. The method of any one of embodiments 1-49, comprising culturing the host cells in a medium having an excess of nutrients, e.g., a medium that is not nutrient-limited.

[0094] 51. The method of any one of embodiments 1-50, comprising culturing the host cell in a medium that promotes expression, e.g., increases expression and / or activity of Mck1 and / or Kns1.

[0095] 52. The method of any one of embodiments 1-51, wherein the host cell has increased expression and / or activity of Trm1.

[0096] 53. The method of any one of embodiments 1-52, wherein the host cell has a decrease in the activity of Maf1, for example, by phosphorylation of Maf1, for example, by phosphorylation of serine at position 45 of Maf1.

[0097] 54. The method of embodiment 53, wherein a decrease in the activity of Maf1 results in increased TREM production.

[0098] 55. The method of embodiment 53 or 54, wherein the activity of Maf1 can be reduced by introducing a phosphomimetic Maf1 mutant, for example, a mutant with a serine to aspartic acid mutation at position 45 (S45D); or, for example, by overactivating CK2 / TORC1, which phosphorylates Maf1.

[0099] 56. The following characteristics of the TREM composition (or an intermediate in the production of the TREM composition): (i) at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure; (ii) less than 0.1 ng / ml, 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of host cell protein (HCP) contamination; (iii) less than 0.1 ng, 1 ng, 5 ng, 10 ng, 15 ng, 20 ng, 25 ng, 30 ng, 35 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng of host cell protein (HCP) contamination per milligram (mg) of the TREM composition; (iv) less than 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of DNA, e.g., host cell DNA; (v) less than 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% fragments; (vi) low levels or absence of endotoxin, e.g., a negative result as measured by the Limulus amebocyte lysate (LAL) test; (vii) in vitro translation activity, for example, as measured by the assay described in Example 15; (viii) At least 0.1ng / mL, 0.5ng / mL, 1ng / mL, 5ng / mL, 10ng / mL, 50ng / mL, 0.1ug / mL, 0.5ug / mL, 1ug / mL, 2ug / mL, 5ug / mL, 10ug / mL, 20ug / mL, 30ug / mL, 40ug / mL, 50ug / mL, 60ug / mL, 70ug / mL, 80ug / mL, 100ug / mL, 200ug / mL, 300ug / mL, 500ug / mL, 1000ug / mL, 5000ug / mL, 10,000ug / mL, or 100,000ug / mL TREM concentration; (ix) Sterility, e.g., according to cGMP guidelines for sterile preparations, e.g., the composition or preparation supports the growth of less than 100 viable microorganisms when tested under sterile conditions, and the composition or preparation meets USP <71> and / or the composition or preparation meets the specifications of the U.S.P. <85> meets the standards for sterility; or (x) For example, the composition or preparation is free of viral contamination or has an undetectable level of viral contamination. 56. The method of any one of embodiments 1-55, further comprising measuring one or more of:

[0100] 57. The method of embodiment 56, further comprising comparing the measurement value to a reference value or standard.

[0101] 58. Adjust the TREM composition accordingly (i) increase the purity of the TREM composition; (ii) reducing the amount of HCPs in the composition; (iii) reduce the amount of DNA in the composition; (iv) reducing the amount of fragments in the composition; (v) reduces the amount of endotoxin in the composition; (vi) increases the in vitro translation activity of the composition; (vii) increasing the TREM concentration of the composition; or (viii) increasing the sterility of the composition 58. The method of embodiment 57, further comprising:

[0102] 59. A method of making a TREM composition, comprising: contacting the TREM containing reaction mixture with a reagent, e.g., a capture reagent or a separation reagent, that comprises a nucleic acid sequence complementary to the TREM; thereby producing a TREM composition.

[0103] 60. The method of embodiment 59, further comprising denaturing the TREM, e.g., prior to hybridization with the capture reagent.

[0104] 61. The method of embodiment 59, further comprising regenerating the TREM, for example, after hybridization and / or release from the capture reagent.

[0105] 62. The method of any of embodiments 59-61, further comprising using a single capture reagent to create a TREM composition in which, for example, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95% of the TREMs have sequence complementarity with the capture reagent.

[0106] 63. The method of any of embodiments 59-61, further comprising using multiple capture reagents to create a TREM composition, for example, having multiple different TREMs.

[0107] 64. A method of making a pharmaceutical composition, comprising: a) providing a purified TREM composition, e.g., a purified TREM composition made by culturing mammalian host cells containing DNA or RNA encoding a TREM under conditions sufficient to express the TREM, and purifying the expressed TREM from the host cell culture to produce a purified TREM composition; b) For example, the following characteristics of the purified TREM composition: (i) at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure; (ii) less than 0.1 ng / ml, 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of host cell protein (HCP) contamination; (iii) less than 0.1 ng, 1 ng, 5 ng, 10 ng, 15 ng, 20 ng, 25 ng, 30 ng, 35 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng of host cell protein (HCP) contamination per milligram (mg) of the TREM composition; (iv) less than 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of DNA, e.g., host cell DNA; (v) TREM fragments that are less than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the full-length TREM; (vi) low levels or absence of endotoxin, e.g., a negative result as measured by the Limulus amebocyte lysate (LAL) test; (vii) in vitro translation activity, for example, as measured by the assay described in Example 15; (viii) At least 0.1ng / mL, 0.5ng / mL, 1ng / mL, 5ng / mL, 10ng / mL, 50ng / mL, 0.1ug / mL, 0.5ug / mL, 1ug / mL, 2ug / mL, 5ug / mL, 10ug / mL, 20ug / mL, 30ug / mL, 40ug / mL, 50ug / mL, 60ug / mL, 70ug / mL, 80ug / mL, 100ug / mL, 200ug / mL, 300ug / mL, 500ug / mL, 1000ug / mL, 5000ug / mL, 10,000ug / mL, or 100,000ug / mL TREM concentration; (ix) Sterility, e.g., according to cGMP guidelines for sterile preparations, e.g., the composition or preparation supports the growth of less than 100 viable microorganisms when tested under sterile conditions, and the composition or preparation meets USP <71> and / or the composition or preparation meets the specifications of the U.S.P. <85> meets the standards for sterility; or (x) For example, the composition or preparation is free of viral contamination or has an undetectable level of viral contamination. providing a value by evaluating or testing for one or more of: c) optionally, formulating the purified TREMs composition as a pharmaceutical formulation (e.g., combining the TREMs composition with pharmaceutical excipients) if the reference criteria for one or more characteristics are met; thereby producing a pharmaceutical composition. A method comprising:

[0108] 65. The method of embodiment 64, further comprising comparing the measurement value to a reference value or standard.

[0109] 66. Adjust the composition accordingly (i) increase the purity of the TREM composition; (ii) reducing the amount of HCPs in the composition; (iii) reduce the amount of DNA in the composition; (iv) reducing the amount of fragments in the composition; (v) reduces the amount of endotoxin in the composition; (vi) increases the in vitro translation activity of the composition; (vii) increasing the TREM concentration of the composition; or (viii) increasing the sterility of the composition 66. The method of embodiment 65, further comprising:

[0110] 67. A composition comprising a purified tRNA effector molecule (TREM) (e.g., a purified TREM composition made according to the methods described herein), (i) an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof; or (ii) comprises an RNA sequence comprising the consensus sequence provided herein; and Optionally, the composition wherein the RNA sequence is less than 100% identical to the RNA sequence encoded by the DNA sequence listed in Table 1.

[0111] 68. A GMP-grade recombinant TREM composition (e.g., a TREM composition made in accordance with cGMP and / or similar requirements), (i) an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof; or (ii) comprises an RNA sequence comprising the consensus sequence provided herein; and Optionally, a GMP-grade recombinant TREM composition, wherein the RNA sequence is less than 100% identical to the RNA sequence encoded by the DNA sequence listed in Table 1.

[0112] 69. A pharmaceutical tRNA effector molecule (TREM) composition comprising: (i) an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof; or (ii) comprises an RNA sequence comprising the consensus sequence provided herein; and Optionally, a pharmaceutical tRNA effector molecule (TREM) composition, wherein the RNA sequence is less than 100% identical to the RNA sequence encoded by the DNA sequence listed in Table 1.

[0113] 70. The pharmaceutical TREM composition of claim 69, comprising a purified tRNA effector molecule (TREM) (e.g., a purified TREM composition made according to the methods described herein).

[0114] 71. The composition or pharmaceutical composition of any one of embodiments 67 to 70, wherein the TREM is made according to any one of embodiments 1 to 66.

[0115] 72. The composition or pharmaceutical composition of any one of embodiments 67-70, wherein the TREM comprises one or more post-transcriptional modifications listed in Table 2.

[0116] 73. The composition or pharmaceutical composition of embodiment 72, wherein the TREM comprises one or more post-transcriptional modifications listed in Table 2.

[0117] 74. At least 0.5g, 1g, 2g, 3g, 4g, 5g, 6g, 7g, 8g, 9g, 10g, 15g, 20g, 30g, 40g, 50g, 100g, 200g, 300g, 400g or 500g of a recombinant TREM composition.

[0118] A recombinant TREM composition of 75.0.5 g to 500 g, 0.5 g to 400 g, 0.5 g to 300 g, 0.5 g to 200 g, 0.5 g to 100 g, 0.5 g to 50 g, 0.5 g to 40 g, 0.5 g to 30 g, 0.5 g to 20 g, 0.5 g to 10 g, 0.5 g to 9 g, 0.5 g to 8 g, 0.5 g to 7 g, 0.5 g to 6 g, 0.5 g to 5 g, 0.5 g to 4 g, 0.5 g to 3 g, 0.5 g to 2 g, 0.5 g to 1 g, 1 g to 500 g, 2 g to 500 g, 5 g to 500 g, 10 g to 500 g, 20 g to 500 g, 30 g to 500 g, 40 g to 500 g, 50 g to 500 g, 100 g to 500 g, 200 g to 500 g, 300 g to 500 g, or 400 g to 500 g.

[0119] 76. Formula I ZZZ R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 x -R 48 -R​49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula: R is a ribonucleotide residue; (i) ZZZ represents one of the 20 amino acids: (ii) Formula I corresponds to all species; and (iii) x=1~271 (e.g. x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x= 1~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x=1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~1 2, x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~2 71, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1 , x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) A TREM composition comprising a consensus sequence of

[0120] 77.Formula II ZZZ R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula: R is a ribonucleotide residue; (i) ZZZ represents one of the 20 amino acids: (ii) Formula II corresponds to a mammal; and (iii) x=1~271 (e.g. x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x= 1~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x=1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~1 2, x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~2 71, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1 , x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) A TREM composition comprising a consensus sequence of

[0121] 78.Formula III ZZZ R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 -R 72 (In the formula: R is a ribonucleotide residue; (i) ZZZ represents one of the 20 amino acids: (ii) Formula III corresponds to humans; and (iii) x=1~271 (e.g. x=1~250, x=1~225, x=1~200, x=1~175, x=1~150, x=1~125, x=1~100, x= 1~75, x=1~50, x=1~40, x=1~30, x=1~29, x=1~28, x=1~27, x=1~26, x=1~25, x=1~24, x=1~23, x=1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~1 2, x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~2 71, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1 , x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=1 8, x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271) A TREM composition comprising a consensus sequence of

[0122] 79. The composition or pharmaceutical composition of any one of embodiments 67-78, wherein the composition comprises one or more, e.g., a plurality of, TREMs.

[0123] 80. The composition or pharmaceutical composition of any one of embodiments 67-79, wherein the composition comprises one or more unique TREMs, for example one or more TREMs comprising different anticodon sequences.

[0124] 81. The composition or pharmaceutical composition of any one of embodiments 67-80, wherein the composition comprises one or more unique TREMs, for example TREMs that recognize different codons.

[0125] 82. A TREM composition (or an intermediate in the production of a TREM composition) having the following characteristics: (i) at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure; (ii) less than 0.1 ng / ml, 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of host cell protein (HCP) contamination; (iii) less than 0.1 ng, 1 ng, 5 ng, 10 ng, 15 ng, 20 ng, 25 ng, 30 ng, 35 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng of host cell protein (HCP) contamination per milligram (mg) of the TREM composition; (iv) less than 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of DNA, e.g., host cell DNA; (v) TREM fragments that are less than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the full-length TREM; (vi) low levels or absence of endotoxin, e.g., a negative result as measured by the Limulus amebocyte lysate (LAL) test; (vii) in vitro translation activity, for example, as measured by the assay described in Example 15; (viii) At least 0.1ng / mL, 0.5ng / mL, 1ng / mL, 5ng / mL, 10ng / mL, 50ng / mL, 0.1ug / mL, 0.5ug / mL, 1ug / mL, 2ug / mL, 5ug / mL, 10ug / mL, 20ug / mL, 30ug / mL, 40ug / mL, 50ug / mL, 60ug / mL, 70ug / mL, 80ug / mL, 100ug / mL, 200ug / mL, 300ug / mL, 500ug / mL, 1000ug / mL, 5000ug / mL, 10,000ug / mL, or 100,000ug / mL TREM concentration; (ix) Sterility, e.g., according to cGMP guidelines for sterile preparations, e.g., the composition or preparation supports the growth of less than 100 viable microorganisms when tested under sterile conditions, and the composition or preparation meets USP <71> and / or the composition or preparation meets the specifications of the U.S.P. <85> meets the standards for sterility; or (x) For example, the composition or preparation is free of viral contamination or has an undetectable level of viral contamination. The composition or pharmaceutical composition of any one of embodiments 67 to 81, comprising one or more of:

[0126] 83. A method for modulating a tRNA pool in a cell, comprising: providing a purified TREM composition and contacting cells with the TREM composition; thereby regulating the tRNA pool in the cell.

[0127] 84. A method of contacting a cell, tissue, or subject with a TREM, comprising: contacting the cell, tissue, or subject with a purified TREM composition; A method thereby comprising contacting a cell, tissue, or subject with a TREM.

[0128] 85. A method of presenting TREM to a cell, tissue, or subject together with TREM, comprising: contacting the cell, tissue, or subject with a purified TREM composition; thereby presenting TREM to a cell, tissue, or subject.

[0129] 86. A method of forming a cell, tissue, or subject contacted with TREM, comprising: contacting the cell, tissue, or subject with a purified TREM composition; thereby forming a cell, tissue, or subject contacted with TREM.

[0130] 87. A method of using TREM, comprising: contacting the cell, tissue, or subject with a purified TREM composition; A method involving the use of TREM thereby.

[0131] 88. A method of applying TREM to a cell, tissue, or subject, comprising: contacting the cell, tissue, or subject with a purified TREM composition; A method thereby comprising applying TREM to a cell, tissue, or subject.

[0132] 89. A method of exposing a cell, tissue, or subject to TREM, comprising: contacting the cell, tissue, or subject with a purified TREM composition; A method thereby comprising exposing a cell, tissue, or subject to TREM.

[0133] 90. A method of forming a mixture of TREM and a cell, tissue, or subject, comprising: contacting the cell, tissue, or subject with a TREM composition; thereby forming a mixture of TREM and a cell, tissue, or subject.

[0134] 91. A method for delivering TREM to a cell, tissue, or subject, comprising: A method comprising providing a cell, tissue, or subject and contacting the cell, tissue, or subject with a TREM composition, eg, a purified TREM composition, eg, a pharmaceutical TREM composition.

[0135] 92. A method, e.g., an ex vivo method, of modulating the metabolism, e.g., translational capacity, of an organelle, comprising: A method comprising providing a preparation of organelles, such as mitochondria or chloroplasts, and contacting the organelles with a pharmaceutical TREM composition.

[0136] 93. A method of treating a subject, e.g., regulating the metabolism, e.g., translation capacity, of a cell in a subject, comprising: providing, e.g., administering to a subject, an exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; treating a subject therewith.

[0137] 94. The method of any one of embodiments 83-93, wherein the TREM composition is made according to any one of embodiments 1-66, or the TREM comprises a composition provided in any one of embodiments 67-82.

[0138] 95. The TREM composition is providing a mammalian host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining the mammalian cells under conditions sufficient to express a TREM; and / or Purifying TREMs from mammalian host cells, for example, according to the methods described herein. The method of any one of embodiments 83 to 93, wherein the method is made by

[0139] 96. The method of embodiment 95, wherein the mammalian host cell is selected from a non-human cell or cell line, or a human cell or cell line, such as HEK293T cells (e.g., Freestyle 293-F cells), HT-1080 cells, PER.C6 cells, HKB-11 cells, CAP cells, HuH-7 cells, BHK 21 cells, MRC-S cells, MDCK cells, VERO cells, WI-38 cells, Chinese hamster ovary (CHO) cells, or MCF7 cells.

[0140] 97. The purification process may comprise, for example, the following steps, in the order listed: (i) isolating nucleic acids from cellular debris to provide an RNA preparation; (ii) separating RNAs with less than a threshold number of nucleotides, e.g., less than 500 nt, less than 400 nt, less than 300 nt, less than 250 nt, less than 200 nt, less than 150 nt, from larger RNA species in the RNA preparation to produce a small RNA preparation; and / or (iii) Separating TREMs from other RNA species in small RNA preparations by affinity-based separation, e.g., sequence affinity-based separation. 97. The method of any one of embodiments 95-96, including one, two or all of:

[0141] 98. TREM (i) an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof; or (ii) comprises an RNA sequence comprising the consensus sequence provided herein; and Optionally, the RNA sequence is less than 100% identical to the RNA sequence encoded by the DNA sequence listed in Table 1.

[0142] 99. The method of any one of embodiments 83-98, wherein the method is an in vitro method, for example, wherein cells or tissues are contacted with the TREM composition in vitro.

[0143] 100. The method of any one of embodiments 83 to 98, wherein the method is an ex vivo method, e.g., cells or tissue are contacted with the TREM composition ex vivo, and optionally the contacted cells or tissue are introduced, e.g., administered, to a subject, e.g., the subject from which the cells or tissue were derived, or a different subject.

[0144] 101. The method of any one of embodiments 83-98, wherein the method is an in vivo method, for example, wherein a subject, or tissues or cells of a subject, are contacted with the TREM composition in vivo.

[0145] 102. The method of any of embodiments 99-101, comprising contacting a TREM composition, e.g., a pharmaceutical TREM composition, with cells.

[0146] 103. The method of any of embodiments 99-101, comprising contacting a TREM composition, e.g., a pharmaceutical TREM composition, with the tissue.

[0147] 104. The method of any of embodiments 99-100 or 102, comprising administering a TREM composition, e.g., a pharmaceutical TREM composition, to a subject.

[0148] 105. The method of any of embodiments 100 or 104, wherein the TREM composition is administered with a carrier or delivery agent, such as a liposome, a polymer (e.g., a polymer conjugate), a particle, a microsphere, a microparticle, or a nanoparticle.

[0149] 106. The method of any of embodiments 99-105, wherein the cells are cancerous.

[0150] 107. The method of any of embodiments 99-105, wherein the cells are non-cancerous.

[0151] 108. Cells or tissues muscle cells or tissue (e.g., skeletal muscle cells or tissue, smooth muscle cells or tissue, or cardiac muscle cells or tissue); epithelial cells or tissues; connective cells or tissues (e.g., adipose cells or tissues, bone cells or tissues, or blood cells); or Nerve cells or tissue (e.g., sensory neurons, motor neurons, or interneurons) The method of any of embodiments 99 to 102 or 104 to 107, comprising:

[0152] 109. The method of any of embodiments 99-108, wherein the method comprises administering to the subject cells that have been contacted with the TREM composition ex vivo or in vitro.

[0153] 110. A cell comprising a TREM produced according to any one of embodiments 1 to 66.

[0154] 111. A cell comprising a TREM according to any one of embodiments 67 to 82.

[0155] 112. A cell containing an exogenous nucleic acid comprising a nucleic acid sequence, e.g., DNA or RNA, encoding a TREM, wherein the nucleic acid sequence is: (i) control region sequences; (ii) a sequence encoding a modified TREM; (iii) a sequence encoding two or more TREMs; (iv) tRNA Met a sequence other than a sequence; or (v) a promoter sequence containing a Pol III recognition site, such as a U6 promoter, a 7SK promoter, or an H1 promoter, or a fragment thereof Cells containing

[0156] 113. The method of any of embodiments 111-112, wherein the host cell is capable of post-transcriptional modification of TREM.

[0157] 114. The method of any of embodiments 111-113, wherein the host cell is capable of a post-transcriptional modification of TREM, for example a post-transcriptional modification selected from Table 2.

[0158] 115. The method of any of embodiments 111-114, wherein the host cell has been modified to modulate, e.g., increase, its ability to effect a post-transcriptional modification of a TREM, e.g., a post-transcriptional modification selected from Table 2, e.g., the host cell has been modified to allow increased or decreased expression of one or more of a gene, e.g., a gene encoding an enzyme from Table 2, or a gene encoding an enzyme having nuclease activity (e.g., endonuclease activity or ribonuclease activity), such as, or Dicer, angiogenin, RNaseA, RNaseP, RNaseZ, Rny1, or PrrC.

[0159] 116. The method of any of embodiments 111-115, wherein the host cell is a mammalian cell capable of post-transcriptional modification of TREM, for example, a post-transcriptional modification selected from Table 2.

[0160] 117. The method of any of embodiments 111-116, wherein the host cells comprise cells or cell lines selected from HEK293T cells (e.g., Freestyle 293-F cells), HT-1080 cells, PER.C6 cells, HKB-11 cells, CAP cells, HuH-7 cells, BHK 21 cells, MRC-S cells, MDCK cells, VERO cells, WI-38 cells, Chinese hamster ovary (CHO) cells, or MCF7 cells.

[0161] 118. The method of any of embodiments 111-117, wherein the host cells comprise cells or cell lines selected from HeLa cells, HEK293 cells, HT-1080 cells, PER.C6 cells, HKB-11 cells, CAP cells, or HuH-7 cells.

[0162] 119. The method of any of embodiments 111-1118, wherein the host cell has increased expression of an oncogene, such as Ras, c-myc, or c-jun.

[0163] 120. The method of any of embodiments 111-119, wherein the host cell has reduced expression of a tumor suppressor, for example, p53 or Rb.

[0164] 121. The method of any of embodiments 111-120, wherein the host cell has increased expression of RNA polymerase III (RNA Pol III).

[0165] 122. The host cell Met , e.g., tRNA iMet or tRNA eMet 122. The method of any of embodiments 111-121, having increased expression of:

[0166] 123. The method of any of embodiments 111-122, comprising culturing the host cells in a medium that promotes cellular hyperproliferation (e.g., promotes signaling pathways that are amplified in cancer cells).

[0167] 124. The method of any of embodiments 111-123, comprising culturing the host cells in a growth-promoting medium, e.g., medium containing or supplemented with one or a combination of growth factors, cytokines, or hormones, e.g., serum (e.g., fetal bovine serum (FBS)), fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor beta (TGFb), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), or tumor necrosis factor (TNF).

[0168] 125. The method of any of embodiments 111-124, comprising, for example, culturing the host cell in a medium that promotes post-transcriptional processing of the TREM.

[0169] 126. Conditions, e.g., media that promote overexpression or overactivation of enzymes involved in post-transcriptional processing, e.g., a) removal of the 5' leader sequence, for example by RNase P; b) 3' trailer sequence exonuclease activity, e.g., RNase II, PNP ase, RNase PH or RNase T activity; c) CCA addition at the 3' end, for example, by nucleotidyl transferase; d) intron splicing, for example, by one or more (e.g., all) of a splicing endonuclease, a cyclic phosphodiesterase, an adenylyltransferase, a ligase, or a 2' phosphotransferase; e) For example, modifying enzymes, for example the following enzymatic activities: (i) Adenosine A 34 Inosine I 34 deamination to; (ii) adenosine m 1 A 58 methylation of; (iii) NCM 5 Um 34 or ncm 5 s 2 U 34 Modification generation; (iv)ct 6 A modification; isopentylation 6 A 37 Modification;A 37 From i 6 A 37 generating modifications to; or (v) enzymatic modification having one or more of the modifications listed in Table 2; or The method of any of embodiments 111-125, comprising culturing the host cell under conditions that promote the synthetases involved in amino acid loading.

[0170] 127. The method of any of embodiments 111-126, comprising culturing the host cells in a medium with an excess of nutrients, e.g., a medium that is not nutrient-limited.

[0171] 128. The method of any of embodiments 111-127, comprising culturing the host cell in a medium that promotes expression, e.g., increases expression and / or activity of Mck1 and / or Kns1.

[0172] 129. The method of any of embodiments 111-128, wherein the host cell has increased expression and / or activity of Trm1.

[0173] 130. The method of any of embodiments 111-129, wherein the host cell has a decrease in the activity of Maf1, for example, by phosphorylation of Maf1, for example, by phosphorylation of serine at position 45 of Maf1.

[0174] 131. The method of embodiment 130, wherein a decrease in the activity of Maf1 results in increased TREM production.

[0175] 132. The method of embodiment 130 or 131, wherein the activity of Maf1 can be reduced by introducing a phosphomimetic Maf1 mutant, for example, a mutant with a serine to aspartic acid mutation at position 45 (S45D); or by overactivating CK2 / TORC1, which phosphorylates Maf1, for example.

[0176] 133. A reaction mixture comprising a TREM and a reagent, such as a capture reagent or a separation reagent.

[0177] 134. A bioreactor comprising a plurality of mammalian host cells described herein that contain exogenous DNA or RNA encoding a TREM.

[0178] 135. (i) at least 1 × 10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , or 1 × 10 14 Contains host cells; (ii) comprises between 100 mL and 100 liters of culture medium, e.g., at least 100 mL, 250 mL, 500 mL, 750 mL, 1 liter, 2 liters, 3 liters, 4 liters, 5 liters, 6 liters, 7 liters, 8 liters, 9 liters, 10 liters, 15 liters, 20 liters, 25 liters, 30 liters, 40 liters, 50 liters, 60 liters, 70 liters, 80 liters, 90 liters, or 100 liters of culture medium; (iii) the bioreactor is selected from a continuous flow bioreactor, a batch process bioreactor, a perfusion bioreactor, and a fed-batch bioreactor; or (iv) the bioreactor is maintained under conditions sufficient to express TREM; The bioreactor of embodiment 134.

[0179] 136. A master cell bank comprising, for example, host cells as described herein.

[0180] 137. Master cell bank contains at least 1 × 10 7 , 1×10 8 , 1×10 9 , 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , 1×10 14 , 1×10 15 , 1×10 20 , 1×10 25 , or 1 × 10 30 137. The master cell bank of embodiment 136, comprising host cells.

[0181] 138. A method for evaluating a composition of TREM, e.g., GMP-grade TREM (i.e., TREM made in accordance with cGMP and / or similar requirements), comprising evaluating the following characteristics of a purified TREM composition: (i) at least 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% pure; (ii) less than 0.1 ng / ml, 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of host cell protein (HCP) contamination; (iii) less than 0.1 ng, 1 ng, 5 ng, 10 ng, 15 ng, 20 ng, 25 ng, 30 ng, 35 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, or 100 ng of host cell protein (HCP) contamination per milligram (mg) of the TREM composition; (iv) less than 1 ng / ml, 5 ng / ml, 10 ng / ml, 15 ng / ml, 20 ng / ml, 25 ng / ml, 30 ng / ml, 35 ng / ml, 40 ng / ml, 50 ng / ml, 60 ng / ml, 70 ng / ml, 80 ng / ml, 90 ng / ml, or 100 ng / ml of DNA, e.g., host cell DNA; (v) TREM fragments that are less than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the full-length TREM; (vi) low levels or absence of endotoxin, e.g., a negative result as measured by the Limulus amebocyte lysate (LAL) test; (vii) in vitro translation activity, for example, as measured by the assay described in Example 15; (viii) At least 0.1ng / mL, 0.5ng / mL, 1ng / mL, 5ng / mL, 10ng / mL, 50ng / mL, 0.1ug / mL, 0.5ug / mL, 1ug / mL, 2ug / mL, 5ug / mL, 10ug / mL, 20ug / mL, 30ug / mL, 40ug / mL, 50ug / mL, 60ug / mL, 70ug / mL, 80ug / mL, 100ug / mL, 200ug / mL, 300ug / mL, 500ug / mL, 1000ug / mL, 5000ug / mL, 10,000ug / mL, or 100,000ug / mL TREM concentration; (ix) Sterile, e.g., the composition or preparation supports the growth of less than 100 viable microorganisms when tested under sterile conditions, and the composition or preparation meets the U.S.P. <71> and / or the composition or preparation meets the specifications of USP as set forth by the cGMP guidelines for sterile dosage forms produced by aseptic processing. <85> meets the standards for sterility; or (x) For example, the composition or preparation is free of viral contamination or has an undetectable level of viral contamination. obtaining a value for one or more of the

[0182] 139. TREM (i) control region sequences; (ii) a sequence encoding a modified TREM; (iii) a sequence encoding two or more TREMs; or (iv) tRNA Met Non-array arrays The method of making of any one of embodiments 1 to 66, the composition or pharmaceutical composition of any one of embodiments 67 to 82, the method of any one of embodiments 83 to 109, the cell of any one of embodiments 110 to 132, the reaction mixture of embodiment 133, the bioreactor of embodiment 134 or 135, the master cell bank of embodiment 136 or 137, or the method of evaluating of embodiment 138, wherein the cell is encoded by or expressed from a nucleic acid sequence comprising:

[0183] 140. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 74, wherein the nucleic acid sequence comprises a promoter sequence.

[0184] 141. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 139 or 140, wherein the nucleic acid sequence comprises a promoter sequence comprising an RNA polymerase III (Pol III) recognition site, e.g., a Pol III binding site, e.g., a U6 promoter sequence or a fragment thereof.

[0185] 142. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 139 to 141, wherein the nucleic acid sequence comprises a promoter sequence comprising a mutation, e.g., a promoter-enhancing mutation, e.g., a mutation that increases transcription initiation, e.g., a mutation that increases TFIIIB binding.

[0186] 143. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 139 to 142, wherein the nucleic acid sequence comprises a promoter sequence that increases Pol III binding and leads to increased tRNA production, e.g., increased TREM production.

[0187] 144. TREM (a) stability of the product, e.g., protein, and / or (b) Ribosome occupancy of the product the method of making of any one of embodiments 1 to 66 or 139 to 143, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 143, the method of any one of embodiments 83 to 109 or 139 to 143, the cell of any one of embodiments 110 to 132 or 139 to 143, the reaction mixture of embodiment 133 or 139 to 143, the bioreactor of embodiment 134 to 135 or 139 to 143, the master cell bank of embodiment 136 to 137 or 139 to 143, or the method of evaluating of embodiment 138 or 139 to 143,

[0188] 145. TREM Does it regulate ribosome occupancy; whether it regulates protein translation or stability; Does it regulate mRNA stability? modulates protein folding or structure; whether it regulates protein transduction or compartmentalization; Does it regulate codon usage; Regulating cell fate; or modulating a signaling pathway, e.g., a cellular signaling pathway; The method of making of any one of embodiments 1 to 66 or 139 to 144, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 144, the method of any one of embodiments 83 to 109 or 139 to 144, the cell of any one of embodiments 110 to 132 or 139 to 144, the reaction mixture of embodiment 133 or 139 to 144, the bioreactor of embodiment 134 to 135 or 139 to 144, the master cell bank of embodiment 136 to 137 or 139 to 144, or the method of evaluating of embodiment 138 or 139 to 144.

[0189] 146. The method of making of any one of embodiments 1 to 66 or 139 to 144, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 144, the method of any one of embodiments 83 to 109 or 139 to 144, the cell of any one of embodiments 110 to 132 or 139 to 144, the reaction mixture of embodiments 133 or 139 to 144, the bioreactor of embodiments 134 to 135 or 139 to 144, the master cell bank of embodiments 136 to 137 or 139 to 144, or the method of evaluating of embodiment 138 or 139 to 144, wherein the TREM comprises a post-transcriptional modification from Table 2.

[0190] 147. The method of making of any one of embodiments 1 to 66 or 139 to 146, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 146, the method of any one of embodiments 83 to 109 or 139 to 146, the cell of any one of embodiments 110 to 132 or 139 to 146, the reaction mixture of embodiment 133 or 139 to 146, the bioreactor of embodiment 134 to 135 or 139 to 146, the master cell bank of embodiment 136 to 137 or 139 to 146, or the method of evaluating of embodiment 138 or 139 to 146, wherein the TREM comprises a cognate adaptor function and the TREM mediates the acceptance and incorporation of an amino acid that is naturally linked to the anticodon of the TREM in the initiation or elongation of a peptide chain.

[0191] 148. The method of making of any one of embodiments 1 to 66 or 139 to 147, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 147, the method of any one of embodiments 83 to 109 or 139 to 147, the cell of any one of embodiments 110 to 132 or 139 to 147, the reaction mixture of embodiment 133 or 139 to 147, the bioreactor of embodiment 134 to 135 or 139 to 147, the master cell bank of embodiment 136 to 137 or 139 to 147, or the method of evaluating of embodiment 138 or 139 to 147, wherein the TREM comprises a non-cognate adaptor function and the TREM mediates the acceptance and incorporation of an amino acid other than the amino acid naturally attached to the anticodon of the TREM in the initiation or elongation of a peptide chain, e.g., a non-cognate amino acid, and the non-cognate amino acid residue is, for example, a desired residue, e.g., a residue that does not mediate a disorder or an undesired trait, e.g., a wild-type residue.

[0192] 149. The method of making any one of embodiments 1 to 66 or 139 to 148, embodiment 67, wherein the TREM comprises an anticodon sequence complementary to a codon that specifies a first amino acid residue, e.g., an undesired or undesired codon, e.g., a codon associated with a disorder or undesired trait, e.g., a mutant codon, and the TREM mediates the incorporation of a second amino acid residue, e.g., a desired codon, e.g., an amino acid not associated with a disorder or undesired trait, e.g., a wild-type amino acid. the composition or pharmaceutical composition of any one of embodiments 83 to 109 or 139 to 148, the method of any one of embodiments 110 to 132 or 139 to 148, the reaction mixture of embodiments 133 or 139 to 148, the bioreactor of embodiments 134 to 135 or 139 to 148, the master cell bank of embodiments 136 to 137 or 139 to 148, or the method of evaluating of embodiments 138 or 139 to 148.

[0193] 150. The method of making of any one of embodiments 1 to 66 or 139 to 149, the composition or pharmaceutical composition of any one of embodiments 67 to 75, 79 to 82 or 139 to 149, the method of any one of embodiments 83 to 109 or 139 to 149, the cell of any one of embodiments 110 to 132 or 139 to 149, the reaction mixture of embodiment 133 or 139 to 149, the bioreactor of embodiment 134 to 135 or 139 to 149, the master cell bank of embodiment 136 to 137 or 139 to 149, or the method of evaluating of embodiment 138 or 139 to 149, wherein the TREM comprises an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to the RNA sequence of a naturally occurring tRNA.

[0194] 151. The method of making of any one of embodiments 1-66 or 139-150, the composition or pharmaceutical composition of any one of embodiments 67-75, 79-82 or 139-150, the method of any one of embodiments 83-109 or 139-150, the cell of any one of embodiments 110-132 or 139-150, the reaction mixture of embodiment 133 or 139-150, the bioreactor of embodiment 134-135 or 139-150, the master cell bank of embodiment 136-137 or 139-150, or the method of evaluating of embodiment 138 or 139-150, wherein the TREM comprises an RNA sequence that is at least 80% (e.g., at least 85%, at least 90%, at least 95%, at least 97%, at least 98%, at least 99%) identical to an RNA encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.

[0195] 152. The method of making of any one of embodiments 1 to 66 or 139 to 151, the composition or pharmaceutical composition of any one of embodiments 67 to 75, 79 to 82 or 139 to 151, the method of any one of embodiments 83 to 109 or 139 to 151, the cell of any one of embodiments 110 to 132 or 139 to 151, the reaction mixture of embodiments 133 or 139 to 151, the bioreactor of embodiments 134 to 135 or 139 to 151, the master cell bank of embodiments 136 to 137 or 139 to 151, or the method of evaluating of embodiments 138 or 139 to 151, wherein the TREM comprises an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment thereof.

[0196] 153. The method of making of any one of embodiments 1 to 66 or 139 to 152, the composition or pharmaceutical composition of any one of embodiments 67 to 75, 79 to 82 or 139 to 152, the method of any one of embodiments 83 to 109 or 139 to 152, the cell of any one of embodiments 110 to 132 or 139 to 152, the reaction mixture of embodiment 133 or 139 to 152, the bioreactor of embodiment 134 to 135 or 139 to 152, the master cell bank of embodiment 136 to 137 or 139 to 152, or the method of evaluating of embodiment 138 or 139 to 152, wherein the TREM comprises an RNA sequence at least XX% identical to an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment thereof, where XX is selected from 80, 85, 90, 95, 96, 97, 98, or 99.

[0197] 154. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 153, wherein XX is 80.

[0198] 155. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 153, wherein XX is 85.

[0199] 156. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 153, wherein XX is 90.

[0200] 157. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 153, wherein XX is 95.

[0201] 158. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 153, wherein XX is 97.

[0202] 159. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 153, wherein XX is 98.

[0203] 160. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 153, wherein XX is 99.

[0204] 161. The DNA sequence is SEQ ID NO: 1 or a fragment thereof, or SEQ ID NO: 2 or a fragment thereof, or SEQ ID NO: 3 or a fragment thereof, or SEQ ID NO: 4 or a fragment thereof, or SEQ ID NO: 5 or a fragment thereof, or SEQ ID NO: 6 or a fragment thereof, or SEQ ID NO: 7 or a fragment thereof, or SEQ ID NO: 8 or a fragment thereof, or SEQ ID NO: 9 or a fragment thereof, or SEQ ID NO: 10 or a fragment thereof, or SEQ ID NO: 11 or a fragment thereof, or SEQ ID NO: 12 or a fragment thereof, or SEQ ID NO: 13 or a fragment thereof, or SEQ ID NO: 14 or a fragment thereof, or SEQ ID NO: 15 or a fragment thereof, or SEQ ID NO: 16 or a fragment thereof, or SEQ ID NO: 17 or a fragment thereof, or SEQ ID NO: 18 or a fragment thereof, or SEQ ID NO: 19 or a fragment thereof, or SEQ ID NO: 20 or a fragment thereof, or SEQ ID NO: 21 or a fragment thereof, or SEQ ID NO: 22 or a fragment thereof, or SEQ ID NO: 23 or a fragment thereof, or SEQ ID NO: 24 or a fragment thereof, or SEQ ID NO: 25 or a fragment thereof, or SEQ ID NO: 26 or a fragment thereof, or SEQ ID NO: 27 or a fragment thereof, or SEQ ID NO: 28 or a fragment thereof, or SEQ ID NO: 29 or a fragment thereof, or SEQ ID NO:30 or a fragment thereof, or SEQ ID NO:31 or a fragment thereof, or SEQ ID NO:32 or a fragment thereof, or SEQ ID NO:33 or a fragment thereof, or SEQ ID NO:34 or a fragment thereof, or SEQ ID NO:35 or a fragment thereof, or SEQ ID NO:36 or a fragment thereof, or SEQ ID NO:37 or a fragment thereof, or SEQ ID NO:38 or a fragment thereof, or SEQ ID NO:39 or a fragment thereof, or SEQ ID NO:40 or a fragment thereof, or SEQ ID NO:41 or a fragment thereof, or SEQ ID NO:42 or a fragment thereof, or SEQ ID NO:43 or a fragment thereof, or SEQ ID NO:44 or a fragment thereof, or SEQ ID NO:45 or a fragment thereof, or SEQ ID NO:46 or a fragment thereof, or SEQ ID NO:47 or a fragment thereof, or SEQ ID NO:48 or a fragment thereof, or SEQ ID NO:49 or a fragment thereof, or SEQ ID NO:50 or a fragment thereof, or SEQ ID NO:51 or a fragment thereof, or SEQ ID NO:52 or a fragment thereof, or SEQ ID NO:53 or a fragment thereof, or SEQ ID NO:54 or a fragment thereof, or SEQ ID NO:55 or a fragment thereof, or SEQ ID NO:56 or a fragment thereof, or SEQ ID NO:57 or a fragment thereof, or SEQ ID NO:58 or a fragment thereof,or SEQ ID NO:59 or a fragment thereof, or SEQ ID NO:60 or a fragment thereof, or SEQ ID NO:61 or a fragment thereof, or SEQ ID NO:62 or a fragment thereof, or SEQ ID NO:63 or a fragment thereof, or SEQ ID NO:64 or a fragment thereof, or SEQ ID NO:65 or a fragment thereof, or SEQ ID NO:66 or a fragment thereof, or SEQ ID NO:67 or a fragment thereof, or SEQ ID NO:68 or a fragment thereof, or SEQ ID NO:69 or a fragment thereof, or SEQ ID NO:70 or a fragment thereof, or SEQ ID NO:71 or a fragment thereof, or SEQ ID NO:72 or a fragment thereof, or SEQ ID NO:73 or a fragment thereof, or SEQ ID NO:74 or a fragment thereof, or SEQ ID NO:75 or a fragment thereof, or SEQ ID NO:76 or a fragment thereof, or SEQ ID NO:77 or a fragment thereof, or SEQ ID NO:78 or a fragment thereof, or SEQ ID NO:79 or a fragment thereof, or SEQ ID NO:80 or a fragment thereof, or SEQ ID NO:81 or a fragment thereof, or SEQ ID NO:82 or a fragment thereof, or SEQ ID NO:83 or a fragment thereof, or SEQ ID NO:84 or a fragment thereof, or SEQ ID NO:85 or a fragment thereof, or SEQ ID NO:86 or a fragment thereof, or SEQ ID NO:87 or a fragment thereof or SEQ ID NO:88 or a fragment thereof, or SEQ ID NO:89 or a fragment thereof, or SEQ ID NO:90 or a fragment thereof, or SEQ ID NO:91 or a fragment thereof, or SEQ ID NO:92 or a fragment thereof, or SEQ ID NO:93 or a fragment thereof, or SEQ ID NO:94 or a fragment thereof, or SEQ ID NO:95 or a fragment thereof, or SEQ ID NO:96 or a fragment thereof, or SEQ ID NO:97 or a fragment thereof, or SEQ ID NO:98 or a fragment thereof, or SEQ ID NO:99 or a fragment thereof, or SEQ ID NO:100 or a fragment thereof, or SEQ ID NO:101 or a fragment thereof, or SEQ ID NO:102 or a fragment thereof, or SEQ ID NO:103 or a fragment thereof, or SEQ ID NO:104 or a fragment thereof, or SEQ ID NO:105 or a fragment thereof, or SEQ ID NO:106 or a fragment thereof, or SEQ ID NO:107 or a fragment thereof, or SEQ ID NO:108 or a fragment thereof, or SEQ ID NO:109 or a fragment thereof, or SEQ ID NO:110 or a fragment thereof, or SEQ ID NO:111 or a fragment thereof, or SEQ ID NO:112 or a fragment thereof, or SEQ ID NO:113 or a fragment thereof, or SEQ ID NO:114 or a fragment thereof, or SEQ ID NO:115 or a fragment thereof,or SEQ ID NO: 116 or a fragment thereof, or SEQ ID NO: 117 or a fragment thereof, or SEQ ID NO: 118 or a fragment thereof, or SEQ ID NO: 119 or a fragment thereof, or SEQ ID NO: 120 or a fragment thereof, or SEQ ID NO: 121 or a fragment thereof, or SEQ ID NO: 122 or a fragment thereof, or SEQ ID NO: 123 or a fragment thereof, or SEQ ID NO: 124 or a fragment thereof, or SEQ ID NO: 125 or a fragment thereof, or SEQ ID NO: 126 or a fragment thereof, or SEQ ID NO: 127 or a fragment thereof, or SEQ ID NO: 128 or a fragment thereof, or SEQ ID NO: 129 or or a fragment thereof, or SEQ ID NO: 130 or a fragment thereof, or SEQ ID NO: 131 or a fragment thereof, or SEQ ID NO: 132 or a fragment thereof, or SEQ ID NO: 133 or a fragment thereof, or SEQ ID NO: 134 or a fragment thereof, or SEQ ID NO: 135 or a fragment thereof, or SEQ ID NO: 136 or a fragment thereof, or SEQ ID NO: 137 or a fragment thereof, or SEQ ID NO: 138 or a fragment thereof, or SEQ ID NO: 139 or a fragment thereof, or SEQ ID NO: 140 or a fragment thereof, or SEQ ID NO: 141 or a fragment thereof, or SEQ ID NO: 142 or a fragment thereof, or SEQ ID NO: 143 or a fragment thereof, or SEQ ID NO: 144 or a fragment thereof, or SEQ ID NO: 145 or a fragment thereof, or SEQ ID NO: 146 or a fragment thereof, or SEQ ID NO: 147 or a fragment thereof, or SEQ ID NO: 148 or a fragment thereof, or SEQ ID NO: 149 or a fragment thereof, or SEQ ID NO: 150 or a fragment thereof, or SEQ ID NO: 151 or a fragment thereof, or SEQ ID NO: 152 or a fragment thereof, or SEQ ID NO: 153 or a fragment thereof, or SEQ ID NO: 154 or a fragment thereof, or SEQ ID NO: 155 or a fragment thereof, or SEQ ID NO: 156 or a fragment thereof, or the sequence No. 157 or a fragment thereof, or SEQ ID NO: 158 or a fragment thereof, or SEQ ID NO: 159 or a fragment thereof, or SEQ ID NO: 160 or a fragment thereof, or SEQ ID NO: 161 or a fragment thereof, or SEQ ID NO: 162 or a fragment thereof, or SEQ ID NO: 163 or a fragment thereof, or SEQ ID NO: 164 or a fragment thereof, or SEQ ID NO: 165 or a fragment thereof, or SEQ ID NO: 166 or a fragment thereof, or SEQ ID NO: 167 or a fragment thereof, or SEQ ID NO: 168 or a fragment thereof, or SEQ ID NO: 169 or a fragment thereof, or SEQ ID NO: 170 or a fragment thereof,or SEQ ID NO: 171 or a fragment thereof, or SEQ ID NO: 172 or a fragment thereof, or SEQ ID NO: 173 or a fragment thereof, or SEQ ID NO: 174 or a fragment thereof, or SEQ ID NO: 175 or a fragment thereof, or SEQ ID NO: 176 or a fragment thereof, or SEQ ID NO: 177 or a fragment thereof, or SEQ ID NO: 178 or a fragment thereof, or SEQ ID NO: 179 or a fragment thereof, or SEQ ID NO: 180 or a fragment thereof, or SEQ ID NO: 181 or a fragment thereof, or SEQ ID NO: 182 or a fragment thereof, or SEQ ID NO: 183 or a fragment thereof, or SEQ ID NO: 184 or or a fragment thereof, or SEQ ID NO: 185 or a fragment thereof, or SEQ ID NO: 186 or a fragment thereof, or SEQ ID NO: 187 or a fragment thereof, or SEQ ID NO: 188 or a fragment thereof, or SEQ ID NO: 189 or a fragment thereof, or SEQ ID NO: 190 or a fragment thereof, or SEQ ID NO: 191 or a fragment thereof, or SEQ ID NO: 192 or a fragment thereof, or SEQ ID NO: 193 or a fragment thereof, or SEQ ID NO: 194 or a fragment thereof, or SEQ ID NO: 195 or a fragment thereof, or SEQ ID NO: 196 or a fragment thereof, or SEQ ID NO: 197 or a fragment thereof, or SEQ ID NO: 198 or a fragment thereof, or SEQ ID NO: 199 or a fragment thereof, or SEQ ID NO: 200 or a fragment thereof, or SEQ ID NO: 201 or a fragment thereof, or SEQ ID NO: 202 or a fragment thereof, or SEQ ID NO: 203 or a fragment thereof, or SEQ ID NO: 204 or a fragment thereof, or SEQ ID NO: 205 or a fragment thereof, or SEQ ID NO: 206 or a fragment thereof, or SEQ ID NO: 207 or a fragment thereof, or SEQ ID NO: 208 or a fragment thereof, or SEQ ID NO: 209 or a fragment thereof, or SEQ ID NO: 210 or a fragment thereof, or SEQ ID NO: 211 or a fragment thereof, or the sequence SEQ ID NO: 212 or a fragment thereof, or SEQ ID NO: 213 or a fragment thereof, or SEQ ID NO: 214 or a fragment thereof, or SEQ ID NO: 215 or a fragment thereof, or SEQ ID NO: 216 or a fragment thereof, or SEQ ID NO: 217 or a fragment thereof, or SEQ ID NO: 218 or a fragment thereof, or SEQ ID NO: 219 or a fragment thereof, or SEQ ID NO: 220 or a fragment thereof, or SEQ ID NO: 221 or a fragment thereof, or SEQ ID NO: 222 or a fragment thereof, or SEQ ID NO: 223 or a fragment thereof, or SEQ ID NO: 224 or a fragment thereof, or SEQ ID NO: 225 or a fragment thereof,or SEQ ID NO: 226 or a fragment thereof, or SEQ ID NO: 227 or a fragment thereof, or SEQ ID NO: 228 or a fragment thereof, or SEQ ID NO: 229 or a fragment thereof, or SEQ ID NO: 230 or a fragment thereof, or SEQ ID NO: 231 or a fragment thereof, or SEQ ID NO: 232 or a fragment thereof, or SEQ ID NO: 233 or a fragment thereof, or SEQ ID NO: 234 or a fragment thereof, or SEQ ID NO: 235 or a fragment thereof, or SEQ ID NO: 236 or a fragment thereof, or SEQ ID NO: 237 or a fragment thereof, or SEQ ID NO: 238 or a fragment thereof, or SEQ ID NO: 239 or or a fragment thereof, or SEQ ID NO: 240 or a fragment thereof, or SEQ ID NO: 241 or a fragment thereof, or SEQ ID NO: 242 or a fragment thereof, or SEQ ID NO: 243 or a fragment thereof, or SEQ ID NO: 244 or a fragment thereof, or SEQ ID NO: 245 or a fragment thereof, or SEQ ID NO: 246 or a fragment thereof, or SEQ ID NO: 247 or a fragment thereof, or SEQ ID NO: 248 or a fragment thereof, or SEQ ID NO: 249 or a fragment thereof, or SEQ ID NO: 250 or a fragment thereof, or SEQ ID NO: 251 or a fragment thereof, or SEQ ID NO: 252 or a fragment thereof, or SEQ ID NO: 253 or a fragment thereof, or SEQ ID NO: 254 or a fragment thereof, or SEQ ID NO: 255 or a fragment thereof, or SEQ ID NO: 256 or a fragment thereof, or SEQ ID NO: 257 or a fragment thereof, or SEQ ID NO: 258 or a fragment thereof, or SEQ ID NO: 259 or a fragment thereof, or SEQ ID NO: 260 or a fragment thereof, or SEQ ID NO: 261 or a fragment thereof, or SEQ ID NO: 262 or a fragment thereof, or SEQ ID NO: 263 or a fragment thereof, or SEQ ID NO: 264 or a fragment thereof, or SEQ ID NO: 265 or a fragment thereof, or SEQ ID NO: 266 or a fragment thereof, or the sequence No. 267 or a fragment thereof, or SEQ ID NO: 268 or a fragment thereof, or SEQ ID NO: 269 or a fragment thereof, or SEQ ID NO: 270 or a fragment thereof, or SEQ ID NO: 271 or a fragment thereof, or SEQ ID NO: 272 or a fragment thereof, or SEQ ID NO: 273 or a fragment thereof, or SEQ ID NO: 274 or a fragment thereof, or SEQ ID NO: 275 or a fragment thereof, or SEQ ID NO: 276 or a fragment thereof, or SEQ ID NO: 277 or a fragment thereof, or SEQ ID NO: 278 or a fragment thereof, or SEQ ID NO: 279 or a fragment thereof, or SEQ ID NO: 280 or a fragment thereof,or SEQ ID NO: 281 or a fragment thereof, or SEQ ID NO: 282 or a fragment thereof, or SEQ ID NO: 283 or a fragment thereof, or SEQ ID NO: 284 or a fragment thereof, or SEQ ID NO: 285 or a fragment thereof, or SEQ ID NO: 286 or a fragment thereof, or SEQ ID NO: 287 or a fragment thereof, or SEQ ID NO: 288 or a fragment thereof, or SEQ ID NO: 289 or a fragment thereof, or SEQ ID NO: 290 or a fragment thereof, or SEQ ID NO:291 or a fragment thereof, or SEQ ID NO:292 or a fragment thereof, or SEQ ID NO:293 or a fragment thereof, or SEQ ID NO:294 or a fragment thereof, or SEQ ID NO:295 or a fragment thereof, or SEQ ID NO:296 or a fragment thereof, or SEQ ID NO:297 or a fragment thereof, or SEQ ID NO:298 or a fragment thereof, or SEQ ID NO:299 or a fragment thereof, or SEQ ID NO:300 or a fragment thereof, or SEQ ID NO:301 or a fragment thereof, or SEQ ID NO:302 or a fragment thereof, or SEQ ID NO:303 or a fragment thereof, or SEQ ID NO:304 or or a fragment thereof, or SEQ ID NO: 305 or a fragment thereof, or SEQ ID NO: 306 or a fragment thereof, or SEQ ID NO: 307 or a fragment thereof, or SEQ ID NO: 308 or a fragment thereof, or SEQ ID NO: 309 or a fragment thereof, or SEQ ID NO: 310 or a fragment thereof, or SEQ ID NO: 311 or a fragment thereof, or SEQ ID NO: 312 or a fragment thereof, or SEQ ID NO: 313 or a fragment thereof, or SEQ ID NO: 314 or a fragment thereof, or SEQ ID NO: 315 or a fragment thereof, or SEQ ID NO: 316 or a fragment thereof, or SEQ ID NO: 317 or a fragment thereof, or SEQ ID NO: 31 8 or a fragment thereof, or SEQ ID NO:319 or a fragment thereof, or SEQ ID NO:320 or a fragment thereof, or SEQ ID NO:321 or a fragment thereof, or SEQ ID NO:322 or a fragment thereof, or SEQ ID NO:323 or a fragment thereof, or SEQ ID NO:324 or a fragment thereof, or SEQ ID NO:325 or a fragment thereof, or SEQ ID NO:326 or a fragment thereof, or SEQ ID NO:327 or a fragment thereof, or SEQ ID NO:328 or a fragment thereof, or SEQ ID NO:329 or a fragment thereof, or SEQ ID NO:330 or a fragment thereof, or SEQ ID NO:331 or a fragment thereof, or the sequence No. 332 or a fragment thereof, or SEQ ID NO: 333 or a fragment thereof, or SEQ ID NO: 334 or a fragment thereof, or SEQ ID NO: 335 or a fragment thereof, or SEQ ID NO: 336 or a fragment thereof, or SEQ ID NO: 337 or a fragment thereof, or SEQ ID NO: 338 or a fragment thereof, or SEQ ID NO: 339 or a fragment thereof, or SEQ ID NO: 340 or a fragment thereof, or SEQ ID NO: 341 or a fragment thereof, or SEQ ID NO: 342 or a fragment thereof, or SEQ ID NO: 343 or a fragment thereof, or SEQ ID NO: 344 or a fragment thereof, or SEQ ID NO: 345 or a fragment thereof,or SEQ ID NO: 346 or a fragment thereof, or SEQ ID NO: 347 or a fragment thereof, or SEQ ID NO: 348 or a fragment thereof, or SEQ ID NO: 349 or a fragment thereof, or SEQ ID NO: 350 or a fragment thereof, or SEQ ID NO: 351 or a fragment thereof, or SEQ ID NO: 352 or a fragment thereof, or SEQ ID NO: 353 or a fragment thereof, or SEQ ID NO: 354 or a fragment thereof, or SEQ ID NO: 355 or a fragment thereof, or SEQ ID NO: 356 or a fragment thereof, or SEQ ID NO: 357 or a fragment thereof, or SEQ ID NO: 358 or a fragment thereof, or SEQ ID NO: 359 or or a fragment thereof, or SEQ ID NO: 360 or a fragment thereof, or SEQ ID NO: 361 or a fragment thereof, or SEQ ID NO: 362 or a fragment thereof, or SEQ ID NO: 363 or a fragment thereof, or SEQ ID NO: 364 or a fragment thereof, or SEQ ID NO: 365 or a fragment thereof, or SEQ ID NO: 366 or a fragment thereof, or SEQ ID NO: 367 or a fragment thereof, or SEQ ID NO: 368 or a fragment thereof, or SEQ ID NO: 369 or a fragment thereof, or SEQ ID NO: 370 or a fragment thereof, or SEQ ID NO: 371 or a fragment thereof, or SEQ ID NO: 372 or a fragment thereof, or SEQ ID NO: 373 or a fragment thereof, or SEQ ID NO: 374 or a fragment thereof, or SEQ ID NO: 375 or a fragment thereof, or SEQ ID NO: 376 or a fragment thereof, or SEQ ID NO: 377 or a fragment thereof, or SEQ ID NO: 378 or a fragment thereof, or SEQ ID NO: 379 or a fragment thereof, or SEQ ID NO: 380 or a fragment thereof, or SEQ ID NO: 381 or a fragment thereof, or SEQ ID NO: 382 or a fragment thereof, or SEQ ID NO: 383 or a fragment thereof, or SEQ ID NO: 384 or a fragment thereof, or SEQ ID NO: 385 or a fragment thereof, or SEQ ID NO: 386 or a fragment thereof, or the sequence No. 387 or a fragment thereof, or SEQ ID NO: 388 or a fragment thereof, or SEQ ID NO: 389 or a fragment thereof, or SEQ ID NO: 390 or a fragment thereof, or SEQ ID NO: 391 or a fragment thereof, or SEQ ID NO: 392 or a fragment thereof, or SEQ ID NO: 393 or a fragment thereof, or SEQ ID NO: 394 or a fragment thereof, or SEQ ID NO: 395 or a fragment thereof, or SEQ ID NO: 396 or a fragment thereof, or SEQ ID NO: 397 or a fragment thereof, or SEQ ID NO: 398 or a fragment thereof, or SEQ ID NO: 399 or a fragment thereof, or SEQ ID NO: 400 or a fragment thereof,or SEQ ID NO:401 or a fragment thereof, or SEQ ID NO:402 or a fragment thereof, or SEQ ID NO:403 or a fragment thereof, or SEQ ID NO:404 or a fragment thereof, or SEQ ID NO:405 or a fragment thereof, or SEQ ID NO:406 or a fragment thereof, or SEQ ID NO:407 or a fragment thereof, or SEQ ID NO:408 or a fragment thereof, or SEQ ID NO:409 or a fragment thereof, or SEQ ID NO:410 or a fragment thereof, or SEQ ID NO:411 or a fragment thereof, or SEQ ID NO:412 or a fragment thereof, or SEQ ID NO:413 or a fragment thereof, or SEQ ID NO:414 or a fragment thereof, or SEQ ID NO:415 or a fragment thereof, or SEQ ID NO:416 or a fragment thereof, or SEQ ID NO:417 or a fragment thereof, or SEQ ID NO:418 or a fragment thereof, or SEQ ID NO:419 or a fragment thereof, or SEQ ID NO:420 or a fragment thereof, or SEQ ID NO:421 or a fragment thereof, or SEQ ID NO:422 or a fragment thereof, or SEQ ID NO:423 or a fragment thereof, or SEQ ID NO:424 or a fragment thereof, or SEQ ID NO:425 or a fragment thereof, or SEQ ID NO:426 or or a fragment thereof, or SEQ ID NO:427 or a fragment thereof, or SEQ ID NO:428 or a fragment thereof, or SEQ ID NO:429 or a fragment thereof, or SEQ ID NO:430 or a fragment thereof, or SEQ ID NO:431 or a fragment thereof, or SEQ ID NO:432 or a fragment thereof, or SEQ ID NO:433 or a fragment thereof, or SEQ ID NO:434 or a fragment thereof, or SEQ ID NO:435 or a fragment thereof, or SEQ ID NO:436 or a fragment thereof, or SEQ ID NO:437 or a fragment thereof, or SEQ ID NO:438 or a fragment thereof, or SEQ ID NO:439 or a fragment thereof, or SEQ ID NO:440 or a fragment thereof, or SEQ ID NO:441 or a fragment thereof, or SEQ ID NO:442 or a fragment thereof, or SEQ ID NO:443 or a fragment thereof, or SEQ ID NO:444 or a fragment thereof, or SEQ ID NO:445 or a fragment thereof, or SEQ ID NO:446 or a fragment thereof, or SEQ ID NO:447 or a fragment thereof, or SEQ ID NO:448 or a fragment thereof, or SEQ ID NO:449 or a fragment thereof, or SEQ ID NO:450 or a fragment thereof, or SEQ ID NO:451 or a fragment thereof; Optionally, the fragment comprises one or more of the following: a linker 1 region, an AStD stem region; a linker 2 region; a stem-loop region, e.g., a D arm region; a linker 3 region; a stem-loop region, e.g., an AC arm region; a variable region; a stem-loop region, e.g., a T arm region; and a linker 4 region (e.g., these regions are as described herein).

[0205] 162. The composition or pharmaceutical composition of any one of embodiments 76-82, the method of any one of embodiments 94-109, or the cell of any one of claims 110-132, wherein ZZZ represents any of the following amino acids: alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, methionine, leucine, lysine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

[0206] 163. TREM has the following characteristics selected from: a) under physiological conditions, residue R0 forms a linker region, e.g., linker 1 region; b) Under physiological conditions, residues R1-R2-R3-R4-R5-R6-R7 and residues R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 forms a stem region, e.g., the AStD stem region; c) under physiological conditions, residues R8-R9 form a linker region, e.g., linker 2 region; d) Under physiological conditions, residue -R 10 -R 11 -R 12 -R 13 -R 14 R 15 -R 16 -R 17 -R18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 forms a stem-loop region, e.g., a D-arm region; e) Under physiological conditions, residue -R 29 forms a linker region, e.g., linker 3 region; f) Under physiological conditions, residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 forms a stem-loop region, e.g., an AC arm region; g) Under physiological conditions, residues -[R 47 ] X does it contain a variable region; h) Under physiological conditions, residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 forms a stem-loop region, e.g., a T-arm region; or i) Under physiological conditions, residue R 72forms a linker region, e.g., linker 4 region (For example, the structure R0-R1-R2-R3-R4-R5-R6-R7-R8-R9-R 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 -R 29 -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 -[R 47 ] x -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 -R 65 -R 66 -R 67 -R 68 -R 69 -R70 -R 71 -R 72 where R is a ribonucleotide residue. the method of making of any one of embodiments 1 to 66 or 139 to 161, the composition or pharmaceutical composition of any one of embodiments 67 to 75, 79 to 82 or 139 to 161, the method of any one of embodiments 83 to 109 or 139 to 161, the cell of any one of embodiments 110 to 132 or 139 to 161, the reaction mixture of embodiment 133 or 139 to 161, the bioreactor of embodiment 134 to 135 or 139 to 161, the master cell bank of embodiment 136 to 137 or 139 to 161, or the method of evaluating of embodiment 138 or 139 to 161,

[0207] 164. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 163, comprising any one of features (a) to (i).

[0208] 165. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 163, comprising any two of characteristics (a) to (i).

[0209] 166. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 163, comprising any three of characteristics (a) to (i).

[0210] 167. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 163, comprising any four of characteristics (a) to (i).

[0211] 168. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 163, comprising any five of characteristics (a) to (i).

[0212] 169. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 163, comprising any six of characteristics (a) to (i).

[0213] 170. The composition or pharmaceutical composition, method, or cell of embodiment 163, comprising any seven of characteristics (a) to (i).

[0214] 171. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 163, comprising all of features (a) to (i).

[0215] 172. The method of making of any one of embodiments 1 to 66 or 139 to 171, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 171, the method of any one of embodiments 83 to 109 or 139 to 171, the cell of any one of embodiments 110 to 132 or 139 to 171, the reaction mixture of embodiment 133 or 139 to 171, the bioreactor of embodiments 134 to 135 or 139 to 171, the master cell bank of embodiments 136 to 137 or 139 to 171, or the method of evaluating of embodiment 138 or 139 to 171, wherein the TREM comprises a consensus sequence provided herein.

[0216] 173. TREM is a compound of formula I ZZZ (In the formula, ZZZ the method of making of any one of embodiments 1 to 66 or 139 to 171, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 171, the method of any one of embodiments 83 to 109 or 139 to 171, the cell of any one of embodiments 110 to 132 or 139 to 171, the reaction mixture of embodiment 133 or 139 to 171, the bioreactor of embodiment 134 to 135 or 139 to 171, the master cell bank of embodiment 136 to 137 or 139 to 171, or the method of evaluating of embodiment 138 or 139 to 171, comprising a consensus sequence of the formula:

[0217] 174. TREM is a compound of formula II ZZZ (In the formula, ZZZ the method of making of any one of embodiments 1 to 66 or 139 to 171, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 171, the method of any one of embodiments 83 to 109 or 139 to 171, the cell of any one of embodiments 110 to 132 or 139 to 171, the reaction mixture of embodiment 133 or 139 to 171, the bioreactor of embodiment 134 to 135 or 139 to 171, the master cell bank of embodiment 136 to 137 or 139 to 171, or the method of evaluating of embodiment 138 or 139 to 171, comprising a consensus sequence of the formula:

[0218] 175. TREM is a compound of formula III ZZZ (In the formula, ZZZ the method of making of any one of embodiments 1 to 66 or 139 to 171, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 171, the method of any one of embodiments 83 to 109 or 139 to 171, the cell of any one of embodiments 110 to 132 or 139 to 171, the reaction mixture of embodiment 133 or 139 to 171, the bioreactor of embodiment 134 to 135 or 139 to 171, the master cell bank of embodiment 136 to 137 or 139 to 171, or the method of evaluating of embodiment 138 or 139 to 171, comprising a consensus sequence of the formula:

[0219] 176.TREM is R 47the method of making of any one of embodiments 1 to 66 or 139 to 175, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 175, the method of any one of embodiments 83 to 109 or 139 to 175, the cell of any one of embodiments 110 to 132 or 139 to 175, the reaction mixture of embodiments 133 or 139 to 175, the bioreactor of embodiments 134 to 135 or 139 to 175, the master cell bank of embodiments 136 to 137 or 139 to 175, or the method of evaluating of embodiment 138 or 139 to 175, wherein the cell comprises a variable region at position 136.

[0220] 177. The variable region may be 1-271 residues long (e.g., 1-250, 1-225, 1-200, 1-175, 1-150, 1-125, 1-100, 1-75, 1-50, 1-40, 1-30, 1-29, 1-28, 1-27, 1-26, 1-25, 1-24, 1-23, 1-22, 1-21, 1-20, 1-19, 1-18, 1-17, 1-16, 1-15, 1-14, 1-13, 1-12, 1-11, 1-10, 10-271, 20-271, 30-271, 40-271, 50-271, 60-271, 70-271, 80-271, 1 177. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 176, wherein the amino acid sequence is 00-271, 125-271, 150-271, 175-271, 200-271, 225-271, 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, 30, 40, 50, 60, 70, 80, 90, 100, 110, 125, 150, 175, 200, 225, 250, or 271 residues).

[0221] 178. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 176 or 177, wherein the variable region comprises any one, all, or a combination of adenine, cytosine, guanine, or uracil.

[0222] 179. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 176 to 178, wherein the variable region comprises a deoxyribonucleic acid (DNA) sequence disclosed in Table 3, e.g., a ribonucleic acid (RNA) sequence encoded by any one of SEQ ID NOs: 452 to 561 disclosed in Table 3.

[0223] 180. TREM is characterized by: a) When the TREM, e.g., the AC stem-loop of the TREM, comprises an exogenous insert, the exogenous insert is 5 or fewer consecutive ribonucleotide residues in length; b) when the TREM, e.g., the AC stem-loop of the TREM, comprises an exogenous insert, the remainder of the molecule comprises a non-naturally occurring sequence, e.g., a non-naturally occurring sequence of 1, 2, 3, 4, 5 or more ribonucleotide residues; c) when the TREM, e.g., the AC stem loop of the TREM, comprises an exogenous insert, the exogenous insert does not comprise an effector element, e.g., an effector element that has a primary sequence, secondary, or tertiary structure-dependent biological function; d) When the TREM, e.g., the AC stem loop of the TREM, comprises a foreign insert, the foreign insert does not comprise the epsilon domain of human hepatitis B virus; the dimerization domain of HIV; or an aptamer that binds to malachite green, dextran, or streptavidin; e) TREM can be loaded with amino acids; f) TREMs are translationally competent and can, for example, regulate the elongation of nascent polypeptides; g) TREM is not a naturally occurring molecule; h) TREM is not a naturally occurring molecule that has anti-angiogenic properties, as determined, for example, by inhibition of endothelial cell proliferation; i) TREM is not anti-angiogenic; and j) The method of making of any one of embodiments 1 to 66 or 139 to 179, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 179, the method of any one of embodiments 83 to 109 or 139 to 179, the cell of any one of embodiments 110 to 132 or 139 to 179, the reaction mixture of embodiment 133 or 139 to 179, the bioreactor of embodiment 134 to 135 or 139 to 179, the master cell bank of embodiment 136 to 137 or 139 to 179, or the method of evaluating of embodiment 138 or 139 to 179, comprising TREM not giving rise to naturally occurring anti-angiogenic fragments in homologous cells (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9 or all, or any combination thereof).

[0224] 181. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising feature (f).

[0225] 182. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising a characteristic selected from (a)-(f) and a characteristic selected from (g)-(j).

[0226] 183. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising characteristics (g) and / or (d).

[0227] 184. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 183, further comprising feature (h) or (i).

[0228] 185. A characteristic selected from the following: a) whether the composition contains at least 1, 2, 5, 10, or 1,000 grams of TREM; b) the composition does not contain full-length tRNA and naturally occurring anti-angiogenic fragments thereof; or c) The composition comprises a TREM according to any one of embodiments 67 to 82. 185. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 180 to 184, comprising:

[0229] 186. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180 or 181, comprising a characteristic selected from (a)-(e) and a characteristic selected from (g)-(j).

[0230] 187. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any one of features (a) to (f).

[0231] 188. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any two of characteristics (a) to (f).

[0232] 189. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any three of characteristics (a) to (f).

[0233] 190. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any four of characteristics (a)-(f).

[0234] 191. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any five of characteristics (a) to (f).

[0235] 192. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising all of features (a)-(f).

[0236] 193. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any one of features (f)-(j).

[0237] 194. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any two of features (f) to (j).

[0238] 195. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any three of features (f)-(j).

[0239] 196. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising any four of features (f)-(j).

[0240] 197. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, comprising all of features (f)-(j).

[0241] 198. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 180, further comprising any one, two, three, or all of features (g)-(j).

[0242] 199. The composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 198, the method of any one of embodiments 83 to 109 or 139 to 198, the cell of any one of embodiments 110 to 132 or 139 to 198, the reaction mixture of embodiment 133 or 139 to 198, the bioreactor of embodiment 134 to 135 or 139 to 198, the master cell bank of embodiment 136 to 137 or 139 to 198, or the method of evaluating of embodiment 138 or 139 to 198, wherein TREM recognizes a stop codon.

[0243] 200. The composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of embodiment 199, wherein TREM mediates the acceptance and uptake of amino acids.

[0244] 201. The composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 198, the method of any one of embodiments 83 to 109 or 139 to 198, the cell of any one of embodiments 110 to 132 or 139 to 198, the reaction mixture of embodiment 133 or 139 to 198, the bioreactor of embodiment 134 to 135 or 139 to 198, the master cell bank of embodiment 136 to 137 or 139 to 198, or the method of evaluating of embodiment 138 or 139 to 198, wherein TREM does not recognize a stop codon.

[0245] 202. The method of making of any one of embodiments 1 to 66 or 139 to 198, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 201, the method of any one of embodiments 83 to 109 or 139 to 201, the cell of any one of embodiments 110 to 132 or 139 to 201, the reaction mixture of embodiments 133 or 139 to 201, the bioreactor of embodiments 134 to 135 or 139 to 201, the master cell bank of embodiments 136 to 137 or 139 to 201, or the method of evaluating of embodiments 138 or 139 to 201, wherein the TREM does not comprise a naturally occurring bacterial tRNA or fragment thereof (e.g., an E. coli tRNA or fragment thereof), or a naturally occurring yeast tRNA or fragment thereof.

[0246] 203. The method of making of any one of embodiments 1 to 66 or 139 to 198, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 201, the method of any one of embodiments 83 to 109 or 139 to 201, the cell of any one of embodiments 110 to 132 or 139 to 201, the reaction mixture of embodiments 133 or 139 to 201, the bioreactor of embodiments 134 to 135 or 139 to 201, the master cell bank of embodiments 136 to 137 or 139 to 201, or the method of evaluating of embodiments 138 or 139 to 201, wherein the TREM is formulated as a lyophilized TREM composition.

[0247] 204. The method of making of any one of embodiments 1 to 66 or 139 to 198, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 201, the method of any one of embodiments 83 to 109 or 139 to 201, the cell of any one of embodiments 110 to 132 or 139 to 201, the reaction mixture of embodiments 133 or 139 to 201, the bioreactor of embodiments 134 to 135 or 139 to 201, the master cell bank of embodiments 136 to 137 or 139 to 201, or the method of evaluating of embodiments 138 or 139 to 201, wherein the TREM is formulated as a liquid TREM composition.

[0248] 205. The method of making of any one of embodiments 1 to 66 or 139 to 198, the composition or pharmaceutical composition of any one of embodiments 67 to 82 or 139 to 201, the method of any one of embodiments 83 to 109 or 139 to 201, the cell of any one of embodiments 110 to 132 or 139 to 201, the reaction mixture of embodiments 133 or 139 to 201, the bioreactor of embodiments 134 to 135 or 139 to 201, the master cell bank of embodiments 136 to 137 or 139 to 201, or the method of evaluating of embodiments 138 or 139 to 201, wherein the TREM is formulated as a frozen TREM composition.

[0249] 206. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 1, or a fragment thereof.

[0250] 207. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 2, or a fragment thereof.

[0251] 208. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 3, or a fragment thereof.

[0252] 209. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 4, or a fragment thereof.

[0253] 210. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 5, or a fragment thereof.

[0254] 211. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 6, or a fragment thereof.

[0255] 212. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 7, or a fragment thereof.

[0256] 213. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 8, or a fragment thereof.

[0257] 214. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 9, or a fragment thereof.

[0258] 215. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 10, or a fragment thereof.

[0259] 216. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 11, or a fragment thereof.

[0260] 217. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 12, or a fragment thereof.

[0261] 218. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 13, or a fragment thereof.

[0262] 219. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 14, or a fragment thereof.

[0263] 220. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 15, or a fragment thereof.

[0264] 221. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 16, or a fragment thereof.

[0265] 222. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 17, or a fragment thereof.

[0266] 223. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 18, or a fragment thereof.

[0267] 224. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 19, or a fragment thereof.

[0268] 225. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 20, or a fragment thereof.

[0269] 226. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 21, or a fragment thereof.

[0270] 227. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 22, or a fragment thereof.

[0271] 228. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 23, or a fragment thereof.

[0272] 229. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 24, or a fragment thereof.

[0273] 230. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 25, or a fragment thereof.

[0274] 231. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 26, or a fragment thereof.

[0275] 232. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 27, or a fragment thereof.

[0276] 233. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 28, or a fragment thereof.

[0277] 234. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 29, or a fragment thereof.

[0278] 235. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 30, or a fragment thereof.

[0279] 236. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 31, or a fragment thereof.

[0280] 237. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 32, or a fragment thereof.

[0281] 238. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 33, or a fragment thereof.

[0282] 239. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 34, or a fragment thereof.

[0283] 240. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 35, or a fragment thereof.

[0284] 241. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 36, or a fragment thereof.

[0285] 242. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 37, or a fragment thereof.

[0286] 243. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 38, or a fragment thereof.

[0287] 244. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 39, or a fragment thereof.

[0288] 245. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 40, or a fragment thereof.

[0289] 246. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 41, or a fragment thereof.

[0290] 247. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 42, or a fragment thereof.

[0291] 248. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 43, or a fragment thereof.

[0292] 249. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 44, or a fragment thereof.

[0293] 250. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 45, or a fragment thereof.

[0294] 251. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 46, or a fragment thereof.

[0295] 252. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 47, or a fragment thereof.

[0296] 253. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 48, or a fragment thereof.

[0297] 254. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 49, or a fragment thereof.

[0298] 255. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 50, or a fragment thereof.

[0299] 256. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 51, or a fragment thereof.

[0300] 257. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 52, or a fragment thereof.

[0301] 258. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 53, or a fragment thereof.

[0302] 259. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 54, or a fragment thereof.

[0303] 260. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 55, or a fragment thereof.

[0304] 261. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 56, or a fragment thereof.

[0305] 262. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 57, or a fragment thereof.

[0306] 263. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 58, or a fragment thereof.

[0307] 264. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 59, or a fragment thereof.

[0308] 265. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 60, or a fragment thereof.

[0309] 266. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 61, or a fragment thereof.

[0310] 267. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 62, or a fragment thereof.

[0311] 268. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 63, or a fragment thereof.

[0312] 269. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 64, or a fragment thereof.

[0313] 270. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 65, or a fragment thereof.

[0314] 271. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 66, or a fragment thereof.

[0315] 272. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 67, or a fragment thereof.

[0316] 273. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 68, or a fragment thereof.

[0317] 274. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 69, or a fragment thereof.

[0318] 275. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 70, or a fragment thereof.

[0319] 276. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 71, or a fragment thereof.

[0320] 277. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 72, or a fragment thereof.

[0321] 278. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 73, or a fragment thereof.

[0322] 279. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 74, or a fragment thereof.

[0323] 280. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 75, or a fragment thereof.

[0324] 281. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 76, or a fragment thereof.

[0325] 282. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 77, or a fragment thereof.

[0326] 283. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 78, or a fragment thereof.

[0327] 284. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 79, or a fragment thereof.

[0328] 285. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 80, or a fragment thereof.

[0329] 286. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 81, or a fragment thereof.

[0330] 287. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 82, or a fragment thereof.

[0331] 288. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 83, or a fragment thereof.

[0332] 289. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 84, or a fragment thereof.

[0333] 290. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 85, or a fragment thereof.

[0334] 291. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 86, or a fragment thereof.

[0335] 292. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 87, or a fragment thereof.

[0336] 293. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 88, or a fragment thereof.

[0337] 294. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 89, or a fragment thereof.

[0338] 295. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 90, or a fragment thereof.

[0339] 296. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 91, or a fragment thereof.

[0340] 297. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 92, or a fragment thereof.

[0341] 298. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 93, or a fragment thereof.

[0342] 299. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 94, or a fragment thereof.

[0343] 300. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 95, or a fragment thereof.

[0344] 301. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 96, or a fragment thereof.

[0345] 302. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 97, or a fragment thereof.

[0346] 303. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 98, or a fragment thereof.

[0347] 304. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 99, or a fragment thereof.

[0348] 305. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 100, or a fragment thereof.

[0349] 306. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 101, or a fragment thereof.

[0350] 307. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 102, or a fragment thereof.

[0351] 308. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 103, or a fragment thereof.

[0352] 309. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 104, or a fragment thereof.

[0353] 310. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 105, or a fragment thereof.

[0354] 311. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 106, or a fragment thereof.

[0355] 312. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 107, or a fragment thereof.

[0356] 313. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 108, or a fragment thereof.

[0357] 314. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 109, or a fragment thereof.

[0358] 315. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 110, or a fragment thereof.

[0359] 316. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 111, or a fragment thereof.

[0360] 317. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 112, or a fragment thereof.

[0361] 318. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 113, or a fragment thereof.

[0362] 319. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 114, or a fragment thereof.

[0363] 320. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 115, or a fragment thereof.

[0364] 321. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 116, or a fragment thereof.

[0365] 322. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 117, or a fragment thereof.

[0366] 323. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 118, or a fragment thereof.

[0367] 324. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 119, or a fragment thereof.

[0368] 325. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 120, or a fragment thereof.

[0369] 326. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 121, or a fragment thereof.

[0370] 327. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 122, or a fragment thereof.

[0371] 328. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 123, or a fragment thereof.

[0372] 329. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 124, or a fragment thereof.

[0373] 330. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 125, or a fragment thereof.

[0374] 331. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 126, or a fragment thereof.

[0375] 332. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 127, or a fragment thereof.

[0376] 333. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 128, or a fragment thereof.

[0377] 334. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 129, or a fragment thereof.

[0378] 335. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 130, or a fragment thereof.

[0379] 336. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 131, or a fragment thereof.

[0380] 337. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 132, or a fragment thereof.

[0381] 338. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 133, or a fragment thereof.

[0382] 339. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 134, or a fragment thereof.

[0383] 340. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 135, or a fragment thereof.

[0384] 341. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 136, or a fragment thereof.

[0385] 342. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 137, or a fragment thereof.

[0386] 343. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 138, or a fragment thereof.

[0387] 344. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 139, or a fragment thereof.

[0388] 345. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 140, or a fragment thereof.

[0389] 346. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 141, or a fragment thereof.

[0390] 347. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 142, or a fragment thereof.

[0391] 348. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 143, or a fragment thereof.

[0392] 349. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 144, or a fragment thereof.

[0393] 350. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 145, or a fragment thereof.

[0394] 351. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 146, or a fragment thereof.

[0395] 352. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 147, or a fragment thereof.

[0396] 353. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 148, or a fragment thereof.

[0397] 354. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 149, or a fragment thereof.

[0398] 355. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 150, or a fragment thereof.

[0399] 356. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 151, or a fragment thereof.

[0400] 357. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 152, or a fragment thereof.

[0401] 358. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 153, or a fragment thereof.

[0402] 359. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 154, or a fragment thereof.

[0403] 360. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 155, or a fragment thereof.

[0404] 361. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 156, or a fragment thereof.

[0405] 362. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 157, or a fragment thereof.

[0406] 363. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 158, or a fragment thereof.

[0407] 364. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 159, or a fragment thereof.

[0408] 365. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 160, or a fragment thereof.

[0409] 366. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 161, or a fragment thereof.

[0410] 367. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 162, or a fragment thereof.

[0411] 368. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 163, or a fragment thereof.

[0412] 369. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 164, or a fragment thereof.

[0413] 370. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 165, or a fragment thereof.

[0414] 371. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 166, or a fragment thereof.

[0415] 372. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 167, or a fragment thereof.

[0416] 373. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 168, or a fragment thereof.

[0417] 374. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 169, or a fragment thereof.

[0418] 375. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 170, or a fragment thereof.

[0419] 376. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 171, or a fragment thereof.

[0420] 377. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 172, or a fragment thereof.

[0421] 378. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 173, or a fragment thereof.

[0422] 379. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 174, or a fragment thereof.

[0423] 380. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 175, or a fragment thereof.

[0424] 381. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 176, or a fragment thereof.

[0425] 382. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 177, or a fragment thereof.

[0426] 383. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 178, or a fragment thereof.

[0427] 384. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 179, or a fragment thereof.

[0428] 385. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 180, or a fragment thereof.

[0429] 386. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 181, or a fragment thereof.

[0430] 387. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 182, or a fragment thereof.

[0431] 388. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 183, or a fragment thereof.

[0432] 389. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 184, or a fragment thereof.

[0433] 390. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 185, or a fragment thereof.

[0434] 391. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 186, or a fragment thereof.

[0435] 392. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 187, or a fragment thereof.

[0436] 393. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 188, or a fragment thereof.

[0437] 394. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 189, or a fragment thereof.

[0438] 395. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 190, or a fragment thereof.

[0439] 396. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 191, or a fragment thereof.

[0440] 397. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 192, or a fragment thereof.

[0441] 398. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 193, or a fragment thereof.

[0442] 399. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 194, or a fragment thereof.

[0443] 400. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 195, or a fragment thereof.

[0444] 401. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 196, or a fragment thereof.

[0445] 402. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 197, or a fragment thereof.

[0446] 403. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 198, or a fragment thereof.

[0447] 404. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 199, or a fragment thereof.

[0448] 405. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 200, or a fragment thereof.

[0449] 406. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 201, or a fragment thereof.

[0450] 407. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 202, or a fragment thereof.

[0451] 408. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 203, or a fragment thereof.

[0452] 409. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 204, or a fragment thereof.

[0453] 410. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 205, or a fragment thereof.

[0454] 411. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 206, or a fragment thereof.

[0455] 412. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 207, or a fragment thereof.

[0456] 413. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 208, or a fragment thereof.

[0457] 414. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 209, or a fragment thereof.

[0458] 415. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 210, or a fragment thereof.

[0459] 416. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 211, or a fragment thereof.

[0460] 417. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 212, or a fragment thereof.

[0461] 418. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 213, or a fragment thereof.

[0462] 419. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 214, or a fragment thereof.

[0463] 420. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 215, or a fragment thereof.

[0464] 421. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 216, or a fragment thereof.

[0465] 422. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 217, or a fragment thereof.

[0466] 423. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 218, or a fragment thereof.

[0467] 424. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 219, or a fragment thereof.

[0468] 425. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 220, or a fragment thereof.

[0469] 426. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 221, or a fragment thereof.

[0470] 427. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 222, or a fragment thereof.

[0471] 428. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 223, or a fragment thereof.

[0472] 429. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 224, or a fragment thereof.

[0473] 430. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 225, or a fragment thereof.

[0474] 431. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 226, or a fragment thereof.

[0475] 432. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 227, or a fragment thereof.

[0476] 433. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 228, or a fragment thereof.

[0477] 434. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 229, or a fragment thereof.

[0478] 435. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 230, or a fragment thereof.

[0479] 436. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 231, or a fragment thereof.

[0480] 437. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 232, or a fragment thereof.

[0481] 438. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 233, or a fragment thereof.

[0482] 439. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 234, or a fragment thereof.

[0483] 440. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 235, or a fragment thereof.

[0484] 441. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 236, or a fragment thereof.

[0485] 442. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 237, or a fragment thereof.

[0486] 443. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 238, or a fragment thereof.

[0487] 444. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 239, or a fragment thereof.

[0488] 445. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 240, or a fragment thereof.

[0489] 446. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 241, or a fragment thereof.

[0490] 447. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 242, or a fragment thereof.

[0491] 448. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 243, or a fragment thereof.

[0492] 449. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 244, or a fragment thereof.

[0493] 450. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 245, or a fragment thereof.

[0494] 451. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 246, or a fragment thereof.

[0495] 452. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 247, or a fragment thereof.

[0496] 453. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 248, or a fragment thereof.

[0497] 454. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 249, or a fragment thereof.

[0498] 455. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 250, or a fragment thereof.

[0499] 456. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 251, or a fragment thereof.

[0500] 457. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 252, or a fragment thereof.

[0501] 458. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 253, or a fragment thereof.

[0502] 459. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 254, or a fragment thereof.

[0503] 460. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 255, or a fragment thereof.

[0504] 461. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 256, or a fragment thereof.

[0505] 462. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 257, or a fragment thereof.

[0506] 463. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 258, or a fragment thereof.

[0507] 464. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 259, or a fragment thereof.

[0508] 465. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 260, or a fragment thereof.

[0509] 466. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 261, or a fragment thereof.

[0510] 467. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 262, or a fragment thereof.

[0511] 468. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 263, or a fragment thereof.

[0512] 469. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 264, or a fragment thereof.

[0513] 470. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 265, or a fragment thereof.

[0514] 471. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 266, or a fragment thereof.

[0515] 472. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 267, or a fragment thereof.

[0516] 473. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 268, or a fragment thereof.

[0517] 474. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 269, or a fragment thereof.

[0518] 475. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 270, or a fragment thereof.

[0519] 476. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 271, or a fragment thereof.

[0520] 477. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 272, or a fragment thereof.

[0521] 478. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 273, or a fragment thereof.

[0522] 479. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 274, or a fragment thereof.

[0523] 480. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 275, or a fragment thereof.

[0524] 481. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 276, or a fragment thereof.

[0525] 482. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 277, or a fragment thereof.

[0526] 483. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 278, or a fragment thereof.

[0527] 484. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 279, or a fragment thereof.

[0528] 485. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 280, or a fragment thereof.

[0529] 486. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 281, or a fragment thereof.

[0530] 487. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 282, or a fragment thereof.

[0531] 488. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 283, or a fragment thereof.

[0532] 489. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 284, or a fragment thereof.

[0533] 490. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 285, or a fragment thereof.

[0534] 491. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 286, or a fragment thereof.

[0535] 492. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 287, or a fragment thereof.

[0536] 493. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 288, or a fragment thereof.

[0537] 494. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 289, or a fragment thereof.

[0538] 495. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 290, or a fragment thereof.

[0539] 496. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 291, or a fragment thereof.

[0540] 497. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 292, or a fragment thereof.

[0541] 498. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 293, or a fragment thereof.

[0542] 499. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 294, or a fragment thereof.

[0543] 500. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 295, or a fragment thereof.

[0544] 501. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 296, or a fragment thereof.

[0545] 502. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 297, or a fragment thereof.

[0546] 503. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 298, or a fragment thereof.

[0547] 504. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 299, or a fragment thereof.

[0548] 505. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 300, or a fragment thereof.

[0549] 506. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 301, or a fragment thereof.

[0550] 507. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 302, or a fragment thereof.

[0551] 508. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 303, or a fragment thereof.

[0552] 509. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 304, or a fragment thereof.

[0553] 510. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 305, or a fragment thereof.

[0554] 511. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 306, or a fragment thereof.

[0555] 512. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 307, or a fragment thereof.

[0556] 513. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 308, or a fragment thereof.

[0557] 514. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 309, or a fragment thereof.

[0558] 515. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 310, or a fragment thereof.

[0559] 516. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 311, or a fragment thereof.

[0560] 517. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 312, or a fragment thereof.

[0561] 518. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 313, or a fragment thereof.

[0562] 519. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 314, or a fragment thereof.

[0563] 520. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 315, or a fragment thereof.

[0564] 521. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 316, or a fragment thereof.

[0565] 522. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 317, or a fragment thereof.

[0566] 523. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 318, or a fragment thereof.

[0567] 524. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 319, or a fragment thereof.

[0568] 525. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 320, or a fragment thereof.

[0569] 526. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 321, or a fragment thereof.

[0570] 527. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 322, or a fragment thereof.

[0571] 528. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 323, or a fragment thereof.

[0572] 529. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 324, or a fragment thereof.

[0573] 530. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 325, or a fragment thereof.

[0574] 531. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 326, or a fragment thereof.

[0575] 532. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 327, or a fragment thereof.

[0576] 533. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 328, or a fragment thereof.

[0577] 534. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 329, or a fragment thereof.

[0578] 535. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 330, or a fragment thereof.

[0579] 536. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 331, or a fragment thereof.

[0580] 537. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 332, or a fragment thereof.

[0581] 538. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 333, or a fragment thereof.

[0582] 539. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 334, or a fragment thereof.

[0583] 540. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 335, or a fragment thereof.

[0584] 541. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 336, or a fragment thereof.

[0585] 542. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 337, or a fragment thereof.

[0586] 543. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 338, or a fragment thereof.

[0587] 544. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 339, or a fragment thereof.

[0588] 545. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 340, or a fragment thereof.

[0589] 546. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 341, or a fragment thereof.

[0590] 547. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 342, or a fragment thereof.

[0591] 548. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 343, or a fragment thereof.

[0592] 549. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 344, or a fragment thereof.

[0593] 550. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 345, or a fragment thereof.

[0594] 551. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 346, or a fragment thereof.

[0595] 552. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 347, or a fragment thereof.

[0596] 553. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 348, or a fragment thereof.

[0597] 554. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 349, or a fragment thereof.

[0598] 555. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 350, or a fragment thereof.

[0599] 556. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 351, or a fragment thereof.

[0600] 557. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 352, or a fragment thereof.

[0601] 558. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 353, or a fragment thereof.

[0602] 559. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 354, or a fragment thereof.

[0603] 560. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 355, or a fragment thereof.

[0604] 561. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 356, or a fragment thereof.

[0605] 562. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 357, or a fragment thereof.

[0606] 563. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 358, or a fragment thereof.

[0607] 564. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 359, or a fragment thereof.

[0608] 565. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 360, or a fragment thereof.

[0609] 566. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 361, or a fragment thereof.

[0610] 567. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 362, or a fragment thereof.

[0611] 568. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 363, or a fragment thereof.

[0612] 569. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 364, or a fragment thereof.

[0613] 570. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 365, or a fragment thereof.

[0614] 571. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 366, or a fragment thereof.

[0615] 572. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 367, or a fragment thereof.

[0616] 573. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 368, or a fragment thereof.

[0617] 574. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 369, or a fragment thereof.

[0618] 575. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 370, or a fragment thereof.

[0619] 576. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 371, or a fragment thereof.

[0620] 577. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 372, or a fragment thereof.

[0621] 578. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 373, or a fragment thereof.

[0622] 579. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 374, or a fragment thereof.

[0623] 580. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 375, or a fragment thereof.

[0624] 581. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 376, or a fragment thereof.

[0625] 582. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 377, or a fragment thereof.

[0626] 583. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 378, or a fragment thereof.

[0627] 584. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 379, or a fragment thereof.

[0628] 585. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 380, or a fragment thereof.

[0629] 586. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 381, or a fragment thereof.

[0630] 587. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 382, or a fragment thereof.

[0631] 588. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 383, or a fragment thereof.

[0632] 589. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 384, or a fragment thereof.

[0633] 590. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 385, or a fragment thereof.

[0634] 591. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 386, or a fragment thereof.

[0635] 592. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 387, or a fragment thereof.

[0636] 593. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 388, or a fragment thereof.

[0637] 594. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 389, or a fragment thereof.

[0638] 595. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 390, or a fragment thereof.

[0639] 596. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 391, or a fragment thereof.

[0640] 597. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 392, or a fragment thereof.

[0641] 598. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 393, or a fragment thereof.

[0642] 599. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 394, or a fragment thereof.

[0643] 600. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 395, or a fragment thereof.

[0644] 601. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 396, or a fragment thereof.

[0645] 602. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 397, or a fragment thereof.

[0646] 603. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 398, or a fragment thereof.

[0647] 604. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 399, or a fragment thereof.

[0648] 605. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 400, or a fragment thereof.

[0649] 606. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 401, or a fragment thereof.

[0650] 607. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 402, or a fragment thereof.

[0651] 608. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 403, or a fragment thereof.

[0652] 609. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 404, or a fragment thereof.

[0653] 610. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 405, or a fragment thereof.

[0654] 611. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 406, or a fragment thereof.

[0655] 612. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 407, or a fragment thereof.

[0656] 613. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 408, or a fragment thereof.

[0657] 614. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 409, or a fragment thereof.

[0658] 615. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 410, or a fragment thereof.

[0659] 616. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 411, or a fragment thereof.

[0660] 617. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 412, or a fragment thereof.

[0661] 618. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 413, or a fragment thereof.

[0662] 619. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 414, or a fragment thereof.

[0663] 620. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 415, or a fragment thereof.

[0664] 621. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 416, or a fragment thereof.

[0665] 622. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 417, or a fragment thereof.

[0666] 623. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 418, or a fragment thereof.

[0667] 624. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 419, or a fragment thereof.

[0668] 625. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 420, or a fragment thereof.

[0669] 626. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 421, or a fragment thereof.

[0670] 627. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 422, or a fragment thereof.

[0671] 628. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 423, or a fragment thereof.

[0672] 629. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 424, or a fragment thereof.

[0673] 630. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 425, or a fragment thereof.

[0674] 631. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 426, or a fragment thereof.

[0675] 632. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 427, or a fragment thereof.

[0676] 633. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 428, or a fragment thereof.

[0677] 634. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 429, or a fragment thereof.

[0678] 635. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 430, or a fragment thereof.

[0679] 636. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 431, or a fragment thereof.

[0680] 637. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 432, or a fragment thereof.

[0681] 638. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 433, or a fragment thereof.

[0682] 639. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 434, or a fragment thereof.

[0683] 640. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 435, or a fragment thereof.

[0684] 641. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 436, or a fragment thereof.

[0685] 642. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 437, or a fragment thereof.

[0686] 643. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 438, or a fragment thereof.

[0687] 644. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 439, or a fragment thereof.

[0688] 645. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 440, or a fragment thereof.

[0689] 646. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 441, or a fragment thereof.

[0690] 647. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 442, or a fragment thereof.

[0691] 648. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 443, or a fragment thereof.

[0692] 649. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 444, or a fragment thereof.

[0693] 650. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 445, or a fragment thereof.

[0694] 651. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 446, or a fragment thereof.

[0695] 652. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 447, or a fragment thereof.

[0696] 653. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 448, or a fragment thereof.

[0697] 654. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 449, or a fragment thereof.

[0698] 655. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 450, or a fragment thereof.

[0699] 656. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 451, or a fragment thereof.

[0700] 657. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 562, or a fragment thereof.

[0701] 658. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 563, or a fragment thereof.

[0702] 659. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 564, or a fragment thereof.

[0703] 660. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 565, or a fragment thereof.

[0704] 661. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 566, or a fragment thereof.

[0705] 662. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 567, or a fragment thereof.

[0706] 663. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 568, or a fragment thereof.

[0707] 664. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 569, or a fragment thereof.

[0708] 665. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 570, or a fragment thereof.

[0709] 666. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 571, or a fragment thereof.

[0710] 667. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 572, or a fragment thereof.

[0711] 668. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 573, or a fragment thereof.

[0712] 669. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 574, or a fragment thereof.

[0713] 670. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 575, or a fragment thereof.

[0714] 671. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 576, or a fragment thereof.

[0715] 672. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 577, or a fragment thereof.

[0716] 673. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 578, or a fragment thereof.

[0717] 674. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 579, or a fragment thereof.

[0718] 675. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 580, or a fragment thereof.

[0719] 676. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 581, or a fragment thereof.

[0720] 677. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 582, or a fragment thereof.

[0721] 678. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 583, or a fragment thereof.

[0722] 679. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 584, or a fragment thereof.

[0723] 680. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 585, or a fragment thereof.

[0724] 681. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 586, or a fragment thereof.

[0725] 682. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 587, or a fragment thereof.

[0726] 683. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 588, or a fragment thereof.

[0727] 684. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 589, or a fragment thereof.

[0728] 685. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 590, or a fragment thereof.

[0729] 686. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 591, or a fragment thereof.

[0730] 687. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 592, or a fragment thereof.

[0731] 688. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 593, or a fragment thereof.

[0732] 689. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 594, or a fragment thereof.

[0733] 690. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 595, or a fragment thereof.

[0734] 691. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 596, or a fragment thereof.

[0735] 692. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 597, or a fragment thereof.

[0736] 693. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 598, or a fragment thereof.

[0737] 694. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 599, or a fragment thereof.

[0738] 695. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 600, or a fragment thereof.

[0739] 696. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 601, or a fragment thereof.

[0740] 697. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 602, or a fragment thereof.

[0741] 698. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 603, or a fragment thereof.

[0742] 699. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 604, or a fragment thereof.

[0743] 700. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 605, or a fragment thereof.

[0744] 701. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 606, or a fragment thereof.

[0745] 702. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 607, or a fragment thereof.

[0746] 703. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 608, or a fragment thereof.

[0747] 704. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 609, or a fragment thereof.

[0748] 705. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 610, or a fragment thereof.

[0749] 706. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 611, or a fragment thereof.

[0750] 707. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 612, or a fragment thereof.

[0751] 708. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 613, or a fragment thereof.

[0752] 709. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1-205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 614, or a fragment thereof.

[0753] 710. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 615, or a fragment thereof.

[0754] 711. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 616, or a fragment thereof.

[0755] 712. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 617, or a fragment thereof.

[0756] 713. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 618, or a fragment thereof.

[0757] 714. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 619, or a fragment thereof.

[0758] 715. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 620, or a fragment thereof.

[0759] 716. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 1 to 205, wherein the TREM comprises an RNA sequence encoded by the DNA sequence of SEQ ID NO: 621, or a fragment thereof.

[0760] 717. The method, composition or pharmaceutical composition, cell, reaction mixture, bioreactor, or master cell bank of any one of embodiments 206-716, wherein the fragment comprises one or more, but not all, of a linker 1 region, an AStD stem region; a linker 2 region; a stem-loop region, e.g., a D arm region; a linker 3 region; a stem-loop region, e.g., an AC arm region; a variable region; a stem-loop region, e.g., a T arm region; and a linker 4 region (e.g., these regions are as described herein).

[0761] 718. A method for producing a purified tRNA effector molecule (TREM) pharmaceutical composition, comprising: providing an insect host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining insect host cells under conditions sufficient to express TREM; purifying the TREM from the insect host cells, for example, according to the methods described herein; and The purified TREM is formulated as a pharmaceutical composition, for example, by combining the TREM with pharmaceutical excipients; thereby producing a TREM pharmaceutical composition. A method comprising:

[0762] 719. The method of embodiment 718, wherein the insect host cell is selected from an insect cell or cell line, such as an Sf9 cell or cell line.

[0763] 720. A method for producing a purified tRNA effector molecule (TREM) pharmaceutical composition, comprising: providing a yeast host cell containing exogenous nucleic acid, e.g., DNA or RNA, encoding a TREM; maintaining yeast host cells under conditions sufficient to express TREM; Purifying the TREM from the yeast host cell, for example, according to the methods described herein; and The purified TREM is formulated as a pharmaceutical composition, for example, by combining the TREM with pharmaceutical excipients; thereby producing a TREM pharmaceutical composition. A method comprising:

[0764] 721. The method of embodiment 720, wherein the yeast host cell is selected from a yeast cell or cell line, such as an S. cerevisiae or S. pombe cell or cell line.

[0765] 722. The purification process may comprise, for example, the following steps in the order listed: (i) separating nucleic acids from proteins to provide an RNA preparation; (ii) separating RNAs with less than a threshold number of nucleotides, e.g., less than 500 nt, less than 400 nt, less than 300 nt, less than 250 nt, less than 200 nt, less than 150 nt, from larger RNA species in the RNA preparation to produce a small RNA preparation; and / or (iii) Affinity-based separation of TREMs from other RNA species in small RNA preparations, e.g., by sequence affinity. The method of any one of embodiments 718 to 721, including one, two or all of the following:

[0766] Other features, objects, and advantages of the invention will become apparent from the description and claims.

[0767] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. Furthermore, the materials, methods, and examples are illustrative only and not intended to be limiting. [Brief explanation of the drawings]

[0768] [Figure 1] Figure 1A is a graph showing the increase in cell proliferation in three cell lines after transfection with TREMs corresponding to the initiating methionine (iMet). Figure 1A is a graph showing the increase in % cell confluency (a measure of cell proliferation) of U20S cells transfected with Cy3-labeled iMet-CAT-TREM or a Cy3-labeled untagged control. Figure 1B is a graph showing the increase in % cell confluency (a measure of cell proliferation) of H1299 cells transfected with Cy3-labeled iMet-CAT-TREM or a Cy3-labeled untagged control. Figure 1C is a graph showing the increase in % cell confluency (a measure of cell proliferation) of HeLa cells transfected with Cy3-labeled iMet-CAT-TREM or a Cy3-labeled untagged control. [Figure 2] Graph showing increase in NanoLuc reporter expression upon addition of iMET-TREM to translation reactions with cell-free lysate. As a control, translation reactions with buffer were performed. DETAILED DESCRIPTION OF THE INVENTION

[0769] This disclosure features tRNA-based effector molecules (TREMs) and related methods. As disclosed herein, tRNA-based effector molecules (TREMs) are complex molecules that can mediate a variety of cellular processes. Pharmaceutical TREM compositions can be administered to cells, tissues, or subjects to modulate their function.

[0770] definition A "cognate adaptor function TREM," as that term is used herein, refers to a TREM that mediates initiation or elongation by the AA that is naturally associated with the anticodon of the TREM (the cognate AA).

[0771] "Decreased expression," as that term is used herein, refers to a decrease compared to a reference, for example, if modification of a control region or addition of an agent results in decreased expression of the product of interest, which is decreased compared to other similar cells without the modification or addition.

[0772] "Foreign nucleic acid," as that term is used herein, refers to a nucleic acid sequence that is not present in, or differs by at least one nucleotide from, the closest sequence in a reference cell, e.g., the cell into which the foreign nucleic acid is introduced. In one embodiment, the foreign nucleic acid comprises a nucleic acid encoding a TREM.

[0773] "Extraneous TREM," as that term is used herein, means: (a) differs in at least one nucleotide or one post-transcriptional modification from the closest sequence tRNA in a reference cell, e.g., a cell into which the exogenous nucleic acid is introduced; (b) whether it has been introduced into cells other than those in which it was transcribed; (c) it is present in cells other than those in which it naturally occurs; or (d) A TREM that has an expression profile, e.g., a level or distribution, that is not wild-type (e.g., it is expressed at a level higher than wild-type). In some embodiments, the expression profile can be mediated by changes introduced into a nucleic acid that regulates expression or by the addition of an agent that regulates expression of an RNA molecule. In some embodiments, an exogenous TREM comprises one, two, three, or four of characteristics (a)-(d).

[0774] "GMP-grade composition," as that term is used herein, refers to a composition that complies with current Good Manufacturing Practice (cGMP) guidelines or other similar requirements. In certain embodiments, a GMP-grade composition may be used as a pharmaceutical product.

[0775] As used herein, the terms "increase" and "decrease" refer to modulation that results in an increase or decrease, respectively, in the amount of a particular indicator of function, expression, or activity relative to a reference. For example, after administration of a TREM as described herein to a cell, tissue, or subject, the amount of a marker of the indicator as described herein (e.g., protein translation, mRNA stability, protein folding) can be increased or decreased by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 98%, 2X, 3X, 5X, 10X, or more relative to the amount of the marker before administration or relative to the effect of a negative control agent. The indicator can be measured after administration at a time when the administration has had the recited effect, for example, at least 12 hours, 24 hours, 1 week, 1 month, 3 months, or 6 months after treatment begins.

[0776] "Increased expression," as that term is used herein, refers to an increase compared to a reference, for example, where modification of a control region or addition of an agent results in increased expression of the product of interest, which is increased compared to other similar cells without the modification or addition.

[0777] A "non-cognate adapter function TREM," as that term is used herein, refers to a TREM that mediates initiation or extension by an AA other than the AA naturally associated with the anticodon of the TREM (non-cognate AA). In one embodiment, a non-cognate adapter function TREM is also referred to as a mischarged TREM (mTREM).

[0778] A "non-naturally occurring sequence," as that term is used herein, refers to a sequence in which adenine is replaced by a residue other than an analog of adenine, cytosine is replaced by a residue other than an analog of cytosine, guanine is replaced by a residue other than an analog of guanine, and uracil is replaced by a residue other than an analog of uracil. An analog refers to any possible derivative of ribonucleotides A, G, C, or U. In one embodiment, a sequence having a derivative of any one of ribonucleotides A, G, C, or U is a non-naturally occurring sequence.

[0779] "Oncogene," as the term is used herein, refers to a gene that regulates one or more cellular processes, including cell fate determination, cell survival, and genome maintenance. In certain embodiments, an oncogene confers a selective growth advantage, e.g., deregulation, e.g., genetic deregulation (e.g., mutation or amplification) or epigenetic deregulation, to the cell in which it is present. Exemplary oncogenes include Myc (e.g., c-Myc, N-Myc, or L-Myc), c-Jun, Wnt, or RAS.

[0780] A "pharmaceutical TREM composition," as that term is used herein, refers to a TREM composition suitable for pharmaceutical use. Typically, a pharmaceutical TREM composition includes a pharmaceutical excipient. In some embodiments, the TREM will be the only active ingredient in a pharmaceutical TREM composition. In embodiments, a pharmaceutical TREM composition is free, substantially free, or has less than a pharmaceutically acceptable amount of host cell proteins, DNA, e.g., host cell DNA, endotoxins, and bacteria.

[0781] "Post-transcriptional processing," as the term is used herein with respect to a molecule of interest, e.g., a TREM, RNA, or tRNA, refers to the covalent modification of the molecule of interest. In some embodiments, the covalent modification occurs post-transcriptionally. In some embodiments, the covalent modification occurs co-transcriptionally. In some embodiments, the modification is made in vivo, e.g., in the cells used to generate the TREM. In some embodiments, the modification is made ex vivo, e.g., on a TREM isolated or obtained from the cells that generated the TREM. In some embodiments, the post-transcriptional modification is selected from the post-transcriptional modifications listed in Table 2.

[0782] "Recombinant TREM," as that term is used herein, refers to a TREM expressed in a cell that has been modified by human intervention, with modifications that mediate the production of the TREM (e.g., the cell includes an exogenous sequence encoding the TREM), or modifications that mediate expression, e.g., transcriptional expression or post-transcriptional modification, of the TREM. A recombinant TREM may have the same or a different sequence, set of post-transcriptional modifications, or tertiary structure as a reference tRNA, e.g., a naturally occurring tRNA.

[0783] "Synthetic TREM," as that term is used herein, refers to a TREM that is synthesized outside of a cell that has endogenous nucleic acid encoding the TREM, for example, by cell-free solid-phase synthesis. A synthetic TREM may have the same or a different sequence, set of post-transcriptional modifications, or tertiary structure as a naturally occurring tRNA.

[0784] "TREM expressed in heterologous cells," as that term is used herein, refers to TREM produced under non-native conditions. For example, i) produced in cells that are genetically, metabolically different (e.g., have a different profile of gene expression or different levels of cellular components, such as absorbed nutrients), or epigenetically different from naturally occurring cells; ii) produced in cells cultured under conditions that differ from natural conditions (native conditions are those under which cells naturally produce tRNA), such as nutrient, pH, temperature, cell density, or stress conditions; or iii) produced in cells that are localized at a level, ratio, or concentration, or in a compartment or location that differs from the reference, e.g., a level, ratio, or concentration, or in a compartment or location that differs from that occurring under natural conditions. TREM expressed in heterologous cells may have the same or a different sequence, set of post-transcriptional modifications, or tertiary structure as natural tRNA.

[0785] "tRNA," as the term is used herein, refers to a naturally occurring transfer ribonucleic acid in its natural state.

[0786] "tRNA-based effector molecule" or "TREM," as that term is used herein, refers to an RNA molecule that comprises the structure or characteristics (a) through (v) below, and that is a recombinant TREM, a synthetic TREM, or a TREM expressed from a heterologous cell. A TREM may have the structure and function of more than one (e.g., 2, 3, 4, 5, 6, 7, 8, 9) of (a) through (v).

[0787] In certain embodiments, the TREM is non-naturally occurring, as assessed by its structure or the manner in which it is made.

[0788] In certain embodiments, the TREM comprises one or more of the following structures or characteristics: (a') an optional linker region of the consensus sequence provided in the "consensus sequence" section, e.g., the linker 1 region; (a) an amino acid binding domain, e.g., an acceptor stem domain (AStD), that binds to an amino acid (e.g., an AStD comprises an RNA sequence sufficient, when present in an otherwise wild-type tRNA, to accept an amino acid, e.g., its cognate or non-cognate amino acid, and mediate the transfer of the amino acid (AA) in the initiation or elongation of a polypeptide chain). Typically, the AStD comprises a 3'-terminal adenosine (CCA) for acceptor stem loading, which is part of the synthetase recognition. In some embodiments, the AStD has at least 75, 80, 85, 90, 95, or 100% identity to a naturally occurring AStD, e.g., an AStD encoded by a nucleic acid in Table 1. In some embodiments, the TREM may comprise a fragment or analog of an AStD, e.g., an AStD encoded by a nucleic acid in Table 1, where in embodiments the fragment has AStD activity and in other embodiments it does not have AStD activity. (One of skill in the art can determine the appropriate corresponding sequence for any of the domains, stems, loops, or other sequence features described herein from the sequences encoded by the nucleic acids in Table 1. For example, one of skill in the art can determine the sequence corresponding to AStD from the tRNA sequence encoded by the nucleic acids in Table 1.)

[0789] In one embodiment, the AStD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" section or differs from the consensus sequence at no more than 1, 2, 5, or 10 positions.

[0790] In one embodiment, AStD has formula I ZZZ Residues R1-R2-R3-R4-R5-R6-R7 and residues R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 where ZZZ represents any of the 20 amino acids; In one embodiment, AStD has formula II ZZZ Residues R1-R2-R3-R4-R5-R6-R7 and residues R 65-R 66 -R 67 -R 68 -R 69 -R 70 -R 71 where ZZZ represents any of the 20 amino acids; In certain embodiments, AStD has formula III ZZZ Residues R1-R2-R3-R4-R5-R6-R7 and residues R 65 -R 66 -R 67 -R 68 -R 69 -R 70 -R 71 where ZZZ represents any of the 20 amino acids; (a'-1) a linker, e.g., the linker 2 region, comprising residues R8-R9 of the consensus sequence provided in the "consensus sequence" section; (b) a dihydrouridine hairpin domain (DHD) (the DHD, e.g., when present in an otherwise wild-type tRNA, mediates aminoacyl-tRNA synthetase recognition, e.g., comprises an RNA sequence sufficient to act as a recognition site for an aminoacyl-tRNA synthetase for amino acid charging of the TREM). In embodiments, the DHD mediates stabilization of the tertiary structure of the TREM. In certain embodiments, the DHD has at least 75, 80, 85, 90, 95, or 100% identity to a naturally occurring DHD, e.g., a DHD encoded by a nucleic acid in Table 1. In certain embodiments, the TREM may comprise a fragment or analog of a DHD, e.g., a DHD encoded by a nucleic acid in Table 1, wherein the fragment in embodiments has DHD activity and in other embodiments does not have DHD activity.

[0791] In some embodiments, the DHD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" section or differs from the consensus sequence at no more than 1, 2, 5, or 10 positions; In certain embodiments, the DHD has formula I ZZZ Residue R of 10 -R 11 -R 12 -R 13-R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 where ZZZ represents any of the 20 amino acids; In certain embodiments, the DHD has Formula II ZZZ Residue R of 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 where ZZZ represents any of the 20 amino acids; In certain embodiments, the DHD has formula III ZZZ Residue R of 10 -R 11 -R 12 -R 13 -R 14 -R 15 -R 16 -R 17 -R 18 -R 19 -R 20 -R 21 -R 22 -R 23 -R 24 -R 25 -R 26 -R 27 -R 28 where ZZZ represents any of the 20 amino acids; (b'-1) Residue R of the consensus sequence provided in the "consensus sequence" section 29 a linker comprising, for example, a linker 3 region; (c) an anticodon, e.g., an anticodon hairpin domain (ACHD), that binds to the respective codon in the mRNA (e.g., an ACHD includes a sequence, e.g., an anticodon triplet, sufficient to mediate pairing with the codon (with or without wobble) when present in an otherwise wild-type tRNA; in some embodiments, the ACHD has at least 75, 80, 85, 90, 95, or 100% identity to a naturally occurring ACHD, e.g., an ACHD encoded by a nucleic acid in Table 1). In some embodiments, the TREM may include a fragment or analog of an ACHD, e.g., an ACHD encoded by a nucleic acid in Table 1, where the fragment in some embodiments has ACHD activity and in other embodiments does not have ACHD activity.

[0792] In some embodiments, the ACHD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" section or differs from the consensus sequence at no more than 1, 2, 5, or 10 positions; In one embodiment, ACHD has formula I ZZZ Residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 where ZZZ represents any of the 20 amino acids; In one embodiment, ACHD has formula II ZZZ Residue -R 30 -R 31 -R 32 -R 33 -R 34 -R35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 where ZZZ represents any of the 20 amino acids; In certain embodiments, ACHD has formula III ZZZ Residue -R 30 -R 31 -R 32 -R 33 -R 34 -R 35 -R 36 -R 37 -R 38 -R 39 -R 40 -R 41 -R 42 -R 43 -R 44 -R 45 -R 46 where ZZZ represents any of the 20 amino acids; (d) Variable Loop Domain (VLD) (The VLD, e.g., when present in an otherwise wild-type tRNA, mediates aminoacyl-tRNA synthetase recognition, e.g., comprises sufficient RNA sequence to act as a recognition site for an aminoacyl-tRNA synthetase for amino acid charging of the TREM). In embodiments, the VLD mediates stabilization of the tertiary structure of the TREM. In some embodiments, the VLD modulates, e.g., increases, the specificity of the TREM for its cognate amino acid, e.g., the VLD modulates the cognate adaptor function of the TREM. In some embodiments, the VLD has at least 75, 80, 85, 85, 90, 95, or 100% identity to a naturally occurring VLD, e.g., a VLD encoded by a nucleic acid in Table 1. In some embodiments, the TREM may comprise a fragment or analog of a VLD, e.g., a VLD encoded by a nucleic acid in Table 1, wherein the fragment in embodiments has VLD activity and in other embodiments does not have VLD activity.

[0793] In certain embodiments, the VLD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" section.

[0794] In one embodiment, the VLD is a residue of the consensus sequence provided in the "consensus sequence" section -[R 47 ] X x=1-271 (e.g., x=1-250, x=1-225, x=1-200, x=1-175, x=1-150, x=1-125, x=1-100, x=1-75, x=1-50, x=1-40, x=1-30, x=1-29, x=1-28, x=1-27, x=1-26, x=1-25, x=1-24, x=1-23, x =1~22, x=1~21, x=1~20, x=1~19, x=1~18, x=1~17, x=1~16, x=1~15, x=1~14, x=1~13, x=1~12 , x=1~11, x=1~10, x=10~271, x=20~271, x=30~271, x=40~271, x=50~271, x=60~271, x=70~27 1, x=80~271, x=100~271, x=125~271, x=150~271, x=175~271, x=200~271, x=225~271, x=1, x=2, x=3, x=4, x=5, x=6, x=7, x=8, x=9, x=10, x=11, x=12, x=13, x=14, x=15, x=16, x=17, x=18 , x=19, x=20, x=21, x=22, x=23, x=24, x=25, x=26, x=27, x=28, x=29, x=30, x=40, x=50, x=60, x=70, x=80, x=90, x=100, x=110, x=125, x=150, x=175, x=200, x=225, x=250, or x=271); (e) a thymine hairpin domain (THD) (e.g., a THD comprises an RNA sequence sufficient to mediate ribosome recognition, e.g., to act as a recognition site for ribosomes to form a TREM-ribosome complex during translation, when present in an otherwise wild-type tRNA). In some embodiments, the THD has at least 75, 80, 85, 85, 90, 95, or 100% identity to a naturally occurring THD, e.g., a THD encoded by a nucleic acid in Table 1. In some embodiments, the TREM may comprise a fragment or analog of a THD, e.g., a THD encoded by a nucleic acid in Table 1, wherein the fragment in embodiments has THD activity and in other embodiments does not have THD activity.

[0795] In some embodiments, the THD is below the corresponding sequence of the consensus sequence provided in the "consensus sequence" section or differs from the consensus sequence at no more than 1, 2, 5, or 10 positions; In certain embodiments, THD has formula I ZZZ Residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 where ZZZ represents any of the 20 amino acids; In certain embodiments, THD has the formula II ZZZ Residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R60 -R 61 -R 62 -R 63 -R 64 where ZZZ represents any of the 20 amino acids; In certain embodiments, THD is represented by formula III ZZZ Residue -R 48 -R 49 -R 50 -R 51 -R 52 -R 53 -R 54 -R 55 -R 56 -R 57 -R 58 -R 59 -R 60 -R 61 -R 62 -R 63 -R 64 where ZZZ represents any of the 20 amino acids; (e'1) Residue R of the consensus sequence provided in the "consensus sequence" section 72 a linker comprising, for example, a linker 4 region; (f) under physiological conditions, it comprises a stem structure and one or more loop structures, e.g., one, two, or three loops. The loop may comprise a domain described herein, e.g., a domain selected from (a)-(e). The loop may comprise one or more domains. In some embodiments, the stem or loop structure has at least 75, 80, 85, 85, 90, 95, or 100% identity to a naturally occurring stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 1. In some embodiments, the TREM may comprise a fragment or analog of a stem or loop structure, e.g., a stem or loop structure encoded by a nucleic acid in Table 1, where the fragment in embodiments has the activity of the stem or loop structure and in other embodiments does not have the activity of the stem or loop structure; (g) tertiary structure, e.g., L-type tertiary structure; (h) Adaptor function, i.e., TREM, mediates the acceptance of an amino acid, e.g., its cognate amino acid, and mediates the transfer of AA in the initiation or elongation of a polypeptide chain; (i) cognate adaptor function (TREMs mediate acceptance and incorporation of amino acids (e.g., cognate amino acids) that are naturally linked to the anticodon of the TREM initiating or elongating a polypeptide chain); (j) noncognate adaptor function (TREMs mediate the acceptance and incorporation of amino acids other than those naturally linked to the anticodon of the TREM (e.g., noncognate amino acids) in the initiation or elongation of a polypeptide chain); (k) a regulatory function, such as an epigenetic function (e.g., a gene silencing function or a signal pathway regulation function), a cell fate regulation function, an mRNA stability regulation function, a protein stability regulation function, a protein transduction regulation function, or a protein compartmentalization function; (l) structures that allow ribosome binding; (m) a post-transcriptional modification (e.g., it includes one or more modifications in Table 2, e.g., modifications 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 listed in Table 2); (n) a functional property of tRNA, e.g., the ability to inhibit any of the properties (h)-(k) possessed by tRNA; (o) the ability to regulate cell fate; (p) the ability to regulate ribosome occupancy; (q) the ability to regulate protein translation; (r) the ability to regulate mRNA stability; (s) the ability to regulate protein folding and structure; (t) the ability to regulate protein transduction or compartmentalization; (u) the ability to modulate protein stability; or (v) The ability to modulate a signaling pathway, for example, a cellular signaling pathway.

[0796] In certain embodiments, the TREM comprises a full-length tRNA molecule or a fragment thereof.

[0797] In one embodiment, the TREM comprises the following properties: (a) through (e).

[0798] In one embodiment, the TREM comprises the following properties: (a) and (c).

[0799] In one embodiment, the TREM comprises the following characteristics: (a), (c), and (h).

[0800] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), and (b).

[0801] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), and (e).

[0802] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), (b), and (e).

[0803] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), (b), (e), and (g).

[0804] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), and (m).

[0805] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), (m), and (g).

[0806] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), (m), and (b).

[0807] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), (m), and (e).

[0808] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), (m), (g), (b), and (e).

[0809] In one embodiment, the TREM comprises the following characteristics: (a), (c), (h), (m), (g), (b), (e), and (q).

[0810] In one embodiment, the TREM is (i) an amino acid binding domain that binds to an amino acid (e.g., an AStD as described in (a) herein); and (ii) It contains an anticodon (e.g., ACHD as described in (c) herein) that binds to each codon in the mRNA.

[0811] In certain embodiments, the TREM comprises a flexible RNA linker that provides the covalent bond between (i) and (ii).

[0812] In certain embodiments, TREM mediates protein translation.

[0813] In some embodiments, the TREM comprises a linker, e.g., an RNA linker, e.g., a flexible RNA linker, that provides a covalent bond between the first and second structures or domains. In some embodiments, the RNA linker comprises at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 ribonucleotides. The TREM may comprise one or more linkers; for example, in embodiments, a TREM comprising (a), (b), (c), (d), and (e) may have a first linker between the first and second domains and a second linker between the third domain and another domain.

[0814] In some embodiments, a TREM comprises an RNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to, or differs by no more than 1, 2, 3, 4, 5, 10, 15, 20, 25, or 30 ribonucleotides from, an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, a TREM comprises an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, a TREM comprises an RNA sequence encoded by a DNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to, a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, the TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof, that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to, or differs by no more than 1, 2, 3, 4, 5, 10, or 15 ribonucleotides therefrom. In some embodiments, the TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by a DNA sequence listed in Table 1, or a fragment or functional fragment thereof. In some embodiments, the TREM comprises a TREM domain, e.g., a domain described herein, comprising an RNA sequence encoded by a DNA sequence that is at least 60, 65, 70, 75, 80, 85, 90, 95, 96, 97, 98, or 99% identical to, a DNA sequence listed in Table 1, or a fragment or functional fragment thereof.

[0815] In certain embodiments, the TREM is 76 to 90 nucleotides in length. In certain embodiments, the TREM, or a fragment or functional fragment thereof, is 10 to 90 nucleotides, 10 to 80 nucleotides, 10 to 70 nucleotides, 10 to 60 nucleotides, 10 to 50 nucleotides, 10 to 40 nucleotides, 10 to 30 nucleotides, 10 to 20 nucleotides, 20 to 90 nucleotides, 20 to 80 nucleotides, 20 to 70 nucleotides, 20 to 60 nucleotides, 20 to 50 nucleotides, 20 to 40 nucleotides, 30 to 90 nucleotides, 30 to 80 nucleotides, 30 to 70 nucleotides, 30 to 60 nucleotides, or 30 to 50 nucleotides.

[0816] In certain embodiments, the TREM is aminoacylated, eg, charged with an amino acid by an aminoacyl-tRNA synthetase.

[0817] In certain embodiments, the TREM is not loaded with amino acids, eg, unloaded TREM (uTREM).

[0818] In some embodiments, a TREM comprises a less than full-length tRNA. In embodiments, a TREM can correspond to a naturally occurring or non-naturally occurring fragment of a tRNA. Exemplary fragments include a TREM half (e.g., derived from an ACHD, e.g., a cleavage in the anticodon sequence, e.g., the 5' half or the 3' half); a 5' fragment (e.g., derived from a cleavage in the DHD or ACHD, e.g., a fragment including the 5' end); a 3' fragment (e.g., derived from a cleavage in the THD, e.g., a fragment including the 3' end); or an internal fragment (e.g., derived from a cleavage in one or more of the ACHD, DHD, or THD).

[0819] "TREM composition," as the term is used herein, refers to a composition comprising multiple TREMs. A TREM composition may comprise one or more species of TREM. In some embodiments, a composition comprises only a single species of TREM. In some embodiments, a TREM composition comprises a first TREM species and a second TREM species. In some embodiments, a TREM composition comprises X TREM species (X=2, 3, 4, 5, 6, 7, 8, 9, or 10). In some embodiments, a TREM has at least 70, 75, 80, 85, 90, or 95, or 100% identity to a sequence encoded by a nucleic acid in Table 1. A TREM composition may comprise one or more species of TREM. In some embodiments, a TREM composition is purified from a cell culture. In some embodiments, the cell culture from which a TREM is purified comprises at least 1 x 10 7 host cells, 1 x 10 8 host cells, 1 x 10 9 host cells, 1 x 10 10 host cells, 1 x 10 11 host cells, 1 x 10 12 host cells, 1 x 10 13 host cells, or 1 x 10 14 In some embodiments, the TREM composition is at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, or 99% dry weight TREM (for liquid compositions, dry weight refers to the weight after removal of substantially all liquid, e.g., lyophilization). In some embodiments, the composition is a liquid. In some embodiments, the composition is a dry, e.g., lyophilized, material. In some embodiments, the composition is a frozen composition. In some embodiments, the composition is sterile. In some embodiments, the composition comprises at least 0.5 g, 1.0 g, 5.0 g, 10 g, 15 g, 25 g, 50 g, 100 g, 200 g, 400 g, or 500 g (e.g., as measured by dry weight) of TREM.

[0820] "Tumor suppressor," as the term is used herein, refers to a gene that regulates one or more cellular processes, including cell fate determination, cell survival, and genome maintenance. In certain embodiments, a tumor suppressor confers a selective growth advantage to cells in which it is deregulated, e.g., genetically deregulated (e.g., mutated or deleted) or epigenetically deregulated. Exemplary tumor suppressors include p53 or Rb.

[0821] host cell Host cells are cells (e.g., cultured cells) that can be used for expression and / or purification of TREMs. In some embodiments, host cells include mammalian cells, e.g., human cells. In some embodiments, host cells include non-mammalian cells, e.g., yeast cells. In some embodiments, host cells include HeLa cells, HEK293T cells (e.g., Freestyle 293-F cells), HT-1080 cells, PER.C6 cells, HKB-11 cells, CAP cells, HuH-7 cells, BHK 21 cells, MRC-S cells, MDCK cells, VERO cells, WI-38 cells, or Chinese hamster ovary (CHO) cells. In some embodiments, host cells include cancer cells, e.g., solid tumor cells (e.g., breast cancer cells (e.g., MCF7 cells), pancreatic cell lines (e.g., MIA PaCa-2 cells), lung cancer cells, prostate cancer cells, or blood cancer cells). In some embodiments, host cells include cells that express one or more tissue-specific tRNAs. For example, the host cell can include a cell derived from a tissue associated with expression of a tRNA, e.g., a tissue-specific tRNA. In certain embodiments, the host cell expressing the tissue-specific tRNA is engineered to express a TREM, or a fragment thereof.

[0822] In certain embodiments, the host cell is not a bacterial cell, for example, an E. coli cell.

[0823] In certain embodiments, the host cell is one that can be maintained under conditions that allow expression of a TREM.

[0824] In some embodiments, the host cell is capable of post-transcriptionally modifying a TREM, e.g., adding a post-transcriptional modification selected from Table 2. In some embodiments, the host cell expresses (e.g., naturally or heterologously) an enzyme listed in Table 2. In some embodiments, the host cell expresses (e.g., naturally or heterologously) an enzyme, e.g., an enzyme having nuclease activity (e.g., endonuclease activity or ribonuclease activity), such as one or more of Dicer, angiogenin, RNase A, RNase P, RNase Z, Rny1, or PrrC.

[0825] Methods for culturing host cells Host cells can be cultured in a medium that promotes growth, e.g., proliferation or overgrowth, of host cells. Host cells can be cultured in a suitable medium, e.g., any of the following media: DMEM, MEM, MEM alpha, RPMI, F-10 medium, F-12 medium, DMEM / F-12 medium, IMDM, Medium 199, Leibovitz L-15, McCoy's 5A, MDCB medium, or CMRL medium. In some embodiments, the medium is supplemented with glutamine. In some embodiments, the medium is not supplemented with glutamine. In some embodiments, host cells are cultured in a medium with excess nutrients, e.g., not nutrient-limiting. Host cells may be cultured in medium containing or supplemented with one or a combination of growth factors, cytokines, or hormones, such as one or a combination of serum (e.g., fetal bovine serum (FBS)), HEPES, fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin-like growth factor (IGF), transforming growth factor beta (TGFb), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), or tumor necrosis factor (TNF).

[0826] Host cells can also be cultured under conditions that induce stress, e.g., cellular stress, osmotic stress, translational stress, or oncogenic stress. In some embodiments, host cells expressing TREM cultured under conditions that induce stress (e.g., as described herein) result in fragments of TREM, e.g., as described herein.

[0827] Host cells may be cultured in a nutrient-limited medium, e.g., the host cells are cultured in a medium in which the amount of one or more nutrients is limited. Examples of nutrients that can be limiting are amino acids, lipids, carbohydrates, hormones, growth factors, or vitamins. In some embodiments, TREM-expressing host cells cultured in a medium in which the amount of one or more nutrients is limited, e.g., a nutrient-deficient medium, produce fragments of TREM, e.g., as described herein. In some embodiments, TREM-expressing host cells cultured in a medium in which the amount of one or more nutrients is limited, e.g., a nutrient-deficient medium, produce unloaded TREM (e.g., uTREM).

[0828] Host cells can include immortalized cells, e.g., cells that express one or more enzymes involved in immortalization, e.g., TERT. In certain embodiments, host cells can be propagated indefinitely.

[0829] Host cells can be cultured in suspension or as a monolayer. Host cell culture can be carried out in a cell culture vessel or a bioreactor. Cell culture vessels include cell culture dishes, plates, or flasks. Exemplary cell culture vessels include 35 mm, 60 mm, 100 mm, or 150 mm dishes, multi-well plates (e.g., 6-well, 12-well, 24-well, 48-well, or 96-well plates), or T-25, T-75, or T-160 flasks.

[0830] In some embodiments, the host cells may be cultured in a bioreactor. The bioreactor may be, for example, a continuous flow batch bioreactor, a perfusion bioreactor, a batch process bioreactor, or a fed-batch bioreactor. The bioreactor may be maintained under conditions sufficient to express the TREM. Culture conditions may be adjusted to optimize the yield, purity, or structure of the TREM. In some embodiments, the bioreactor may contain at least 1 x 10 7 , 1×10 8 , 1×10 9, 1×10 10 , 1×10 11 , 1×10 12 , 1×10 13 , or 1 × 10 14 In one embodiment, the bioreactor contains 1 x 10 host cells. 7 ~1×10 14 1 x 10 host cells 7 ~0.5×10 14 1 x 10 host cells 7 ~1×10 13 1 x 10 host cells 7 ~0.5×10 13 1 x 10 host cells 7 ~1×10 12 1 x 10 host cells 7 ~0.5×10 12 1 x 10 host cells 7 ~1×10 11 1 x 10 host cells 7 ~0.5×10 11 1 x 10 host cells 7 ~1×10 10 1 x 10 host cells 7 ~0.5×10 10 1 x 10 host cells 7 ~1×10 9 1 x 10 host cells 7 ~0.5×10 9 1 x 10 host cells 7 ~1×10 8 1 x 10 host cells 7 ~0.5×10 8 0.5 x 10 host cells 8 ~1×10 14 1 x 10 host cells 8 ~1×10 14 0.5 x 10 host cells 9 ~1×10 14 1 x 10 host cells 9 ~1×10 14 0.5 x 10 host cells 10 ~1×10 14 1 x 10 host cells 10 ~1×10 14 0.5 x 10 host cells 11~1×10 14 1 x 10 host cells 11 ~1×10 14 0.5 x 10 host cells 12 ~1×10 14 1 x 10 host cells 12 ~1×10 14 0.5 x 10 host cells 13 ~1×10 14 1 x 10 host cells 13 ~1×10 14 host cells; or 0.5 x 10 13 ~1×10 14 The host cell comprises:

[0831] In one embodiment, the bioreactor contains at least 1 x 10 5 Host cells / mL, 2 x 10 5 Host cells / mL, 3 x 10 5 Host cells / mL, 4 x 10 5 Host cells / mL, 5 x 10 5 Host cells / mL, 6 x 10 5 Host cells / mL, 7 x 10 5 Host cells / mL, 8 x 10 5 Host cells / mL, 9 x 10 5 Host cells / mL, 1 x 10 6 Host cells / mL, 2 x 10 6 Host cells / mL, 3 x 10 6 Host cells / mL, 4 x 10 6 Host cells / mL, 5 x 10 6 Host cells / mL, 6 x 10 6 Host cells / mL, 7 x 10 6 Host cells / mL, 8 x 10 6 Host cells / mL, 9 x 10 6 Host cells / mL, 1 x 10 7 Host cells / mL, 2 x 10 7 Host cells / mL, 3 x 10 7 Host cells / mL, 4 x 10 7 Host cells / mL, 5 x 10 7 Host cells / mL, 6 x 10 7 Host cells / mL, 7 x 10 7 Host cells / mL, 8 x 10 7Host cells / mL, 9 x 10 7 Host cells / mL, 1 x 10 8 Host cells / mL, 2 x 10 8 Host cells / mL, 3 x 10 8 Host cells / mL, 4 x 10 8 Host cells / mL, 5 x 10 8 Host cells / mL, 6 x 10 8 Host cells / mL, 7 x 10 8 Host cells / mL, 8 x 10 8 Host cells / mL, 9 x 10 8 host cells / mL, or 1 x 10 9 In one embodiment, the bioreactor contains 1 x 10 host cells / mL. 5 Host cells / mL~1×10 9 Host cells / mL, 5 x 10 5 Host cells / mL~1×10 9 Host cells / mL, 1 x 10 6 Host cells / mL~1×10 9 Host cells / mL; 5×10 6 Host cells / mL~1×10 9 Host cells / mL, 1 x 10 7 Host cells / mL~1×10 9 Host cells / mL, 5 x 10 7 Host cells / mL~1×10 9 Host cells / mL, 1 x 10 8 Host cells / mL~1×10 9 Host cells / mL, 5 x 10 8 Host cells / mL~1×10 9 Host cells / mL, 1 x 10 5 Host cells / mL~5×10 8 Host cells / mL, 1 x 10 5 Host cells / mL~1×10 8 Host cells / mL, 1 x 10 5 Host cells / mL~5×10 7 Host cells / mL, 1 x 10 5 Host cells / mL~1×10 7 Host cells / mL, 1 x 10 5 Host cells / mL~5×10 6 Host cells / mL, 1 x 10 5 Host cells / mL~1×10 6host cells / mL, or 1 x 10 5 Host cells / mL~5×10 5 containing host cells / mL.

[0832] In one embodiment, the batch process bioreactor comprises a 1×10 6 ~1×10 7 Contains host cells / ml.

[0833] In one embodiment, a batch process bioreactor having a volume of 100 mL contains 1 x 10 8 ~1×10 9 The host cell comprises:

[0834] In one embodiment, a batch process bioreactor having a volume of 100 L contains 1 x 10 11 ~1×10 12 The host cell comprises:

[0835] In one embodiment, the fed-batch bioreactor contains 1 x 10 7 ~3×10 7 Contains host cells / ml.

[0836] In one embodiment, a fed-batch bioreactor with a volume of 100 mL contains 1 x 10 9 ~3×10 9 The host cell comprises:

[0837] In one embodiment, a fed-batch bioreactor with a volume of 100 L contains 1 x 10 12 ~3×10 12 The host cell comprises:

[0838] In one embodiment, the perfusion bioreactor contains 1×10 8 Contains host cells / ml.

[0839] In one embodiment, a perfusion bioreactor with a volume of 100 mL contains 1 x 10 10 The host cell comprises:

[0840] In one embodiment, a perfusion bioreactor with a volume of 100 L contains 1 x 10 13 The host cell comprises:

[0841] In one embodiment, the bioreactor is maintained under conditions that promote host cell growth, for example, at a temperature (e.g., 37°C) and gas concentration (e.g., 5% CO2) that is permissive for host cell growth.

[0842] For example, in some embodiments, a bioreactor unit can perform one or more, or all of the following: feeding nutrients and / or carbon sources, injecting a suitable gas (e.g., oxygen), inflow and outflow of fermentation or cell culture medium, separating gas and liquid phases, maintaining temperature, maintaining oxygen and CO2 levels, maintaining pH levels, agitation (e.g., stirring), and / or purifying / sterilizing. An exemplary bioreactor unit may contain multiple reactors within the unit, e.g., a unit can have 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 or more bioreactors in each unit, and / or a facility may contain multiple units with single or multiple reactors within the facility. Any suitable bioreactor diameter may be used.

[0843] In certain embodiments, a bioreactor can have a volume between about 100 mL and about 100 L. Non-limiting examples include volumes of 100 mL, 250 mL, 500 mL, 750 mL, 1 liter, 2 liters, 3 liters, 4 liters, 5 liters, 6 liters, 7 liters, 8 liters, 9 liters, 10 liters, 15 liters, 20 liters, 25 liters, 30 liters, 40 liters, 50 liters, 60 liters, 70 liters, 80 liters, 90 liters, and 100 liters. Furthermore, suitable reactors can be multi-use, single-use, disposable, or non-disposable, and can be formed from any suitable material, including metal allo...

Claims

[Claim 1] The invention described in the specification.

Images