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WO2025064926A1 - Nouveaux peptides signal sécrétoires et leurs utilisations - Google Patents

Nouveaux peptides signal sécrétoires et leurs utilisations Download PDF

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Publication number
WO2025064926A1
WO2025064926A1 PCT/US2024/047828 US2024047828W WO2025064926A1 WO 2025064926 A1 WO2025064926 A1 WO 2025064926A1 US 2024047828 W US2024047828 W US 2024047828W WO 2025064926 A1 WO2025064926 A1 WO 2025064926A1
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Prior art keywords
amino acid
seq
formula
signal peptide
acid sequence
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Inventor
Daniel J. Siegwart
Lukas FARBIAK
William Miller
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University of Texas System
University of Texas at Austin
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University of Texas System
University of Texas at Austin
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85—Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/87—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
    • C12N15/88—Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation using microencapsulation, e.g. using amphiphile liposome vesicle
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/60—Fusion polypeptide containing spectroscopic/fluorescent detection, e.g. green fluorescent protein [GFP]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/61—Fusion polypeptide containing an enzyme fusion for detection (lacZ, luciferase)

Definitions

  • Sequence Listing [0002] This application contains references to amino acid sequences and/or nucleic acid sequences which have been submitted concurrently herewith as the sequence listing xml file entitled “823037_sequencelisting.xml”, file size 36,864 bytes, created on September 20, 2024. The aforementioned sequence listing is hereby incorporated by reference in its entirety pursuant to 37 C.F.R. ⁇ 1.52(e)(5).
  • Field [0003] The present disclosure relates generally to novel signal peptides and more particularly to novel secretory signal peptides for directing an encoded protein to be exported from the cell.
  • a signal peptide is provided.
  • the signal peptide comprises an amino acid sequence selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX.
  • Formula I is represented as: A 1 -A 2 -A 3 -A 4 -A 5 (Formula I) and the identities of A 1 -A 5 are as provided in Table 2; wherein Formula II is represented as: B 1 -B 2 -B 3 -B 4 -B 5 -B 6 -B 7 -B 8 -B 9 -B 10 -B 11 -B 12 -B 13 -B 14 -B 15 (Formula II) and the identities of B 1 -B 15 are as provided in Table 3; wherein Formula III is represented as: C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8
  • Formula XIX is represented as: S 1 -S 2 -S 3 -S 4 -S 5 -S 6 -S 7 -S 8 -S 9 -S 10 -S 11 -S 12 -S 13 -S 14 -S 15 -S 16 -S 17 -S 18 -S 19 -S 20 -S 21 -S 22 -S 23 -S 24 -S 25 -S 26 - S 27 -S 28 -S 29 -S 30 -S 31 -S 32 (Formula XIX) and the identities of S 1 -S 32 are as provided in Table 20; wherein Formula XX is represented as: T 1 -T 2 -T 3 -T 4 -T 5 -T 6 -T 7 -T 8 -T 9 -T 10 -T 11 -T 12 -T 13 -T 14 -T 15
  • the signal peptide comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 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, 31, 32, or 33.
  • a signal peptide comprising an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 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, 31, 32, or 33.
  • a signal peptide as provided for herein is a novel signal peptide.
  • a recombinant polypeptide is provided.
  • the recombinant polypeptide comprises a formula of X 1 -(Y 1 ) a -Z 1 , wherein X 1 is a signal peptide, Y 1 is a peptide linker, and Z 1 is a payload protein, wherein a is an integer selected from 0 and 1.
  • the signal peptide X 1 comprises an amino acid sequence selected from the group consisting of Formula I, II, III, IV, V, VI, VII, VIII, IX, X, XI, XII, XIII, XIV, XV, XVI, XVII, XVIII, XIX.
  • Formula I is represented as: A 1 -A 2 -A 3 -A 4 -A 5 (Formula I) and the identities of A 1 -A 5 are as provided in Table 2; wherein Formula II is represented as: B 1 -B 2 -B 3 -B 4 -B 5 -B 6 -B 7 -B 8 -B 9 -B 10 -B 11 -B 12 -B 13 -B 14 -B 15 (Formula II) ACTIVE/131743364.1 6 Attorney Docket No.
  • Formula XIII is represented as: M 1 -M 2 -M 3 -M 4 -M 5 -M 6 -M 7 -M 8 -M 9 -M 10 -M 11 -M 12 -M 13 -M 14 -M 15 -M 16 -M 17 -M 18 -M 19 -M 20 -M 21 - M 22 -M 23 -M 24 -M 25 -M 26 (Formula XIII) and the identities of M 1 -M 26 are as provided in Table 14; wherein Formula XIV is represented as: N 1 -N 2 -N 3 -N 4 -N 5 -N 6 -N 7 -N 8 -N 9 -N 10 -N 11 -N 12 -N 13 -N 14 -N 15 -N 16 -N 17 -N 18 -N 19 -N 20 -N 21 -
  • the signal peptide X 1 comprises an amino acid sequence having at least 70%, 75%, 80%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 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, 31, 32, or 33.
  • the payload protein is a therapeutic peptide or protein.
  • a nucleic acid molecule is provided. In some embodiments, the nucleic acid molecule encodes for a signal peptide as provided for herein.
  • a nucleic acid molecule is provided. In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein.
  • a vector is provided. In some embodiments, the vector comprises a nucleic acid molecule as provided for herein. In some embodiments, the nucleic acid molecule encodes for a signal peptide as provided for herein.
  • the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein.
  • a cell is provided. In some embodiments, the cell comprises a nucleic acid molecule as provided for herein. In some embodiments, the cell comprises a vector as provided for herein. In some embodiments, the nucleic acid molecule encodes for a signal peptide as provided for herein. In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein. [0018] In some embodiments, a composition is provided. In some embodiments, the composition comprises a nucleic acid molecule as provided for herein.
  • the composition comprises a vector as provided for herein.
  • the nucleic acid molecule encodes for a signal peptide as provided for herein.
  • the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein.
  • a method for treating a disease or disorder in a subject in need thereof is provided.
  • the method comprises administering to the subject an effective among of a nucleic acid molecule as provided for herein to the subject, thereby treating the disease or disorder.
  • the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein.
  • the disease or disorder is cancer.
  • a method for treating cancer in a subject in need thereof comprises administering to the subject a vector comprising a nucleic acid molecule encoding for a signal peptide fused or linked to a payload ACTIVE/131743364.1 11 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT protein, wherein the signal peptide is a signal peptide as provided for herein and the payload protein is a therapeutic peptide or protein useful for the treatment of cancer.
  • FIG. 1A provides a schematic of the construct comprising mCherry with the signal peptide at the N-terminus and its use for signal peptide screening by pDNA transfection in vitro.
  • FIG. 1B illustrates the quantification of mCherry signal assessment in the media of cells transfected with pDNA encoding mCherry with or without a signal peptide as provided for herein directly upstream of the mCherry sequence.
  • FIG. 1C illustrates the quantification of mCherry signal assessment in the media of cells transfected with pDNA encoding mCherry with or without a signal peptide as provided for herein directly upstream of the mCherry sequence.
  • FIG. 1B illustrates the quantification of mCherry signal assessment in the media of cells transfected with pDNA encoding mCherry with or without a signal peptide as provided for herein directly upstream of the mCherry sequence.
  • FIG. 2A provides quantification of mCherry fluorescence in Hela cell lysates and medium at different time points. mCherry with no signal peptide was used as a control (“WT- mCherry”). gLuc, Gaussia luciferase. [0025]
  • FIG. 2B provides quantification of mCherry fluorescence in Hela cell lysate and medium after 72 hours.
  • FIG. 2C provides quantification of mCherry fluorescence in Huh7 cell lysates and medium at 72h after transfection.
  • FIG.3A provides quantification of time-dependent (100 ng mRNA per well) and dose dependent (at 72h) mCherry secretion in Huh7 cells, medium, and cell lysate.
  • FIG. 3B shows quantification of mCherry signal in different cell lines. Cells in 96- well plate were treated with mDLNPs-mRNA, at given time-points.
  • a and B refers to A, B, or a combination of both A and B.
  • a and B refers to a combination of A and B.
  • the numbers expressing quantities of ingredients, properties such as molecular weight, reaction conditions, and so forth, used to describe and claim certain embodiments are to be understood as being modified in some instances by the term "about” or “approximately.”
  • “about” or “approximately” can indicate +/- 10%, +/- 5%, or +/- 1% variation of the value it describes.
  • the numerical parameters set forth herein are approximations that can vary depending upon the desired properties for a particular embodiment. Additionally, where a phrase recites “about x to y,” the term “about” modifies both x and y and can be used interchangeably with the phrase “about x to about y” unless context dictates differently.
  • transformation and “transfection” are intended to refer to a variety of art-recognized techniques for introducing foreign nucleic acid into a host cell, including calcium phosphate or calcium chloride co-precipitation, DEAE-dextran-mediated transfection, lipofection (e.g., using commercially available reagents such as, for example, LIPOFECTIN® (Invitrogen Corp., San Diego, CA), LIPOFECTAMINE® (Invitrogen), ACTIVE/131743364.1 13 Attorney Docket No.
  • LIPOFECTIN® Invitrogen Corp., San Diego, CA
  • LIPOFECTAMINE® Invitrogen
  • ACTIVE/131743364.1 13 Attorney Docket No.
  • Suitable methods for transforming or transfecting host cells can be found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual.2nd, ed., Cold Spring Harbor Laboratory, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., 1989), and other laboratory manuals.
  • Methods and materials of non-viral delivery of nucleic acids to cells further include biolistics, virosomes, liposomes, lipid nanoparticles, immunoliposomes, polycation or lipid- nucleic acid conjugates, naked DNA, artificial virions, and agent-enhanced uptake of DNA.
  • Lipofection is described in U.S. Pat. Nos.5,049,386, 4,946,787; and 4,897,355 and lipofection reagents are sold commercially (e.g., TRANSFECTAMTM and LIPOFECTINTM).
  • Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those disclosed in WO91/17424 and WO 91/16024.
  • the chemical makeup of a peptide will be described herein by a series of amino acid single letter abbreviations or an “amino acid sequence/s” or “sequence/s,” which are conventional and known to those in the art. While reference sequences will be explicitly disclosed, in any aspect and embodiment, a reference sequence may be modified to include conservative amino acid substitutions, as well as variants and fragments, while maintaining the characteristics and functionality of the reference sequence.
  • the term “fused” or “linked” when used in reference to a protein having different domains or heterologous sequences means that the protein domains are part of the same peptide chain that are connected to one another with either peptide bonds or other covalent bonding.
  • the domains or section can be linked or fused directly to one another or another domain or peptide sequence can be between the two domains or sequences and such sequences would still be considered to be fused or linked to one another.
  • ACTIVE/131743364.1 14 Attorney Docket No.
  • UTSD 4319 (106546-823037)(SIGY-005WO) PATENT the various domains or proteins provided for herein are linked or fused directly to one another or a linker sequences, such as the glycine/serine sequences described herein link the two domains together.
  • “Identity” as used herein refers to the subunit sequence identity between two polymeric molecules such as between two nucleic acid or amino acid molecules, such as, between two polynucleotide or polypeptide molecules. When two amino acid sequences have the same residues at the same positions; e.g., if a position in each of two polypeptide molecules is occupied by an Arginine, then they are identical at that position.
  • the identity or extent to which two amino acid or two nucleic acid sequences have the same residues at the same positions in an alignment is often expressed as a percentage.
  • the identity between two amino acid or two nucleic acid sequences is a direct function of the number of matching or identical positions; e.g., if half of the positions in two sequences are identical, the two sequences are 50% identical; if 90% of the positions (e.g., 9 of 10), are matched or identical, the two amino acids sequences are 90% identical.
  • substantially identical is meant a polypeptide or nucleic acid molecule exhibiting at least 50% identity to a reference amino acid sequence (for example, any one of the amino acid sequences described herein) or nucleic acid sequence (for example, any one of the nucleic acid sequences described herein). In some embodiments, such a sequence is at least 60%, 80% or 85%, or 90%, 95% or even 99% identical at the amino acid level or nucleic acid to the sequence used for comparison. Other percentages of identity in reference to specific sequences are described herein.
  • Sequence identity can be measured/determined using sequence analysis software (for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis.53705, BLAST, BESTFIT, GAP, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, MUSCLE or PILEUP/PRETTYBOX programs).
  • sequence analysis software for example, Sequence Analysis Software Package of the Genetics Computer Group, University of Wisconsin Biotechnology Center, 1710 University Avenue, Madison, Wis.53705, BLAST, BESTFIT, GAP, BLAST-2, ALIGN, MEGALIGN (DNASTAR), CLUSTALW, CLUSTAL OMEGA, MUSCLE or PILEUP/PRETTYBOX programs.
  • Conservative substitutions typically include substitutions within the following groups: glycine, alanine; valine, isoleucine, leucine; aspartic acid, glutamic acid, asparagine, glutamine; serine, threonine; lysine, arginine; and phenylalanine, tyrosine.
  • a BLAST program may be used, with a probability score between e3 and e100 indicating a closely related sequence.
  • sequence identity is determined by using BLAST with the default settings.
  • sequence identity is determined using Clustal Omega. ACTIVE/131743364.1 15 Attorney Docket No.
  • composition comprising various proteins
  • these proteins may, in some instances, comprise amino acid sequences that have sequence identity to the amino acid sequences disclosed herein. Therefore, in certain embodiments, depending on the particular sequence, the degree of sequence identity is preferably greater than 50% (e.g., 60%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or more) to the SEQ ID NOs disclosed herein. In addition to these percentages, other percentages of identity are provided for herein.
  • the proteins may have one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) single amino acid deletions relative to the disclosed protein sequences.
  • the proteins may also include one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, etc.) insertions (e.g., each of 1, 2, 3, 4 or 5 amino acids) relative to the disclosed protein sequences.
  • “Encoding” refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (i.e., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom.
  • a gene encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system.
  • Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA.
  • nucleic acid bases As used herein, the following abbreviations for the commonly occurring nucleic acid bases are used: “A” refers to adenosine, “C” refers to cytosine, “G” refers to guanosine, “T” refers to thymidine, and “U” refers to uridine. [0045] Unless otherwise specified, a “nucleotide sequence encoding an amino acid sequence” includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence.
  • nucleotide sequence that encodes a protein or an RNA may also include introns to the extent that the nucleotide sequence encoding the protein may in some versions contain an intron(s).
  • oligonucleotide typically refers to short polynucleotides. It will be understood that when a nucleotide sequence is represented by a DNA sequence (i.e., A, T, C, G), this also provides the corresponding RNA sequence (i.e., A, U, C, G) in which “U” replaces [0047]
  • polynucleotide as used herein is defined as a chain of nucleotides.
  • nucleic acids are polymers of nucleotides.
  • nucleic acids or “nucleic acid molecules” and “polynucleotides” as used herein are interchangeable.
  • polynucleotides include, but are not limited to, all nucleic acid sequences which are obtained by any methods available in the art, including, without limitation, recombinant methods, i.e., the cloning of nucleic acid sequences from a recombinant library or a cell genome, using cloning technology and PCR, and the like, and by synthetic means.
  • peptide As used herein, the terms “peptide,” “polypeptide,” and “protein” are used interchangeably, and refer to a compound comprised of a plurality of amino acid residues covalently linked by peptide bonds. As used herein, the term refers to both short chains, which also commonly are referred to in the art as peptides, oligopeptides and oligomers, for example, and to longer chains, which generally are referred to in the art as proteins, of which there are many types.
  • Polypeptides include, for example, biologically active fragments, substantially homologous polypeptides, oligopeptides, homodimers, heterodimers, variants of polypeptides, modified polypeptides, derivatives, analogs, fusion proteins, among others.
  • the polypeptides include natural peptides, recombinant peptides, synthetic peptides, or a combination thereof.
  • antibody fragment or “antigen binding fragment” refers to antigen binding fragments of antibodies, i.e. antibody fragments that retain the ability to bind specifically to the antigen bound by the full-length antibody, e.g., fragments that retain one or more CDR regions.
  • antibody binding fragments include, but are not limited to, Fab, Fab', F(ab') 2 , and Fv fragments; diabodies; linear antibodies; single- ACTIVE/131743364.1 17 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT chain antibody molecules, e.g., sc-Fv; nanobodies (single domain antibody) and multispecific antibodies formed from antibody fragments.
  • a “Fab fragment” is comprised of one light chain and the C H 1 and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.
  • An “Fc” region contains two heavy chain fragments comprising the C H 2 and C H 3 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.
  • a “Fab' fragment” contains one light chain and a portion or fragment of one heavy chain that contains the V H domain and the C H 1 domain and also the region between the C H 1 and C H 2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab') 2 molecule.
  • a “F(ab') 2 fragment” contains two light chains and two heavy chains containing a portion of the constant region between the C H 1 and C H 2 domains, such that an interchain disulfide bond is formed between the two heavy chains.
  • a F(ab') 2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.
  • the “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.
  • the term “single-chain Fv” or “scFv” antibody refers to antibody fragments comprising the V H and V L domains of an antibody, wherein these domains are present in a single polypeptide chain.
  • the Fv polypeptide further comprises a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
  • a polypeptide linker between the V H and V L domains which enables the scFv to form the desired structure for antigen binding.
  • Antibody molecules can be monospecific (e.g., monovalent or bivalent), bispecific (e.g., bivalent, trivalent, tetravalent, pentavalent, or hexavalent), trispecific (e.g., trivalent, tetravalent, pentavalent, or hexavalent), or with higher orders of specificity (e.g, tetraspecific) and/or higher orders of valency beyond hexavalency.
  • An antibody molecule can comprise a functional fragment of a light chain variable region and a functional fragment of a heavy chain variable region, or heavy and light chains may be fused together into a single polypeptide.
  • any step or composition that uses the transitional phrase of “comprise” or “comprising” can also be said to describe the same with the transitional phase of “consisting of” or “consists.”
  • the term “contacting” means bringing together of two elements in an in vitro system or an in vivo system.
  • “contacting” virus or vector described herein with an individual or patient or cell includes the administration of the virus to an individual or patient, such as a human, as well as, for example, introducing a compound into a sample containing a cellular or purified preparation containing the cell.
  • the term “individual” or “subject,” or “patient” used interchangeably, means any animal, including mammals, such as mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, such as humans.
  • the subject is a human.
  • a subject that is “in need thereof” refers to a subject that has been identified as requiring treatment for the condition that is to be treated and is treated with the specific intent of treating such condition.
  • the conditions can be, for example, any of the conditions described herein.
  • the compositions disclosed herein may be provided to a subject in a variety of ways through administration of the composition to the subject.
  • administer or administration means to provide or the providing of a composition to a subject.
  • Oral administration refers to delivery of an active agent through the mouth.
  • Topical administration refers to the delivery of an active agent to a body surface, such as the skin, a mucosal membrane (e.g., nasal membrane, vaginal membrane, buccal membrane, or the like).
  • a “disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.
  • a “disorder” in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal’s state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal’s state of health.
  • Effective amount or “therapeutically effective amount” are used interchangeably herein, and refer to an amount of a compound, formulation, material, or composition, as described herein effective to achieve a particular biological result or provides a therapeutic or prophylactic benefit. Such results may include, but are not limited to an amount that when ACTIVE/131743364.1 19 Attorney Docket No.
  • UTSD 4319 (106546-823037)(SIGY-005WO) PATENT administered to a mammal causes a detectable level of immune cell activation compared to the immune cell activation detected in the absence of the composition.
  • the immune response can be readily assessed by a plethora of art-recognized methods.
  • the skilled artisan would understand that the amount of the composition administered herein varies and can be readily determined based on a number of factors such as the disease or condition being treated, the age and health and physical condition of the mammal being treated, the severity of the disease, the particular compound being administered, and the like. [0063] Ranges: throughout this disclosure, various aspects of the embodiments can be presented in a range format.
  • range format is merely for convenience and brevity and should not be construed as an inflexible limitation. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 2.7, 3, 4, 5, 5.3, and 6. This applies regardless of the breadth of the range. Unless otherwise explicitly stated to the contrary, a range that is disclosed also includes the endpoints of the range.
  • novel signal peptides may direct payload proteins as provided for herein to be secreted from the cell.
  • the payload proteins may or may not natively contain a signal peptide directing localization of said protein to the specific cellular compartment, e.g., secreted from the cell.
  • the provided novel signal peptides can direct enhanced expression and secretion of a protein that natively contains a secretory signal peptide, or can direct secretion of a payload protein that does not natively contain a secretory signal peptide, e.g., a therapeutic protein, from the cell.
  • a signal peptide is provided.
  • the signal peptide comprises an amino acid sequence as recited in Table 1 below: Table 1: Exemplary Novel Signal Peptides ACTIVE/131743364.1 20 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT ACTIVE/131743364.1 21 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT [0066]
  • the signal peptide comprises an amino acid sequence that is substantially similar to an amino acid sequence as recited in Table 1.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence as recited in Table 1.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 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, 31, 32, or 33.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 1.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 2.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 3.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 4.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 5.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 6.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 7.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) ACTIVE/131743364.1 22 Attorney Docket No.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 9.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 10.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 11.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 12.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 13.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 14.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 15.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 16.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 17.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 18.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an ACTIVE/131743364.1 23 Attorney Docket No.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 20.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 21.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 22.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 23.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 24.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 25. In some embodiments, the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 26.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 27. In some embodiments, the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 28.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 29.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an ACTIVE/131743364.1 24 Attorney Docket No.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 31.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 32.
  • the signal peptide comprises an amino acid sequence that is at least 70% (e.g., at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100%) identical to an amino acid sequence of SEQ ID NO: 33.
  • the signal peptide is a variant of an amino acid sequence as provided in Table 1.
  • the signal peptide comprises an amino acid sequence as defined by Formula I-XXXIII below.
  • Variants of SEQ ID NO: 1 [0069]
  • the signal peptide comprises an amino acid sequence represented by: A 1 -A 2 -A 3 -A 4 -A 5 (Formula I); wherein the identity of each of A 1 – A 5 are as provided for in Table 2 below.
  • Table 2 [0070]
  • a 1 is methionine (M).
  • a 2 is amino acid selected from the group consisting of G and V.
  • A3 is amino acid selected from the group consisting of S and P.
  • A4 is serine (S).
  • a 5 is glycine (G).
  • a variant of SEQ ID NO: 1 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one ACTIVE/131743364.1 25 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT substitution to be within the scope of Formula I.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 1 and a substitution at position 2 of SEQ ID NO: 1.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 1 and a substitution at position 3 of SEQ ID NO: 1.
  • the variant may also comprise any number of substitutions as provided by Formula I. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 1 and a substitution at at least one position corresponding to position 2 or 3 of SEQ ID NO: 1. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 1 and a substitution at more than one position corresponding to position 2 or 3 of SEQ ID NO: 1.
  • the signal peptide comprises an amino acid sequence represented by: B 1 -B 2 -B 3 -B 4 -B 5 -B 6 -B 7 -B 8 -B 9 -B 10 -B 11 -B 12 -B 13 -B 14 -B 15 (Formula II); wherein the identity of each of B 1 – B 15 are as provided for in Table 3 below.
  • Table 3 ACTIVE/131743364.1 26
  • B 1 is methionine (M).
  • B 2 is an amino acid selected from the group consisting of K, L, N, and R.
  • B 3 is an amino acid selected from the group consisting of L, P, and V.
  • B 4 is an amino acid selected from the group consisting of L and F.
  • B 5 is an amino acid selected from the group consisting of L, V, and I.
  • B 6 is an amino acid selected from the group consisting of L and I.
  • B 7 is an amino acid selected from the group consisting of L and A.
  • B 8 is an amino acid selected from the group consisting of A, L, V, G, C, and F.
  • B 9 is an amino acid selected from the group consisting of L, F, T, and I.
  • B 10 is an amino acid selected from the group consisting of L and V.
  • B 11 is an amino acid selected from the group consisting of A, G, T, and L.
  • B 12 is an amino acid selected from the group consisting of L, A, and V.
  • B 13 is an amino acid selected from the group consisting of A, C, V, and S.
  • B 14 is an amino acid selected from the group consisting of L, A, W, and V.
  • B 15 is an amino acid selected from the group consisting of A and C.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 2 of SEQ ID NO: 2.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 3 of SEQ ID NO: 2.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 4 of SEQ ID NO: 2.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 5 of SEQ ID NO: 2. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 6 of SEQ ID NO: 2. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 7 of SEQ ID NO: 2. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 8 of SEQ ID NO: 2. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 9 of SEQ ID NO: 2.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 10 of SEQ ID NO: 2. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 11 of SEQ ID NO: 2. In some embodiments, the signal peptide ACTIVE/131743364.1 27 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 12 of SEQ ID NO: 2. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 13 of SEQ ID NO: 2.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 14 of SEQ ID NO: 2. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 15 of SEQ ID NO: 2. The variant may also comprise any number of substitutions as provided by Formula II. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 2.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 2.
  • Variants of SEQ ID NO: 3 (Formula III)
  • the signal peptide comprises an amino acid sequence represented by: C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 (Formula III); wherein the identity of each of C1 – C16 are as provided for in Table 4 below.
  • C1 is methionine (M).
  • C2 is an amino acid selected from the group consisting of L, K, and R.
  • C3 is an amino acid selected from the group consisting of L, T, V, and P.
  • C 4 is leucine (L).
  • C 5 is leucine (L).
  • C 6 is an amino acid selected from the group consisting of L, I, and V.
  • C 7 is an amino acid selected from the group consisting of L, V, and F.
  • C 8 is an amino acid selected from the group consisting of L, S, V, A.
  • C 9 is an amino acid selected from the group consisting of L, A, and C.
  • C 10 is leucine (L).
  • C 11 is an amino acid selected from the group consisting of L and V.
  • C 12 is an amino acid selected from the group consisting of G, A, and L.
  • C13 is an amino acid selected from the group consisting of L, A, S, and G.
  • C14 is an amino acid selected from the group consisting of A, S, T, and V.
  • C 15 is an amino acid selected from the group consisting of L, S, and W..
  • C 16 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 2 of SEQ ID NO: 3.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 3 of SEQ ID NO: 3.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 6 of SEQ ID NO: 3.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 7 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 8 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 9 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of ACTIVE/131743364.1 29 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT SEQ ID NO: 3 and a substitution at position 11 of SEQ ID NO: 3.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 12 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 13 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 14 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 15 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 16 of SEQ ID NO: 3.
  • the variant may also comprise any number of substitutions as provided by Formula III.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at at least one position corresponding to position 2, 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, or 16 of SEQ ID NO: 3.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at more than one position corresponding to position 2, 3, 6, 7, 8, 9, 11, 12, 13, 14, 15, or 16 of SEQ ID NO: 3.
  • the signal peptide comprises an amino acid sequence represented by: D 1 -D 2 -D 3 -D 4 -D 5 -D 6 -D 7 -D 8 -D 9 -D 10 -D 11 -D 12 -D 13 -D 14 -D 15 -D 16 -D 17 (Formula IV); wherein the identity of each of D 1 – D 17 are as provided for in Table 5 below.
  • Table 5 ACTIVE/131743364.1 30 Attorney Docket No.
  • D 1 is methionine (M).
  • D 2 is an amino acid selected from the group consisting of L, A, G, R, and W.
  • D 3 is an amino acid selected from the group consisting of L and A.
  • D 4 is an amino acid selected from the group consisting of L and F.
  • D5 is an amino acid selected from the group consisting of L, A, and V.
  • D 6 is an amino acid selected from the group consisting of L, V, I, and F.
  • D 7 is an amino acid selected from the group consisting of L and F.
  • D 8 is an amino acid selected from the group consisting of L and F.
  • D 9 is an amino acid selected from the group consisting of L and A.
  • D 10 is an amino acid selected from the group consisting of L, A, and S.
  • D 11 is an amino acid selected from the group consisting of L and F.
  • D 12 is an amino acid selected from the group consisting of L and A.
  • D 13 is an amino acid selected from the group consisting of A, G, L, and P.
  • D 14 is an amino acid selected from the group consisting of L, G, and A.
  • D15 is an amino acid selected from the group consisting of A, V, S, L, and T.
  • D 16 is an amino acid selected from the group consisting of L and Q.
  • D 17 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 3 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a ACTIVE/131743364.1 31 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT substitution at position 4 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 5 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 6 of SEQ ID NO: 4.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 7 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 8 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 9 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 10 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 11 of SEQ ID NO: 4.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 12 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 13 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 14 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 15 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 16 of SEQ ID NO: 4.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 17 of SEQ ID NO: 4.
  • the variant may also comprise any number of substitutions as provided by Formula IV. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of SEQ ID NO: 4. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17 of SEQ ID NO: 4.
  • the signal peptide comprises an amino acid sequence represented by: E 1 -E 2 -E 3 -E 4 -E 5 -E 6 -E 7 -E 8 -E 9 -E 10 -E 11 -E 12 -E 13 -E 14 -E 15 -E 16 -E 17 -E 18 (Formula V); wherein the identity of each of E 1 – E 18 are as provided for in Table 6 below.
  • ACTIVE/131743364.1 32 Attorney Docket No.
  • E1 is methionine (M).
  • E2 is an amino acid selected from the group consisting of K, L, A, and R.
  • E 3 is leucine (L).
  • E 4 is an amino acid selected from the group consisting of L and V.
  • E 5 is leucine (L).
  • E 6 is an amino acid selected from the group consisting of L and V.
  • E 7 is an amino acid selected from the group consisting of L, V, and F.
  • E 8 is an amino acid selected from the group consisting of L, I, and V.
  • E 9 is an amino acid selected from the group consisting of L and F.
  • E 10 is leucine (L).
  • E 11 is an amino acid selected from the group consisting of L, S, and A.
  • E12 is leucine (L).
  • E13 is an amino acid selected from the group consisting of L and V.
  • E14 is an amino acid selected from the group consisting of G, L, and S.
  • E 15 is an amino acid selected from the ACTIVE/131743364.1 33 Attorney Docket No.
  • E 16 is an amino acid selected from the group consisting of V, A, T, and C.
  • E 17 is an amino acid selected from the group consisting of L, Q, and S.
  • E 18 is an amino acid selected from the group consisting of A, G, and S. [0087] It is to be understood that a variant of SEQ ID NO: 5 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula V.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 2 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 4 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 6 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 7 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 8 of SEQ ID NO: 5.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 9 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 11 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 13 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 14 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 15 of SEQ ID NO: 5.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 16 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 17 of SEQ ID NO: 5. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 18 of SEQ ID NO: 5.
  • the variant may also comprise any number of substitutions as provided by Formula V. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at at least one position corresponding to position 2, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 17, or 18 of SEQ ID NO: 5.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at more than one position corresponding to position 2, 4, 6, 7, 8, 9, 11, 13, 14, 15, 16, 17, or 18 of SEQ ID NO: 5.
  • ACTIVE/131743364.1 34 Attorney Docket No.
  • the signal peptide comprises an amino acid sequence represented by: F 1 -F 2 -F 3 -F 4 -F 5 -F 6 -F 7 -F 8 -F 9 -F 10 -F 11 -F 12 -F 13 -F 14 -F 15 -F 16 -F 17 -F 18 -F 19 (Formula VI); wherein the identity of each of F 1 – F 19 are as provided for in Table 7 below.
  • Table 7 [0090]
  • F 1 is methionine (M).
  • F 2 is an amino acid selected from the group consisting of A, K, R, and D.
  • F 3 is an amino acid selected from the group consisting of L, W, F, and A.
  • F 4 is an amino acid selected from the group consisting of L, T, A, and G.
  • F 5 is an amino acid selected from the group consisting of L and P.
  • F6 is ACTIVE/131743364.1 35 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT an amino acid selected from the group consisting of L and S.
  • F 7 is an amino acid selected from the group consisting of L, A, and W.
  • F 8 is an amino acid selected from the group consisting of L, V, and A.
  • F 9 is an amino acid selected from the group consisting of L and F.
  • F 10 is leucine (L).
  • F 11 is an amino acid selected from the group consisting of L and V.
  • F 12 is an amino acid selected from the group consisting of L and A.
  • F 13 is an amino acid selected from the group consisting of L and V.
  • F14 is an amino acid selected from the group consisting of L, A, and C.
  • F 15 is an amino acid selected from the group consisting of T and A.
  • F 16 is an amino acid selected from the group consisting of G and L.
  • F 17 is an amino acid selected from the group consisting of V, A, and S.
  • F 18 is an amino acid selected from the group consisting of L, Q, and H.
  • F 19 is an amino acid selected from the group consisting of A, S, G, and C.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 3 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 4 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 5 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 6 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 7 of SEQ ID NO: 6.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 8 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 9 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 11 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 12 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 13 of SEQ ID NO: 6.
  • the signal peptide comprises the amino acid sequence of ACTIVE/131743364.1 36 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT SEQ ID NO: 6 and a substitution at position 14 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 15 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 16 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 17 of SEQ ID NO: 6.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 18 of SEQ ID NO: 6. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 19 of SEQ ID NO: 6.
  • the variant may also comprise any number of substitutions as provided by Formula VI. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, or 19 of SEQ ID NO: 6.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, or 19 of SEQ ID NO: 6.
  • Variants of SEQ ID NO: 7 (Formula VII)
  • the signal peptide comprises an amino acid sequence represented by: G 1 -G 2 -G 3 -G 4 -G 5 -G 6 -G 7 -G 8 -G 9 -G 10 -G 11 -G 12 -G 13 -G 14 -G 15 -G 16 -G 17 -G 18 -G 19 -G 20 (Formula VII); wherein the identity of each of G 1 – G 20 are as provided for in Table 8 below.
  • G 1 is methionine (M).
  • G 2 is an amino acid selected from the group consisting of A and K.
  • G 3 is an amino acid selected from the group consisting of L, S, and P.
  • G 4 is an amino acid selected from the group consisting of L and P.
  • G 5 is an amino acid selected from the group consisting of L and A.
  • G 6 is leucine (L).
  • G7 is an amino acid selected from the group consisting of L and V.
  • G8 is an amino acid selected from the group consisting of L and A.
  • G 9 is leucine (L).
  • G 10 is an amino acid selected from the group consisting of L and V.
  • G 11 is leucine (L).
  • G 12 is an amino acid selected from the group consisting of L and A.
  • G 13 is leucine (L).
  • G 14 is an amino acid selected from the group consisting of L and A.
  • G 15 is an amino acid selected from the group consisting of L, V, and A.
  • G 16 is an amino acid selected from the group consisting of G, P, A, S, and L.
  • G 17 is an amino acid selected from the group consisting of G, V, L, and S.
  • G 18 is an amino acid selected from the group consisting of A, V, S, and T.
  • G19 is an amino acid selected from the group consisting of L and A.
  • G20 is an amino acid selected from the group consisting of A, G, and S.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 2 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 3 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 4 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 5 of SEQ ID NO: 7.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 7 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 8 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 10 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 12 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 14 of SEQ ID NO: 7.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 15 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 16 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 17 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 18 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 19 of SEQ ID NO: 7.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 20 of SEQ ID NO: 7.
  • the variant may also comprise any number of substitutions as provided by Formula VII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 7, 8, 10, 12, 14, 15, 16, 17, 18, 19, or 20 of SEQ ID NO: 7. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 7, 8, 10, 12, 14, 15, 16, 17, 18, 19, or 20 of SEQ ID NO: 7.
  • the signal peptide comprises an amino acid sequence represented by: ACTIVE/131743364.1 39 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT H 1 -H 2 -H 3 -H 4 -H 5 -H 6 -H 7 -H 8 -H 9 -H 10 -H 11 -H 12 -H 13 -H 14 -H 15 -H 16 -H 17 -H 18 -H 19 -H 20 -H 21 (Formula VIII); wherein the identity of each of H 1 – H 21 are as provided for in Table 9 below.
  • H 1 is methionine (M).
  • H 2 is an amino acid selected from the group consisting of A and K.
  • H 3 is an amino acid selected from the group consisting of L, P, A, and V.
  • H 4 is an amino acid selected from the group consisting of L and S.
  • H 5 is an amino acid selected from the group consisting of L and V.
  • H 6 is an ACTIVE/131743364.1 40 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT amino acid selected from the group consisting of L and A.
  • H 7 is leucine (L).
  • H 8 is an amino acid selected from the group consisting of L and A.
  • H 9 is an amino acid selected from the group consisting of L and A.
  • H 10 is an amino acid selected from the group consisting of L and V.
  • H 11 is leucine (L).
  • H 12 is an amino acid selected from the group consisting of L and V.
  • H 13 is an amino acid selected from the group consisting of L and A.
  • H 14 is an amino acid selected from the group consisting of L and A.
  • H15 is an amino acid selected from the group consisting of L, A, and C.
  • H 16 is an amino acid selected from the group consisting of L and A.
  • H 17 is an amino acid selected from the group consisting of L, A, and T.
  • H 18 is an amino acid selected from the group consisting of L and P.
  • H 19 is an amino acid selected from the group consisting of A, V, S, and G.
  • H 20 is an amino acid selected from the group consisting of Q and L.
  • H 21 is an amino acid selected from the group consisting of A, G, and S.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 2 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 3 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 4 of SEQ ID NO: 8.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 5 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 6 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 8 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 9 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 10 of SEQ ID NO: 8.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 12 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 13 of SEQ ID NO: 8. In some embodiments, the signal peptide ACTIVE/131743364.1 41 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 14 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 15 of SEQ ID NO: 8.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 16 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 17 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 18 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 19 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 20 of SEQ ID NO: 8.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 21 of SEQ ID NO: 8.
  • the variant may also comprise any number of substitutions as provided by Formula VIII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of SEQ ID NO: 8. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 of SEQ ID NO: 8.
  • the signal peptide comprises an amino acid sequence represented by: I 1 -I 2 -I 3 -I 4 -I 5 -I 6 -I 7 -I 8 -I 9 -I 10 -I 11 -I 12 -I 13 -I 14 -I 15 -I 16 -I 17 -I 18 -I 19 -I 20 -I 21 -I 22 (Formula IX); wherein the identity of each of I 1 – I 22 are as provided for in Table 10 below.
  • Table 10 ACTIVE/131743364.1 42 Attorney Docket No.
  • I 1 is methionine (M).
  • I 2 is an amino acid selected from the group consisting of R, A, K, and D.
  • I 3 is an amino acid selected from the group consisting of L and P.
  • I 4 is an amino acid selected from the group consisting of L, R, and A.
  • I 5 is an amino acid selected from the group consisting of V, R, and L.
  • I 6 is an amino acid selected from the group consisting of L, P, and A.
  • I 7 is an amino acid selected from the group consisting of L and A.
  • I 8 is an amino acid selected from the group consisting of L and Q. In some embodiments, I 9 is an amino acid selected from the group consisting of L and V. In some embodiments, I 10 is an amino acid selected from the group consisting of L and A. In some embodiments, I11 is an amino acid selected from the group consisting of L and G. In some embodiments, I 12 is leucine (L). In some embodiments, I 13 is leucine (L). In some embodiments, I 14 is an amino acid selected from the group consisting of L and A. In some embodiments, I 15 is an amino acid selected from the group consisting of L and A. In some embodiments, I 16 is an amino acid selected from the group consisting of L and A.
  • I 17 is an amino acid selected from the ACTIVE/131743364.1 43 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT group consisting of L and A.
  • I 18 is an amino acid selected from the group consisting of P, L, A, and G.
  • I 19 is an amino acid selected from the group consisting of G, L, A, and P.
  • I 20 is an amino acid selected from the group consisting of A, V, G, and S.
  • I 21 is an amino acid selected from the group consisting of R, L, Q, and A.
  • I 22 is an amino acid selected from the group consisting of G, A, S, and C.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 2 of SEQ ID NO: 9.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 3 of SEQ ID NO: 9.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 4 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 5 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 6 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 7 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 8 of SEQ ID NO: 9.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 9 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 10 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 11 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 14 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 15 of SEQ ID NO: 9.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 16 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 17 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 18 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 19 of SEQ ACTIVE/131743364.1 44 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT ID NO: 9.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 20 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 21 of SEQ ID NO: 9. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 22 of SEQ ID NO: 9.
  • the variant may also comprise any number of substitutions as provided by Formula IX. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, or 22 of SEQ ID NO: 9.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 14, 15, 16, 17, 18, 19, 20, 21, or 22 of SEQ ID NO: 9.
  • Variants of SEQ ID NO: 10 [0104]
  • the signal peptide comprises an amino acid sequence represented by: J 1 -J 2 -J 3 -J 4 -J 5 -J 6 -J 7 -J 8 -J 9 -J 10 -J 11 -J 12 -J 13 -J 14 -J 15 -J 16 -J 17 -J 18 -J 19 -J 20 -J 21 -J 22 -J 23 (Formula X); wherein the identity of each of J1 – J23 are as provided for in Table 11 below.
  • J 1 is methionine (M).
  • J 2 is an amino acid selected from the group consisting of K, A, and R.
  • J 3 is an amino acid selected from the group consisting of P, L, G, and S.
  • J 4 is serine (S).
  • J 5 is an amino acid selected from the group consisting of L and A.
  • J 6 is an amino acid selected from the group consisting of A and L.
  • J7 is an amino acid selected from the group consisting of L and A.
  • J 8 is leucine (L).
  • J 9 is an amino acid selected from the group consisting of L and A.
  • J 10 is an amino acid selected from the group consisting of L and V.
  • J 11 is an amino acid selected from the group consisting of L and A.
  • J 12 is leucine (L).
  • J 13 is an amino acid selected from the group consisting of L, V, and A.
  • J 14 is an amino acid selected from the group consisting of L and A.
  • J 15 is an amino acid selected from the group consisting of L and A.
  • J 16 is an amino acid selected from the group consisting of L and A.
  • J 17 is an amino acid selected from the group consisting of L and F.
  • J 18 is an amino acid selected from the group consisting of L, A, and S.
  • J19 is an amino acid selected from the group consisting of S, P, and G.
  • J 20 is an amino acid selected from the group consisting of L, A, and P.
  • J 21 is an amino acid selected from the group consisting of A, V, S, and G.
  • J 22 is an amino acid selected from the group consisting of L and S.
  • J 23 is an amino acid selected from the group consisting of A, G, and S.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 2 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 3 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 5 of SEQ ID NO: 10.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 6 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 7 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 9 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 10 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 11 of SEQ ID NO: 10.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 13 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 14 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 15 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 16 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 17 of SEQ ID NO: 10.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 18 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 19 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 20 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 21 of SEQ ID NO: 10. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 22 of SEQ ID NO: 10.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 23 of SEQ ID NO: 10.
  • the variant may also comprise any number of substitutions as provided by Formula ACTIVE/131743364.1 47 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT X.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at at least one position corresponding to position 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 of SEQ ID NO: 10.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at more than one position corresponding to position 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23 of SEQ ID NO: 10.
  • Variants of SEQ ID NO: 11 [0109]
  • the signal peptide comprises an amino acid sequence represented by: K 1 -K 2 -K 3 -K 4 -K 5 -K 6 -K 7 -K 8 -K 9 -K 10 -K 11 -K 12 -K 13 -K 14 -K 15 -K 16 -K 17 -K 18 -K 19 -K 20 -K 21 -K 22 -K 23 - K 24 (Formula XI); wherein the identity of each of K 1 – K 24 are as provided for in Table 12 below.
  • K 1 is methionine (M).
  • K 2 is an amino acid selected from the group consisting of A and R.
  • K 3 is an amino acid selected from the group consisting of R, P, L, and S.
  • K4 is an amino acid selected from the group consisting of A, S, P, and L.
  • K5 is an amino acid selected from the group consisting of S, R, and G.
  • K 6 is an amino acid selected from the group consisting of L and G.
  • K 7 is an amino acid selected from the group consisting of L and A.
  • K 8 is an amino acid selected from the group consisting of L, A, and S.
  • K 9 is an amino acid selected from the group consisting of L and A.
  • K 10 is an amino acid selected from the group consisting of L, A, G, and V.
  • K 11 is an amino acid selected from the group consisting of L and A.
  • K 12 is an amino acid selected from the group consisting of L and A.
  • K 13 is an amino acid selected from the group consisting of L, A, and V.
  • K14 is an amino acid selected from the group consisting of L and A.
  • K15 is leucine (L).
  • K 16 is an amino acid selected from the group consisting of L and A.
  • K 17 is an amino acid selected from the group consisting of L and A.
  • K 18 is an amino acid selected from the group consisting of L and A.
  • K 19 is an amino acid selected from the group consisting of L, A, and P.
  • K 20 is an amino acid selected from the group consisting of P, G, and S.
  • K 21 is an amino acid selected from the group consisting of P, G, L, and V.
  • K 22 is an amino acid selected from the group consisting of V, S, A, T, and G.
  • K 23 is an amino acid selected from the group consisting of L, R, and E.
  • K24 is an amino acid selected from the group consisting of A, G, and S. ACTIVE/131743364.1 49 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT [0111] It is to be understood that a variant of SEQ ID NO: 11 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XI. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 2 of SEQ ID NO: 11.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 3 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 4 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 5 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 6 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 7 of SEQ ID NO: 11.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 8 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 9 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 10 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 11 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 12 of SEQ ID NO: 11.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 13 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 14 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 16 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 17 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 18 of SEQ ID NO: 11.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 19 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 20 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 21 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of ACTIVE/131743364.1 50 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT SEQ ID NO: 11 and a substitution at position 22 of SEQ ID NO: 11.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 23 of SEQ ID NO: 11. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 24 of SEQ ID NO: 11.
  • the variant may also comprise any number of substitutions as provided by Formula XI. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, or 24 of SEQ ID NO: 11.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 22, 23, or 24 of SEQ ID NO: 11.
  • the signal peptide comprises an amino acid sequence represented by: L 1 -L 2 -L 3 -L 4 -L 5 -L 6 -L 7 -L 8 -L 9 -L 10 -L 11 -L 12 -L 13 -L 14 -L 15 -L 16 -L 17 -L 18 -L 19 -L 20 -L 21 -L 22 -L 23 -L 24 -L 25 (Formula XII); wherein the identity of each of L1 – L25 are as provided for in Table 13 below. Table 13 ACTIVE/131743364.1 51 Attorney Docket No.
  • L 1 is methionine (M).
  • L 2 is an amino acid selected from the group consisting of A, G, and R.
  • L 3 is an amino acid selected from the group consisting of S, L, R, and P.
  • L 4 is an amino acid selected from the group consisting of L, A, R, P, and S.
  • L 5 is an amino acid selected from the group consisting of L, G, and R.
  • L 6 is an amino acid selected from the group consisting of L and R.
  • L 7 is an amino acid selected from the group consisting of A, L, and S.
  • L8 is an amino acid selected from the group consisting of L and P.
  • L9 is leucine (L).
  • L 10 is an amino acid selected from the group consisting of L and S.
  • L 11 is an amino acid selected from the group consisting of L, A, and V.
  • L 12 is an amino acid selected from the group consisting of L and V.
  • L 13 is leucine (L).
  • L 14 is an amino acid selected from the group consisting of L, F, and V.
  • L 15 is leucine (L).
  • L 16 is an amino acid selected from the group consisting of L and A.
  • L 17 is an amino acid selected from the group consisting of L and G.
  • L 18 is an amino acid selected from the group consisting of L and V.
  • L19 is an amino acid selected from the group consisting of L, A, and F.
  • L20 is an amino acid selected from the group consisting of L and P.
  • L 21 is an amino acid selected from the group consisting of P, G, S, and L.
  • L 22 is an amino acid selected from the group consisting of G, S, V, and L.
  • L 23 is an amino acid selected from the group consisting of A, V, S, and T.
  • L 24 is an amino acid selected from the group consisting of L, S, H, and Q.
  • L 25 is an amino acid selected from the group consisting of A, G, and S. [0115] It is to be understood that a variant of SEQ ID NO: 12 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 2 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 3 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 4 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 5 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 6 of SEQ ID NO: 12.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 7 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 8 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 10 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 11 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 12 of SEQ ID NO: 12.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 14 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 16 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 17 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 18 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 19 of SEQ ID NO: 12.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 20 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino ACTIVE/131743364.1 53 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT acid sequence of SEQ ID NO: 12 and a substitution at position 21 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 22 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 23 of SEQ ID NO: 12.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 24 of SEQ ID NO: 12. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 25 of SEQ ID NO: 12.
  • the variant may also comprise any number of substitutions as provided by Formula XII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 of SEQ ID NO: 12.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 10, 11, 12, 14, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 of SEQ ID NO: 12.
  • the signal peptide comprises an amino acid sequence represented by: M 1 -M 2 -M 3 -M 4 -M 5 -M 6 -M 7 -M 8 -M 9 -M 10 -M 11 -M 12 -M 13 -M 14 -M 15 -M 16 -M 17 -M 18 -M 19 -M 20 -M 21 - M 22 -M 23 -M 24 -M 25 -M 26 (Formula XIII); wherein the identity of each of M 1 – M 26 are as provided for in Table 14 below.
  • M1 is methionine (M).
  • M2 is an amino acid selected from the group consisting of A, L, and R.
  • M 3 is an amino acid selected from the group consisting of A, P, L, and G.
  • M 4 is an amino acid selected from the group consisting of L, A, P, R, G, and S.
  • M 5 is an amino acid selected from the group consisting of S, L, and R.
  • M 13 is an amino acid selected from the group consisting of L, F, and A.
  • M 14 is an amino acid selected from the group consisting of L and A.
  • M 15 is an amino acid selected from the group consisting of L and V.
  • M 16 is an amino acid selected from the group consisting of L and V.
  • M 17 is an amino acid selected from the group consisting of L, V, and C.
  • M 18 is an amino acid selected from the group consisting of L and A.
  • M 19 is an amino acid selected from the group consisting of L, A, and S.
  • M 20 is an amino acid selected from the group consisting of L, A, G, and W.
  • M 21 is leucine (L).
  • M 22 is an amino acid selected from the group consisting of S, Q, G, R, and P.
  • M23 is an amino acid selected from the group consisting of P, L, E, and G.
  • M 24 is an amino acid selected from the group consisting of A, V, G, and S.
  • M 25 is an amino acid selected from the group consisting of S, A, R, Q, and L.
  • M 26 is an amino acid selected from the group consisting of A, G, and S. [0119] It is to be understood that a variant of SEQ ID NO: 13 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XIII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 2 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 3 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 4 of SEQ ID NO: 13.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 5 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 6 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 7 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 8 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 9 of SEQ ID NO: 13.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 10 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 11 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 12 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 13 of SEQ ID NO: 13. In some ACTIVE/131743364.1 56 Attorney Docket No.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 14 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 15 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 16 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 17 of SEQ ID NO: 13.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 18 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 19 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 20 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 22 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 23 of SEQ ID NO: 13.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 24 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 25 of SEQ ID NO: 13. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 26 of SEQ ID NO: 13.
  • the variant may also comprise any number of substitutions as provided by Formula XIII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, or 26 of SEQ ID NO: 13.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, or 26 of SEQ ID NO: 13.
  • the signal peptide comprises an amino acid sequence represented by: N 1 -N 2 -N 3 -N 4 -N 5 -N 6 -N 7 -N 8 -N 9 -N 10 -N 11 -N 12 -N 13 -N 14 -N 15 -N 16 -N 17 -N 18 -N 19 -N 20 -N 21 -N 22 -N 23 - N 24 -N 25 -N 26 -N 27 (Formula XIV); wherein the identity of each of N 1 – N 27 are as provided for in Table 15 below.
  • N 1 is methionine (M).
  • N 2 is an amino acid selected from the group consisting of A and R.
  • N 3 is an amino acid selected from the group consisting of L, P, G, R, and S.
  • N 4 is an amino acid selected from the group consisting of G, A, L, S, and R.
  • N 5 is an ACTIVE/131743364.1 58 Attorney Docket No.
  • N 6 is an amino acid selected from the group consisting of L, S, and G.
  • N 7 is an amino acid selected from the group consisting of L and P.
  • N 8 is an amino acid selected from the group consisting of L, A, G, and P.
  • N 9 is leucine (L).
  • N 10 is an amino acid selected from the group consisting of L and A.
  • N 11 is an amino acid selected from the group consisting of L and A.
  • N 12 is leucine (L).
  • N 13 is an amino acid selected from the group consisting of L and A.
  • N14 is an amino acid selected from the group consisting of L and A.
  • N 15 is an amino acid selected from the group consisting of L, V, and A.
  • N 16 is leucine (L).
  • N 17 is an amino acid selected from the group consisting of L and V.
  • N 18 is an amino acid selected from the group consisting of L and V.
  • N 19 is an amino acid selected from the group consisting of L and A.
  • N 20 is an amino acid selected from the group consisting of L and S.
  • N 21 is an amino acid selected from the group consisting of L, G, S, and T.
  • N 22 is an amino acid selected from the group consisting of L, P, G, and I.
  • N 23 is an amino acid selected from the group consisting of P and S.
  • N24 is an amino acid selected from the group consisting of G, P, V, and A.
  • N 25 is an amino acid selected from the group consisting of A, V, T, and G.
  • N 26 is an amino acid selected from the group consisting of L and R.
  • N 27 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 2 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 3 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 4 of SEQ ID NO: 14.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 5 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 6 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at ACTIVE/131743364.1 59 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT position 7 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 8 of SEQ ID NO: 14.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 10 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 11 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 13 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 14 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 15 of SEQ ID NO: 14.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 17 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 18 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 19 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 20 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 21 of SEQ ID NO: 14.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 22 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 23 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 24 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 25 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 26 of SEQ ID NO: 14.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at position 27 of SEQ ID NO: 14.
  • the variant may also comprise any number of substitutions as provided by Formula XIV. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 10, 11, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 of SEQ ID NO: 14. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 14 and a substitution at more than one position ACTIVE/131743364.1 60 Attorney Docket No.
  • the signal peptide comprises an amino acid sequence represented by: O 1 -O 2 -O 3 -O 4 -O 5 -O 6 -O 7 -O 8 -O 9 -O 10 -O 11 -O 12 -O 13 -O 14 -O 15 -O 16 -O 17 -O 18 -O 19 -O 20 -O 21 -O 22 -O 23 - O 24 -O 25 -O 26 -O 27 -O 28 (Formula XV); wherein the identity of each of O 1 – O 28 are as provided for in Table 16 below.
  • O 1 is methionine (M).
  • O 2 is an amino acid selected from the group consisting of A, L, and S.
  • O 3 is an amino acid selected from the group consisting of P, L, R, and G.
  • O4 is an amino acid selected from the group consisting of L, R, and P.
  • O5 is an amino acid selected from the group consisting of R, P, and G.
  • O 6 is an amino acid selected from the group consisting of R, P, S, and L.
  • O 7 is an amino acid selected from the group consisting of P, R, L, G, and K.
  • O 8 is an amino acid selected from the group consisting of R and L.
  • O 9 is an amino acid selected from the group consisting of L, A, P, V, and R.
  • O 10 is an amino acid selected from the group consisting of L and A.
  • O 11 is an amino acid selected from the group consisting of L and S.
  • O 12 is an amino acid selected from the group consisting of L, G, and W.
  • O13 is an amino acid selected from the group consisting of L, A, and V.
  • O14 is leucine (L).
  • O15 is an amino acid selected from the group consisting of L, V, F, and A.
  • O 16 is leucine (L).
  • O 17 is an amino acid selected from the group consisting of L, I, and A.
  • O 18 is leucine (L).
  • O 19 is an amino acid selected from the group consisting of L and V.
  • O 20 is an amino acid selected from the group consisting of L and G.
  • O 21 is an amino acid selected from the group consisting of L and A.
  • O 22 is an amino acid selected from the group consisting of L, A, and Q.
  • O 23 is an amino acid selected from the group consisting of L, P, A, and G.
  • O 24 is an amino acid selected from the group consisting of Q, L, A, P, and G.
  • O25 is an amino acid selected from the group consisting of P, G, and A.
  • O26 is an amino acid selected from the group consisting of A, V, T, and S.
  • O 27 is an amino acid ACTIVE/131743364.1 62 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT selected from the group consisting of L and S.
  • O 28 is an amino acid selected from the group consisting of A, G, and S. [0127] It is to be understood that a variant of SEQ ID NO: 15 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XV. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 2 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 3 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 4 of SEQ ID NO: 15.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 5 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 6 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 7 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 8 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 9 of SEQ ID NO: 15.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 10 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 11 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 12 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 13 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 15 of SEQ ID NO: 15.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 17 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 19 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 20 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 21 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 22 of SEQ ID NO: 15.
  • the signal peptide ACTIVE/131743364.1 63 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 23 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 24 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 25 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 26 of SEQ ID NO: 15.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 27 of SEQ ID NO: 15. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 28 of SEQ ID NO: 15.
  • the variant may also comprise any number of substitutions as provided by Formula XV. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 of SEQ ID NO: 15.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 of SEQ ID NO: 15.
  • the signal peptide comprises an amino acid sequence represented by: P 1 -P 2 -P 3 -P 4 -P 5 -P 6 -P 7 -P 8 -P 9 -P 10 -P 11 -P 12 -P 13 -P 14 -P 15 -P 16 -P 17 -P 18 -P 19 -P 20 -P 21 -P 22 -P 23 -P 24 -P 25 -P 26 - P 27 -P 28 -P 29 (Formula XVI); wherein the identity of each of P 1 – P 29 are as provided for in Table 17 below.
  • P 1 is methionine (M).
  • P 2 is an amino acid selected from the group consisting of P, R, A, and E.
  • P 3 is an amino acid selected from the group consisting of A, R, S, P, and G.
  • P4 is an amino acid selected from the group consisting of S, A, R, and L.
  • P 5 is an amino acid selected from the group consisting of A, R, and G.
  • P 6 is an amino acid selected from the group consisting of P, L, G, A, and R.
  • P 7 is an amino acid selected from the group consisting of P, R, and L.
  • P 8 is an amino acid selected from the group consisting of L, G, and A.
  • P 9 is an amino acid selected from the group consisting of L and R.
  • P 10 is an amino acid selected from the group consisting of L, R, S, P, and G.
  • P 11 is an amino acid selected from the group consisting of L, R, G, and P.
  • P 12 is an amino acid selected from the group consisting of L, V, and A.
  • P 13 is an amino acid selected from the group consisting of L, C, and A.
  • P 14 is an amino acid selected from the group consisting of L and A.
  • P 15 is an amino acid selected from the group consisting of L and V.
  • P 16 is an amino acid selected from the group consisting of L and A.
  • P 17 is an amino acid selected from the group consisting of L, A, and V.
  • P18 is an amino acid selected from the group consisting of L and A.
  • P 19 is an amino acid selected from the group consisting of L and A.
  • P 20 is an amino acid selected from the group consisting of L, A, and V.
  • P 21 is an amino acid selected from the group consisting of L and A.
  • P 22 is an amino acid selected from the group consisting of L, S, and T.
  • P 23 is an amino acid selected from the group consisting of L and P.
  • P 24 is an amino acid selected from the group consisting of L and A.
  • P 25 is an amino acid selected from the group consisting of P, R, G, L, and A.
  • P 26 is an amino acid selected from the group consisting of G, P, S, and L.
  • P 27 is an amino acid selected from the group consisting of A, L, V, T, and S.
  • P28 is an amino acid selected from the group consisting of Q, A, G, R, and S.
  • P 29 is an amino acid selected from the group consisting of A, G, and S.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 2 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 3 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 4 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 5 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 6 of SEQ ID NO: 16.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 7 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 8 of SEQ ID NO: 16. In some ACTIVE/131743364.1 66 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 9 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 10 of SEQ ID NO: 16.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 11 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 12 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 13 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 14 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 15 of SEQ ID NO: 16.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 16 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 17 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 18 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 19 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 20 of SEQ ID NO: 16.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 21 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 22 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 23 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 24 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 25 of SEQ ID NO: 16.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 26 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 27 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 28 of SEQ ID NO: 16. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 29 of SEQ ID NO: 16.
  • the variant may also comprise any number of ACTIVE/131743364.1 67 Attorney Docket No.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at at least one position corresponding to position 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, or 29 of SEQ ID NO: 16.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at more than one position corresponding to position 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, or 29 of SEQ ID NO: 16.
  • the signal peptide comprises an amino acid sequence represented by: Q 1 -Q 2 -Q 3 -Q 4 -Q 5 -Q 6 -Q 7 -Q 8 -Q 9 -Q 10 -Q 11 -Q 12 -Q 13 -Q 14 -Q 15 -Q 16 -Q 17 -Q 18 -Q 19 -Q 20 -Q 21 -Q 22 -Q 23 - Q 24 -Q 25 -Q 26 -Q 27 -Q 28 -Q 29 -Q 30 (Formula XVII); wherein the identity of each of Q 1 – Q 30 are as provided for in Table 18 below.
  • Q 1 is methionine (M).
  • Q 2 is an amino acid selected from the group consisting of A, L, and S.
  • Q 3 is an amino acid selected from the group consisting of G and P.
  • Q 4 is an amino acid selected from the group consisting of P, A, and R.
  • Q 5 is an amino acid selected from the group consisting of R, G, A, V.
  • Q 6 is an amino acid selected from the group consisting of R and S.
  • Q 7 is an amino acid selected from the group consisting of P, R, A, and S.
  • Q 8 is an amino acid selected from the group consisting of A, R, G, and S.
  • Q9 is an amino acid selected from the group consisting of P and R.
  • Q 10 is an amino acid selected from the group consisting of A, P, and S.
  • Q 11 is an amino acid selected from the group consisting of G, L, and R.
  • Q 12 is an amino acid selected from the group consisting of L, R, V, and A.
  • Q 13 is an amino acid selected from the group consisting of L and T.
  • Q 14 is an amino acid selected from the group consisting of L, A, and R.
  • Q 15 is an amino acid selected from the group consisting of L and V.
  • Q 16 is an amino acid selected from the group consisting of L, A, and V.
  • Q 17 is an amino acid selected from the group consisting of L and V.
  • Q 18 is an amino acid selected from the group consisting of L and A.
  • Q19 is an ACTIVE/131743364.1 69 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT amino acid selected from the group consisting of L, A, and I.
  • Q 20 is leucine (L).
  • Q 21 is an amino acid selected from the group consisting of L, A, and G.
  • Q 22 is an amino acid selected from the group consisting of L and V.
  • Q 23 is an amino acid selected from the group consisting of L and V.
  • Q 24 is leucine (L).
  • Q 25 is an amino acid selected from the group consisting of A, P, S, and L.
  • Q 26 is an amino acid selected from the group consisting of R, L, and S.
  • Q 27 is an amino acid selected from the group consisting of G, P, Q, V, and L.
  • Q 28 is an amino acid selected from the group consisting of A, V, T, S, G, and C.
  • Q 29 is an amino acid selected from the group consisting of A, L, and G.
  • Q 30 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 3 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 4 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 5 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 6 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 7 of SEQ ID NO: 17.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 8 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 9 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 10 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 11 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 12 of SEQ ID NO: 17.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 13 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a ACTIVE/131743364.1 70 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT substitution at position 14 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 15 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 16 of SEQ ID NO: 17.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 17 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 18 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 19 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 21 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 22 of SEQ ID NO: 17.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 23 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 25 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 26 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 27 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 28 of SEQ ID NO: 17.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 29 of SEQ ID NO: 17. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at position 30 of SEQ ID NO: 17.
  • the variant may also comprise any number of substitutions as provided by Formula XVII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 25, 26, 27, 28, 29, or 30 of SEQ ID NO: 17.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 17 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 25, 26, 27, 28, 29, or 30 of SEQ ID NO: 17.
  • Variants of SEQ ID NO: 18 (Formula XVIII)
  • the signal peptide comprises an amino acid sequence represented by: ACTIVE/131743364.1 71 Attorney Docket No.
  • R 1 is methionine (M).
  • R 2 is an amino acid selected from the group consisting of A, G, and S.
  • R3 is an amino acid selected from the group consisting of A, P, R, and L.
  • R 4 is an amino acid selected from the group consisting of L, P, and A.
  • R 5 is an amino acid selected from the group consisting of G, A, S, and R.
  • R 6 is an amino acid selected from the group consisting of G, A, R, and L.
  • R 7 is an amino acid selected from the group consisting of R, G, L, and T.
  • R 8 is an amino acid selected from the group consisting of R, S, and G.
  • R 9 is an amino acid selected from the group consisting of A, P, G, and L.
  • R 10 is an amino acid selected from the group consisting of A, L, G, and R.
  • R 11 is an amino acid selected from the group consisting of R, L, A, and C.
  • R12 is an amino acid selected from the group consisting of A, P, L, G, S, and R.
  • R 13 is an amino acid selected from the group consisting of L and R.
  • R 14 is an amino acid selected from the group consisting of L and A.
  • R 15 is an amino acid selected from the group consisting of L, A, and I.
  • R 16 is an amino acid selected from the group consisting of L and G.
  • R 17 is an amino acid selected from the group consisting of L, A, V, P, and S.
  • R 18 is an amino acid selected from the group consisting of L and A.
  • R 19 is an amino acid selected from the group consisting of L and A.
  • R 20 is an amino acid selected from the group consisting of L, A, and V.
  • R 21 is leucine (L).
  • R 22 is an amino acid selected from the group consisting of L and G.
  • R23 is an amino acid selected from the group consisting of L, A, and S.
  • R 24 is an amino acid selected from the group consisting of L, V, and S.
  • R 25 is an amino acid selected from the group consisting of L, G, and A.
  • R 26 is an amino acid selected from the group consisting of L, P, and V.
  • R 27 is an amino acid selected from the group consisting of S, A, R, G, and L.
  • R 28 is an ACTIVE/131743364.1 73 Attorney Docket No.
  • R 29 is an amino acid selected from the group consisting of A, S, V, and G.
  • R 30 is an amino acid selected from the group consisting of S, A, and R.
  • R 31 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 2 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 3 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 4 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 5 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 6 of SEQ ID NO: 18.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 7 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 8 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 9 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 10 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 11 of SEQ ID NO: 18.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 12 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 13 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 14 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 15 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 16 of SEQ ID NO: 18.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 17 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 18 of SEQ ID NO: 18. In some ACTIVE/131743364.1 74 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 19 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 20 of SEQ ID NO: 18.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 22 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 23 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 24 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 25 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 26 of SEQ ID NO: 18.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 27 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 28 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 29 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 30 of SEQ ID NO: 18. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 31 of SEQ ID NO: 18.
  • the variant may also comprise any number of substitutions as provided by Formula XVIII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 of SEQ ID NO: 18.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, or 31 of SEQ ID NO: 18.
  • the signal peptide comprises an amino acid sequence represented by: S 1 -S 2 -S 3 -S 4 -S 5 -S 6 -S 7 -S 8 -S 9 -S 10 -S 11 -S 12 -S 13 -S 14 -S 15 -S 16 -S 17 -S 18 -S 19 -S 20 -S 21 -S 22 -S 23 -S 24 -S 25 -S 26 - S 27 -S 28 -S 29 -S 30 -S 31 -S 32 (Formula XIX); wherein the identity of each of S 1 – S 32 are as provided for in Table 20 below.
  • S1 is methionine (M).
  • S2 is an amino acid selected from the group consisting of A, R, G, and V.
  • S 3 is an amino acid selected from the group consisting of A and S.
  • S 4 is an amino acid selected from the group consisting of S, P, and R.
  • S 5 is an amino acid selected from the group consisting of P, S, and R.
  • S 6 is an amino acid selected from the group consisting of A, G, R, and L.
  • S 7 is an amino acid selected from the group consisting of L and P.
  • S 8 is an amino acid selected from the group consisting of R and G.
  • S 9 is an amino acid selected from the group consisting of G, M, and A.
  • S 10 is an amino acid selected from the group consisting of R and P.
  • S 11 is an amino acid selected from the group consisting of A, G, and R.
  • S12 is glycine (G).
  • S 13 is an amino acid selected from the group consisting of P, G, and S.
  • S 14 is an amino acid selected from the group consisting of R, G, L, and A.
  • S 15 is an amino acid selected from the group consisting of L, H, and S.
  • S 16 is an amino acid selected from the group consisting of L and G.
  • S 17 is an amino acid selected from the group consisting of L and F.
  • S 18 is an amino acid selected from the group consisting of L and A.
  • S 19 is an amino acid selected from the group consisting of L and A.
  • S 20 is an amino acid selected from the group consisting of L, A, and S.
  • S21 is an amino acid selected from the group consisting of L and V.
  • S22 is leucine (L).
  • S23 is an amino acid selected from the group consisting of L, A, and G.
  • S 24 is an amino acid selected from the group consisting of L, A, and G.
  • S 25 is an amino acid selected from the group consisting of L and A.
  • S 26 is an amino acid selected from the group consisting of L, A, and F.
  • S 27 is an amino acid selected from the group consisting of L and V.
  • S 28 is an amino acid selected from the group consisting of P, R, and A.
  • S 29 is an amino acid selected from the group consisting of G and V.
  • S 30 is an amino acid selected ACTIVE/131743364.1 77 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT from the group consisting of V, A, T, and S.
  • S 31 is an amino acid selected from the group consisting of L, G, and R.
  • S 32 is alanine (A). [0143] It is to be understood that a variant of SEQ ID NO: 19 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XIX.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 2 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 3 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 4 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 5 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 6 of SEQ ID NO: 19.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 7 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 8 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 9 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 10 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 11 of SEQ ID NO: 19.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 13 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 14 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 15 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 16 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 17 of SEQ ID NO: 19.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 18 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 19 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 20 of SEQ ID NO: 19. In some embodiments, the signal peptide ACTIVE/131743364.1 78 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 21 of SEQ ID NO: 19.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 23 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 24 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 25 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 26 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 27 of SEQ ID NO: 19.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 28 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 29 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 30 of SEQ ID NO: 19. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 31 of SEQ ID NO: 19.
  • the variant may also comprise any number of substitutions as provided by Formula XIX.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, or 31 of SEQ ID NO: 19.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, or 31 of SEQ ID NO: 19.
  • the signal peptide comprises an amino acid sequence represented by: T 1 -T 2 -T 3 -T 4 -T 5 -T 6 -T 7 -T 8 -T 9 -T 10 -T 11 -T 12 -T 13 -T 14 -T 15 -T 16 -T 17 -T 18 -T 19 -T 20 -T 21 -T 22 -T 23 -T 24 -T 25 - T26-T27-T28-T29-T30-T31-T32-T33 (Formula XX); wherein the identity of each of T 1 – T 33 are as provided for in Table 21 below.
  • T 1 is methionine (M).
  • T 2 is an amino acid selected from the group consisting of A, R, and L.
  • T 3 is an amino acid selected from the group consisting of A, G, and K.
  • T 4 is an amino acid selected from the group consisting of L, A, T, and R.
  • T 5 is an amino acid selected from the group consisting of P and G.
  • T 6 is an amino acid selected from the group consisting of R, P, and G.
  • T 7 is an amino acid selected from the group consisting of L, S, R, and G.
  • T 8 is an amino acid selected from the group consisting of G, P, and R.
  • T 9 is an amino acid selected from the group consisting of S, and G.
  • T 10 is serine (S).
  • T11 is an amino acid selected from the group consisting of A and M.
  • T 12 is an amino acid selected from the group consisting of L, A, and P.
  • T 13 is an amino acid selected from the group consisting of P and A.
  • T 14 is an amino acid selected from the group consisting of L, S, G, and V.
  • T 15 is an amino acid selected from the group consisting of R, S, and A.
  • T 16 is an amino acid selected from the group consisting of L, P, A, and V.
  • T 17 is an amino acid selected from the group consisting of L and A.
  • T 18 is an amino acid selected from the group consisting of L and W.
  • T 19 is an amino acid selected from the group consisting of A, S, and L.
  • T 20 is an amino acid selected from the group consisting of L and T.
  • T21 is an amino acid selected from the group consisting of L, I, and A.
  • T 22 is an amino acid selected from the group consisting of L and A.
  • T 23 is an amino acid selected from the group consisting of L and V.
  • T 24 is an amino acid selected from the group consisting of L, A, and S.
  • T 25 is an amino acid selected from the group consisting of L and A.
  • T 26 is an amino acid selected from the group consisting of L and A.
  • T 27 is an amino acid selected from the group consisting of L, W, and F.
  • T 28 is an amino acid selected from the group consisting of P and V.
  • T 29 is an amino acid selected from the group consisting of P and G.
  • T 30 is an amino acid selected from the group consisting of P, L, and Q.
  • T31 is an amino acid selected from the group consisting of A, G, and V. ACTIVE/131743364.1 81 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT
  • T 32 is an amino acid selected from the group consisting of L and A.
  • T 33 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 2 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 3 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 4 of SEQ ID NO: 20.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 5 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 6 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 7 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 8 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 9 of SEQ ID NO: 20.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 11 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 12 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 13 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 14 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 15 of SEQ ID NO: 20.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 16 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 17 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 18 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 19 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 20 of SEQ ID NO: 20.
  • the signal peptide ACTIVE/131743364.1 82 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 21 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 22 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 23 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 24 of SEQ ID NO: 20.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 25 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 26 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 27 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 28 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 29 of SEQ ID NO: 20.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 30 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 31 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 32 of SEQ ID NO: 20. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 33 of SEQ ID NO: 20.
  • the variant may also comprise any number of substitutions as provided by Formula XX.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33 of SEQ ID NO: 20.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, or 33 of SEQ ID NO: 20.
  • the signal peptide comprises an amino acid sequence represented by: U 1 -U 2 -U 3 -U 4 -U 5 -U 6 -U 7 -U 8 -U 9 -U 10 -U 11 -U 12 -U 13 -U 14 -U 15 -U 16 -U 17 -U 18 -U 19 -U 20 -U 21 -U 22 -U 23 - U 24 -U 25 -U 26 -U 27 -U 28 -U 29 -U 30 -U 31 -U 32 -U 33 -U 34 (Formula XXI); ACTIVE/131743364.1 83 Attorney Docket No.
  • U 1 is methionine (M).
  • U 2 is an amino acid selected from the group consisting of G, A, and S.
  • U 3 is an amino acid selected from the group consisting of P, L, and R.
  • U4 is an amino acid selected from the group consisting of L, P, and A.
  • U 5 is an amino acid selected from the group consisting of S, P, and E.
  • U 6 is an amino acid selected from the group consisting of A, R, and L.
  • U 7 is an amino acid selected from the group consisting of P and S.
  • U 8 is an amino acid selected from the group consisting of P, R, and A.
  • U 9 is an amino acid selected from the group consisting of C, G, A, P.
  • U 10 is an amino acid selected from the group consisting of T and P.
  • U 11 is an amino acid selected from the group consisting of Q, S, and R.
  • U 12 is an amino acid selected from the group consisting of R, H, N, and S.
  • U13 is an amino acid selected from the group consisting of I and P.
  • U14 is an amino acid selected from the group consisting of T, R, G, and K.
  • U 15 is an amino acid selected from the group consisting of W, L, P, Q.
  • U 16 is an amino acid selected from the group consisting of K, L, V, and P.
  • U 17 is an amino acid selected from the group consisting of G, P, R, A, and L.
  • U 18 is an amino acid selected from the group consisting of L, V, A, and H.
  • U 19 is an amino acid selected from the group consisting of L and A.
  • U 20 is leucine (L).
  • U 21 is an amino acid selected from the group consisting of L and T.
  • U 22 is an amino acid selected from the group consisting of L and A.
  • U23 is an amino acid selected from the group consisting of L and S.
  • U24 is leucine (L).
  • U 25 is leucine (L).
  • U 26 is an amino acid selected from the group consisting of N, L, V, and A.
  • U 27 is an amino acid selected from the group consisting of F, L, and A.
  • U 28 is an amino acid selected from the ACTIVE/131743364.1 85 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT group consisting of W, A, and L.
  • U 29 is an amino acid selected from the group consisting of N, L, and S.
  • U 30 is an amino acid selected from the group consisting of L, P, A, and R.
  • U 31 is an amino acid selected from the group consisting of P and R.
  • U 32 is an amino acid selected from the group consisting of T and A.
  • U 33 is an amino acid selected from the group consisting of T, L, A, and Q.
  • U 34 is an amino acid selected from the group consisting of A and G.
  • a variant of SEQ ID NO: 21 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XXI.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 2 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 3 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 4 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 5 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 6 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 7 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 8 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 9 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 10 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 11 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 12 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 13 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 14 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 15 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 16 of SEQ ID NO: 21. In some embodiments, ACTIVE/131743364.1 86 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 17 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 18 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 19 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 21 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 22 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 23 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 26 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 27 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 28 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 29 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 30 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 31 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 32 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 33 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 34 of SEQ ID NO: 21.
  • the variant may also comprise any number of substitutions as provided by Formula XXI.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, or 34 of SEQ ID NO: 21.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 21, 22, 23, 26, 27, 28, 29, 30, 31, 32, 33, or 34 of SEQ ID NO: 21.
  • the signal peptide comprises an amino acid sequence represented by: V 1 -V 2 -V 3 -V 4 -V 5 -V 6 -V 7 -V 8 -V 9 -V 10 -V 11 -V 12 -V 13 -V 14 -V 15 -V 16 -V 17 -V 18 -V 19 -V 20 -V 21 -V 22 -V 23 - V 24 -V 25 -V 26 -V 27 -V 28 -V 29 -V 30 -V 31 -V 32 -V 33 -V 34 -V 35 (Formula XXII); wherein the identity of each of V 1 – V 35 are as provided for in Table 23 below
  • V 1 is methionine (M).
  • V 2 is an amino acid selected from the group consisting of A, R, and R.
  • V 3 is an amino acid selected from the group consisting of P and S.
  • V 4 is an amino acid selected from the group consisting of R, A, W, and P.
  • V 5 is an amino acid selected from the group consisting of A, R, and T.
  • V 6 is an amino acid selected from the group consisting of R and G.
  • V7 is an amino acid selected from the group consisting of R and Q.
  • V 8 is an amino acid selected from the group consisting of R, G, P, and V.
  • V 9 is an amino acid selected from the group consisting of S, G, and K.
  • V 10 is an amino acid selected from the group consisting of P, R, A, and L.
  • V 11 is an amino acid selected from the group consisting of R and G.
  • V 12 is an amino acid selected from the group consisting of R and L.
  • V 13 is an amino acid selected from the group consisting of V, R, G, A, and P.
  • V 14 is an amino acid selected from the group consisting of P and L.
  • V 15 is an amino acid selected from the group consisting of G, L, A, and P.
  • V16 is an amino acid selected from the group consisting of L and P.
  • V17 is an amino acid selected from the group consisting of G, P, and L.
  • V 18 is an amino acid selected from the group consisting of P and W.
  • V 19 is an amino acid selected from the group consisting of G and R.
  • V 20 is an amino acid selected from the group consisting of A, P, and L.
  • V 21 is an amino acid selected from the group consisting of L and P.
  • V 22 is an ACTIVE/131743364.1 89 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT amino acid selected from the group consisting of L and A.
  • V 23 is an amino acid selected from the group consisting of L and S.
  • V 24 is an amino acid selected from the group consisting of L and V.
  • V 25 is leucine (L).
  • V 26 is leucine (L).
  • V 27 is an amino acid selected from the group consisting of F, L, and V.
  • V 28 is leucine (L).
  • V 29 is an amino acid selected from the group consisting of L and G.
  • V 30 is an amino acid selected from the group consisting of L, P, and V.
  • V31 is an amino acid selected from the group consisting of G, A, and L.
  • V 32 is an amino acid selected from the group consisting of G and A.
  • V 33 is an amino acid selected from the group consisting of G, A, and V.
  • V 34 is an amino acid selected from the group consisting of A, V, R, and Q.
  • V 35 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 2 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 3 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 4 of SEQ ID NO: 22.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 5 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 6 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 7 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 8 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 9 of SEQ ID NO: 22.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 10 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 11 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 12 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 13 of SEQ ID NO: 22. In some ACTIVE/131743364.1 90 Attorney Docket No.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 14 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 15 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 16 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 17 of SEQ ID NO: 22.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 18 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 19 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 20 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 21 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 22 of SEQ ID NO: 22.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 23 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 24 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 27 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 29 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 30 of SEQ ID NO: 22.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 31 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 32 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 33 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 34 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 35 of SEQ ID NO: 22.
  • the variant may also comprise any number of substitutions as provided by Formula XXII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, ACTIVE/131743364.1 91 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT 23, 24, 27, 29, 30, 31, 32, 33, 34, or 35 of SEQ ID NO: 22.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 27, 29, 30, 31, 32, 33, 34, or 35 of SEQ ID NO: 22.
  • the signal peptide comprises an amino acid sequence represented by: W1-W2-W3-W4-W5-W6-W7-W8-W9-W10-W11-W12-W13-W14-W15-W16-W17-W18-W19-W20- W 21 -W 22 -W 23 -W 24 -W 25 -W 26 -W 27 -W 28 -W 29 -W 30 -W 31 -W 32 -W 33 -W 34 -W 35 -W 36 (Formula XXIII); wherein the identity of each of W 1 – W 36 are as provided for in Table 24 below.
  • W1 is methionine (M).
  • W2 is an amino acid selected from the group consisting of S, A, and N.
  • W 3 is an amino acid selected from the group consisting of A and L.
  • W 4 is an amino acid selected from the group consisting of A, N, L, and P.
  • W 5 is an amino acid selected from the group consisting of S, A, and K.
  • W 6 is an amino acid selected from the group consisting of S, R, and D.
  • W 7 is an amino acid selected from the group consisting of R, P, and E.
  • W 8 is an amino acid selected from the group consisting of R and A.
  • W 9 is an amino acid selected from the group consisting of A, G, and L.
  • W 10 is an amino acid selected from the group consisting of R and K.
  • W11 is an amino acid selected from the group consisting of A and V.
  • W12 is an amino acid selected from the group consisting of P, L, and R.
  • W 13 is an amino acid selected from the group consisting of G and S.
  • W 14 is an amino acid selected from the group consisting of P and Q.
  • W 15 is an ACTIVE/131743364.1 93 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT amino acid selected from the group consisting of S, V, and D.
  • W 16 is an amino acid selected from the group consisting of L, F, S, and G.
  • W 17 is an amino acid selected from the group consisting of S, P, and H.
  • W 18 is an amino acid selected from the group consisting of L and P.
  • W 19 is an amino acid selected from the group consisting of C, T, and F.
  • W 20 is an amino acid selected from the group consisting of P and A.
  • W 21 is an amino acid selected from the group consisting of L and A.
  • W22 is leucine (L).
  • W23 is an amino acid selected from the group consisting of L, M, V, and A.
  • W 24 is an amino acid selected from the group consisting of L and M.
  • W 25 is leucine (L).
  • W 26 is an amino acid selected from the group consisting of L and S.
  • W 27 is an amino acid selected from the group consisting of L, R, and M.
  • W 28 is an amino acid selected from the group consisting of L, V, and T.
  • W 29 is an amino acid selected from the group consisting of T, L, and M.
  • W 30 is an amino acid selected from the group consisting of P, L, and Q.
  • W 31 is an amino acid selected from the group consisting of P, A, and F.
  • W 32 is an amino acid selected from the group consisting of G, C, and L.
  • W33 is an amino acid selected from the group consisting of P and G.
  • W 34 is an amino acid selected from the group consisting of A, V, I, and L.
  • W 35 is an amino acid selected from the group consisting of T and A.
  • W 36 is an amino acid selected from the group consisting of S, A, and G.
  • SEQ ID NO: 23 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XXIII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 2 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 3 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 4 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 5 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 6 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 7 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino ACTIVE/131743364.1 94 Attorney Docket No.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 8 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 9 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 10 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 11 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 12 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 13 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 14 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 15 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 16 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 17 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 18 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 19 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 20 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 21 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 23 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 24 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 25 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 26 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 27 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 28 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 29 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a ACTIVE/131743364.1 95 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT substitution at position 30 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 31 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 32 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 33 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 34 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 35 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 36 of SEQ ID NO: 23.
  • the variant may also comprise any number of substitutions as provided by Formula XXIII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 of SEQ ID NO: 23.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, or 36 of SEQ ID NO: 23.
  • the signal peptide comprises an amino acid sequence represented by: 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 31 -X 32 -X 33 -X 34 -X 35 -X 36 -X 37 (Formula XXIV); wherein the identity of each of X 1 – X 37 are as provided for in Table 25 below.
  • X 1 is methionine (M).
  • X 2 is an amino acid selected from the group consisting of A, D, P, S, and W.
  • X 3 is an amino acid selected from the group consisting of L, V, A, and K.
  • X 4 is an amino acid selected from the group consisting of G, H, P, and W.
  • X 5 is an amino acid selected from the group consisting of Q, T, R, S, and I.
  • X 6 is an amino acid selected from the group consisting of R, K, S, and L.
  • X 7 is an amino acid selected from the group consisting of L, W, G, R, and T.
  • X8 is an amino acid selected from the group consisting of F, K, P, A, and H.
  • X 9 is an amino acid selected from the group consisting of A, I, and C.
  • X 10 is an amino acid selected from the group consisting of R, A, and T.
  • X 11 is an amino acid selected from the group consisting of S, M, Q, and V.
  • X 12 is an amino acid selected from the group consisting of S, A, and P.
  • X 13 is an amino acid selected from the group consisting of R, L, A, G, and F.
  • X 14 is an amino acid selected from the group consisting of R, P, and G.
  • X 15 is an amino acid selected from the group consisting of A, P, R, S, and H.
  • X 16 is an amino acid selected from the group consisting of G, P, and L.
  • X 17 is an amino acid selected from the group consisting of P, R, A, and S.
  • X18 is an amino acid selected from the group consisting of L, P, and G.
  • X 19 is an amino acid selected from the group consisting of L, C, and Q.
  • X 20 is an amino acid selected from the group consisting of L, G, A, and C.
  • X 21 is an amino acid selected from the group consisting of P, T, L, and C.
  • X 22 is an amino acid selected from the group consisting of L, P, and C.
  • X 23 is an amino acid selected from the group consisting of L, W, A, and C.
  • X 24 is an amino acid selected from the group consisting of L, A, and F.
  • X 25 is leucine (L).
  • X 26 is an amino acid selected from the group consisting of L and V.
  • X 27 is an amino acid selected from the group consisting of L, F, and C.
  • X28 is an amino acid selected from the group consisting of L, V, and F.
  • X 29 is an amino acid selected from the group consisting of L, G, W, and T.
  • X 30 is an amino acid selected from the group consisting of I, A, G, P, and V.
  • X 31 is an amino acid selected from the group consisting of P, L, A, and S.
  • X 32 is an amino acid selected from the group consisting of P, V, G, and S.
  • X 33 is an amino acid selected from the group consisting ofP, G, R, and V.
  • X 34 is an amino acid selected from ACTIVE/131743364.1 98 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT the group consisting of M, S, A, L, and P.
  • X 35 is an amino acid selected from the group consisting of V, R, G, and A.
  • X 36 is an amino acid selected from the group consisting of S, V, A, and T.
  • X 37 is an amino acid selected from the group consisting of A, P, G, and C.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 2 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 3 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 4 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 5 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 6 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 7 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 8 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 9 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 10 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 11 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 12 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 13 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 14 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 15 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 16 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 17 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 18 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 19 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 20 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 21 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 22 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 23 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 24 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 26 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 27 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 28 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 29 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 30 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 31 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 32 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 33 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 34 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 35 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 36 of SEQ ID NO: 24. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 37 of SEQ ID NO: 24.
  • the variant may also comprise any number of substitutions as provided by Formula XXIV.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37 of SEQ ID NO: 24.
  • the signal peptide comprises the amino acid sequence ACTIVE/131743364.1 100 Attorney Docket No.
  • the signal peptide comprises an amino acid sequence represented by: Y 1 -Y 2 -Y 3 -Y 4 -Y 5 -Y 6 -Y 7 -Y 8 -Y 9 -Y 10 -Y 11 -Y 12 -Y 13 -Y 14 -Y 15 -Y 16 -Y 17 -Y 18 -Y 19 -Y 20 -Y 21 -Y 22 -Y 23 - Y24-Y25-Y26-Y27-Y28-Y29-Y30-Y31-Y32-Y33-Y34-Y35-Y36-Y37-Y38 (Formula XXV); wherein the identity of each of Y 1 – Y 38 are as provided for in Table 26 below.
  • Y1 is methionine (M).
  • Y2 is an amino acid selected from the group consisting of G, W, A, I, and L.
  • Y 3 is an amino acid selected from the group consisting of S, R, T, and I.
  • Y 4 is an amino acid selected from the group consisting of E, K, W, D, T, L, and V.
  • Y 5 is an amino acid selected from the group consisting of R, S, G, E, and H.
  • Y 6 is an amino acid selected from the group consisting of S, L, A, I, and T.
  • Y 7 is an amino acid selected from the group consisting of P, S, R, C, V, and E.
  • Y 8 is an amino acid selected from the group consisting of R, N, H, I, L, and G.
  • Y 9 is an amino acid selected from the group consisting of R, P, V, M, and G.
  • Y10 is an amino acid selected from the group consisting of R, P, G, T, S, and H.
  • Y11 is an amino acid selected from the group consisting of F, A, E, L, S, and C
  • Y 12 is an amino acid selected from the group consisting of P, C, K, T, and S.
  • Y 13 is an amino acid selected from the group consisting of L, C, Q, A, and F.
  • Y 14 is an ACTIVE/131743364.1 102 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT amino acid selected from the group consisting of L, R, Q, G, and H.
  • Y 15 is an amino acid selected from the group consisting of S, V, N, H, Q, and L.
  • Y 16 is an amino acid selected from the group consisting of A, R, S, V, T, and P.
  • Y 17 is an amino acid selected from the group consisting of T, S, H, G, A, and K.
  • Y 18 is an amino acid selected from the group consisting of A, G, K, M, S, and F.
  • Y 19 is an amino acid selected from the group consisting of A, M, T, L, and S.
  • Y 20 is an amino acid selected from the group consisting of A, P, Q, R, S, and W.
  • Y21 is an amino acid selected from the group consisting of P, E, L, A, T, and R.
  • Y 22 is an amino acid selected from the group consisting of G, S, R, P, L, and N.
  • Y 23 is an amino acid selected from the group consisting of V, P, and L.
  • Y 24 is an amino acid selected from the group consisting of L, S, G, W, and A.
  • Y 25 is an amino acid selected from the group consisting of L, A, S, and F.
  • Y 26 is an amino acid selected from the group consisting of L, Q, and V.
  • Y 27 is an amino acid selected from the group consisting of L, S, V, C, and I.
  • Y 28 is an amino acid selected from the group consisting of L, F, A, and V.
  • Y 29 is an amino acid selected from the group consisting of L, A, and I.
  • Y30 is an amino acid selected from the group consisting of L, H, A, and S.
  • Y 31 is an amino acid selected from the group consisting of C, S, A, V, W, F, and L.
  • Y 32 is an amino acid selected from the group consisting of L, F, G, C, S, and A.
  • Y 33 is an amino acid selected from the group consisting of L, A, T, and V.
  • Y 34 is an amino acid selected from the group consisting of G, M, T, A, Q, and E.
  • Y 35 is an amino acid selected from the group consisting of A, S, H, Y, and W.
  • Y 36 is an amino acid selected from the group consisting of T, V, S, A, and C.
  • Y 37 is an amino acid selected from the group consisting of R, T, A, N, Y, and S.
  • Y 38 is an amino acid selected from the group consisting of A and G.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 2 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 3 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a ACTIVE/131743364.1 103 Attorney Docket No.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 5 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 6 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 7 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 8 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 9 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 10 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 11 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 12 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 13 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 14 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 15 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 16 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 17 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 18 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 19 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 20 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 21 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 22 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 23 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 24 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 25 of SEQ ACTIVE/131743364.1 104 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 26 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 27 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 28 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 29 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 30 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 31 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 32 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 33 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 34 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 35 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 36 of SEQ ID NO: 25. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 37 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at position 38 of SEQ ID NO: 25.
  • the variant may also comprise any number of substitutions as provided by Formula XXV.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at at least one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, or 38 of SEQ ID NO: 25.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 25 and a substitution at more than one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, or 38 of SEQ ID NO: 25.
  • the signal peptide comprises an amino acid sequence represented by: Z 1 -Z 2 -Z 3 -Z 4 -Z 5 -Z 6 -Z 7 -Z 8 -Z 9 -Z 10 -Z 11 -Z 12 -Z 13 -Z 14 -Z 15 -Z 16 -Z 17 -Z 18 -Z 19 -Z 20 -Z 21 -Z 22 -Z 23 -Z 24 -Z 25 - Z 26 -Z 27 -Z 28 -Z 29 -Z 30 -Z 31 -Z 32 -Z 33 -Z 34 -Z 35 -Z 36 -Z 37 -Z 38 -Z 39 (Formula XXVI); ACTIVE/131743364.1 105 Attorney Docket No.
  • Z 1 is methionine (M).
  • Z 2 is an amino acid selected from the group consisting of L, A, and E.
  • Z 3 is an amino acid selected from the group consisting of C, L, V, and W.
  • Z 4 is an amino acid selected from the group consisting of I, G, L, and F.
  • Z 5 is an amino acid selected from the group consisting of Y, L, R, and S.
  • Z 6 is an amino acid selected from the group consisting of G, P, and C.
  • Z7 is an amino acid selected from the group consisting of T, G, R, and V.
  • Z 8 is an amino acid selected from the group consisting of L, T, and G.
  • Z 9 is an amino acid selected from the group consisting of F, S, G, and A.
  • Z 10 is an amino acid selected from the group consisting of T, Y, and L.
  • Z 11 is an amino acid selected from the group consisting of T, L, S, and A.
  • Z 12 is an amino acid selected from the group consisting of S, F, and E.
  • Z 13 is an amino acid selected from the group consisting of L, H, P, and R.
  • Z 14 is an amino acid selected from the group consisting of P, C, K, and Y.
  • Z 15 is an amino acid selected from the group consisting of T, P, L, and C.
  • Z16 is an amino acid selected from the group consisting of K, W, D, and R.
  • Z17 is an amino acid selected from the group consisting of S, P, N, and R.
  • Z 18 is an amino acid selected from the group consisting of L, R, and S.
  • Z 19 is an amino acid selected from the group consisting of N, Q, V, and P.
  • Z 20 is an amino acid selected from the group consisting of ACTIVE/131743364.1 107 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT M, Q, P, and G.
  • Z 21 is an amino acid selected from the group consisting of G, P, K, and I.
  • Z 22 is an amino acid selected from the group consisting of I, A, G, and T.
  • Z 23 is an amino acid selected from the group consisting of S, L, K, and C.
  • Z 24 is an amino acid selected from the group consisting of L, W, M, and C.
  • Z 25 is an amino acid selected from the group consisting of T, P, K, and V.
  • Z 26 is an amino acid selected from the group consisting of T, I, and L.
  • Z 27 is an amino acid selected from the group consisting of L and I.
  • Z28 is an amino acid selected from the group consisting of L and A.
  • Z 29 is an amino acid selected from the group consisting of I, A, V, and L.
  • Z 30 is an amino acid selected from the group consisting of L, F, and N.
  • Z 31 is an amino acid selected from the group consisting of S, A, L, and C.
  • Z 32 is an amino acid selected from the group consisting of V, L, G, and S.
  • Z 33 is an amino acid selected from the group consisting of L, A, and G.
  • Z 34 is an amino acid selected from the group consisting of V, S, and L.
  • Z 35 is an amino acid selected from the group consisting of L, S, G, and P.
  • Z 36 is an amino acid selected from the group consisting of L, V, N, and M.
  • Z 37 is an amino acid selected from the group consisting of S and A.
  • Z38 is an amino acid selected from the group consisting of T, E, V, and L.
  • Z 39 is alanine (A).
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 2 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 3 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 4 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 5 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 6 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 7 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 8 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 9 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 10 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 11 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 12 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 13 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 14 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 15 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 16 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 17 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 18 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 19 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 20 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 21 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 22 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 23 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 24 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 25 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 26 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 27 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 28 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 29 of SEQ ID NO: 26. In some embodiments, the signal peptide ACTIVE/131743364.1 109 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 30 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 31 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 32 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 33 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 34 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 35 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 36 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 37 of SEQ ID NO: 26. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at position 38 of SEQ ID NO: 26.
  • the variant may also comprise any number of substitutions as provided by Formula XXVI. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at at least one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, or 38 of SEQ ID NO: 26.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 26 and a substitution at more than one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, or 38 of SEQ ID NO: 26.
  • the signal peptide comprises an amino acid sequence represented by: (AA) 1 -(AA) 2 -(AA) 3 -(AA) 4 -(AA) 5 -(AA) 6 -(AA) 7 -(AA) 8 -(AA) 9 -(AA) 10 -(AA) 11 -(AA) 12 -(AA) 13 - (AA) 14 -(AA) 15 -(AA) 16 -(AA) 17 -(AA) 18 -(AA) 19 -(AA) 20 -(AA) 21 -(AA) 22 -(AA) 23 -(AA) 24 -(AA) 25 - (AA)26-(AA)27-(AA)28-(AA)29-(AA)30-(AA)31-(AA)32-(AA)33-(AA)34-(AA)35-(AA)36-(AA)37-
  • (AA) 1 is methionine (M).
  • (AA) 2 is an amino acid selected from the group consisting of R, A, G, and L.
  • (AA) 3 is an amino acid selected from the group consisting of H, A, R, F, and V.
  • (AA) 4 is an amino acid selected from the group consisting of A, G, T, M, and L.
  • (AA) 5 is an amino acid selected from the group consisting of S, H, A, and C.
  • (AA)6 is an amino acid selected from the group consisting of A, I, T, and G.
  • (AA) 7 is an amino acid selected from the group consisting of P, Q, R, and F.
  • (AA) 8 is an amino acid selected from the group consisting of G, N, A, and P.
  • (AA) 9 is an amino acid selected from the group consisting of G, A, L, and E.
  • (AA) 10 is an amino acid selected from the group consisting of R, C, S, and A.
  • (AA) 11 is an amino acid selected from the group consisting of G, R, Q, and M.
  • (AA) 12 is an amino acid selected from the group consisting of A, T, G, S, and P.
  • (AA) 13 is an amino acid selected from the group consisting of L, K, A, and S.
  • (AA) 14 is an amino acid selected from the group consisting of S, A, H, and G.
  • (AA)15 is an amino acid selected from the group consisting of R, A, C, P, and N.
  • (AA) 16 is an amino acid selected from the group consisting of F, A, R, L, and S.
  • (AA) 17 is an amino acid selected from the group consisting of A, V, C, and R.
  • (AA) 18 is an amino acid selected from the group consisting of P, V, A, and F.
  • (AA) 19 is an amino acid selected from the group consisting of C, R, W, H, and P.
  • (AA) 20 is an amino ACTIVE/131743364.1 112 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT acid selected from the group consisting of I, G, L, S, and A.
  • (AA) 21 is an amino acid selected from the group consisting of S, M, G, and C.
  • (AA) 22 is an amino acid selected from the group consisting of S, G, P, and L.
  • (AA) 23 is an amino acid selected from the group consisting of G, F, Q, and A.
  • (AA) 24 is an amino acid selected from the group consisting of A, L, I, and P.
  • (AA) 25 is an amino acid selected from the group consisting of L, R, F, and G.
  • (AA) 26 is an amino acid selected from the group consisting of S, C, Y, and A.
  • (AA)27 is an amino acid selected from the group consisting of L, K, W, and T.
  • (AA) 28 is an amino acid selected from the group consisting of L, I, C, V, and Y.
  • (AA) 29 is an amino acid selected from the group consisting of L and A.
  • (AA) 30 is an amino acid selected from the group consisting of L, V, I, and A.
  • (AA) 31 is an amino acid selected from the group consisting of F, S, I, and L.
  • (AA) 32 is an amino acid selected from the group consisting of L, F, and V.
  • (AA) 33 is an amino acid selected from the group consisting of L, C, and A.
  • (AA) 34 is an amino acid selected from the group consisting of G, C, V, and H.
  • (AA) 35 is an amino acid selected from the group consisting of C, H, Q, M, and L.
  • (AA)36 is an amino acid selected from the group consisting of Y, L, V, M, and S.
  • (AA) 37 is an amino acid selected from the group consisting of V, A, G, S, and L.
  • (AA) 38 is an amino acid selected from the group consisting of S, L, and V.
  • (AA) 39 is an amino acid selected from the group consisting of A, T, L, V, and S.
  • (AA) 40 is an amino acid selected from the group consisting of Q, L, and F.
  • (AA) 41 is an amino acid selected from the group consisting of G and A. [0175] It is to be understood that a variant of SEQ ID NO: 27 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XXVII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 2 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 3 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 4 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 5 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of ACTIVE/131743364.1 113 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT SEQ ID NO: 27 and a substitution at position 6 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 7 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 8 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 9 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 10 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 11 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 12 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 13 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 14 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 15 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 16 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 17 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 18 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 19 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 20 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 21 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 22 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 23 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 24 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 25 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 26 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at ACTIVE/131743364.1 114 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT position 27 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 28 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 29 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 30 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 31 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 32 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 33 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 34 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 35 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 36 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 37 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 38 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 39 of SEQ ID NO: 27. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 40 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at position 41 of SEQ ID NO: 27.
  • the variant may also comprise any number of substitutions as provided by Formula XXVII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at at least one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 of SEQ ID NO: 27.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 27 and a substitution at more than one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 of SEQ ID NO: 27.
  • Variants of SEQ ID NO: 28 (Formula XXVIII)
  • the signal peptide comprises an amino acid sequence represented by: ACTIVE/131743364.1 115 Attorney Docket No.
  • (BB)1 is methionine (M).
  • (BB)2 is an amino acid selected from the group consisting of A and P.
  • (BB)3 is an amino acid selected from the group consisting of P and G.
  • (BB) 4 is an amino acid selected from the group consisting of S and P.
  • (BB) 5 is an amino acid selected from the group consisting of P and R.
  • (BB) 6 is an amino acid selected from the group consisting of R and G.
  • (BB) 7 is an amino acid selected from the group consisting of T and A.
  • (BB) 8 is an amino acid selected from the group consisting of G and A.
  • (BB) 9 is an amino acid selected from the group consisting of S and G.
  • (BB) 10 is an amino acid selected from the group consisting of R and G.
  • (BB) 11 is an amino acid selected from the group consisting of Q and L.
  • (BB)12 is an amino acid selected from the group consisting of D and A.
  • (BB)13 is an amino acid selected from the group consisting of A and P.
  • (BB) 14 is an ACTIVE/131743364.1 117 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT amino acid selected from the group consisting of T and E.
  • (BB) 15 is an amino acid selected from the group consisting of A and M.
  • (BB) 16 is an amino acid selected from the group consisting of L and R.
  • (BB) 17 is an amino acid selected from the group consisting of P and G.
  • (BB) 18 is an amino acid selected from the group consisting of S and A.
  • (BB) 19 is an amino acid selected from the group consisting of M and G.
  • (BB) 20 is an amino acid selected from the group consisting of S and A.
  • (BB) 21 is an amino acid selected from the group consisting of S and A.
  • (BB)22 is an amino acid selected from the group consisting of T and G.
  • (BB) 23 is an amino acid selected from the group consisting of F and L.
  • (BB) 24 is an amino acid selected from the group consisting of W and L.
  • (BB) 25 is alanine (A).
  • (BB) 26 is an amino acid selected from the group consisting of F and L.
  • (BB) 27 is an amino acid selected from the group consisting of M and L.
  • (BB) 28 is an amino acid selected from the group consisting of I and L.
  • (BB) 29 is leucine (L).
  • (BB) 30 is an amino acid selected from the group consisting of A and L.
  • (BB) 31 is an amino acid selected from the group consisting of S and L.
  • (BB)32 is leucine (L).
  • (BB)33 is leucine (L).
  • (BB) 34 is an amino acid selected from the group consisting of I and L.
  • (BB) 35 is an amino acid selected from the group consisting of A and L.
  • (BB) 36 is an amino acid selected from the group consisting of Y and G.
  • (BB) 37 is an amino acid selected from the group consisting of C and L.
  • (BB) 38 is an amino acid selected from the group consisting of S and G.
  • (BB) 39 is an amino acid selected from the group consisting of Q and G.
  • (BB) 40 is an amino acid selected from the group consisting of L and R.
  • (BB) 41 is an amino acid selected from the group consisting of A and V.
  • (BB) 42 is an amino acid selected from the group consisting of A and E.
  • (BB)43 is glycine (G).
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 2 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 3 of SEQ ID NO: 28. In some ACTIVE/131743364.1 118 Attorney Docket No.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 4 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 5 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 6 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 7 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 8 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 9 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 10 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 11 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 12 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 13 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 14 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 15 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 16 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 17 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 18 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 19 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 20 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 21 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 22 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 23 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 24 of SEQ ID NO: 28. In some embodiments, the signal peptide ACTIVE/131743364.1 119 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 26 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 27 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 28 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 30 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 31 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 34 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 35 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 36 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 37 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 38 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 39 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 40 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 41 of SEQ ID NO: 28. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at position 42 of SEQ ID NO: 28.
  • the variant may also comprise any number of substitutions as provided by Formula XXVIII. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, or 42 of SEQ ID NO: 28.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 28 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 30, 31, 34, 35, 36, 37, 38, 39, 40, 41, or 42 of SEQ ID NO: 28.
  • Variants of SEQ ID NO: 29 (Formula XXIX)
  • the signal peptide comprises an amino acid sequence represented by: ACTIVE/131743364.1 120 Attorney Docket No.
  • (CC) 1 is methionine (M).
  • (CC) 2 is an amino acid selected from the group consisting of E and H.
  • (CC) 3 is an amino acid selected from the group consisting of C, L, and K.
  • (CC) 4 is an amino acid selected from the group consisting of A, G, and E.
  • (CC)5 is an amino acid selected from the group consisting of L and A.
  • (CC) 6 is an amino acid selected from the group consisting of L, G, and E.
  • (CC) 7 is an amino acid selected from the group consisting of L, G, and M.
  • (CC) 8 is an amino acid selected from the group consisting of L and A.
  • (CC) 9 is an amino acid selected from the group consisting of C, S, and I.
  • (CC) 10 is an amino acid selected from the group consisting of A, T, and G.
  • (CC) 11 is an amino acid selected from the group consisting of F, L, and P.
  • (CC) 12 is an amino acid selected from the group consisting of P, S, and Q.
  • (CC) 13 is an amino acid selected from the group consisting of A, H, and L.
  • (CC) 14 is an amino acid selected from the group consisting of A, C, and D.
  • (CC) 15 is an amino acid selected from the group consisting of G, P, and E.
  • (CC) 16 is an amino acid selected from the group consisting of S, W, and K.
  • (CC)17 is an amino acid selected from the group consisting of G, P, and R.
  • (CC) 18 is an amino acid selected from the group consisting of P, R, and W.
  • (CC) 19 is an amino acid selected from the group consisting of P, R, and G.
  • (CC) 20 is an amino acid selected from the group consisting of R, Q, and W.
  • (CC) 21 is an amino acid selected from the group consisting of G, A, and R.
  • (CC) 22 is an amino acid selected from the group consisting of L and P.
  • (CC) 23 is an amino acid selected from the group consisting of A, L, and G.
  • (CC) 24 is an amino acid selected from the group consisting of G and D.
  • (CC) 25 is an amino acid selected from the group consisting of L and G.
  • (CC)26 is an amino acid selected from the group consisting of S and G.
  • (CC) 27 is an amino acid selected from the group consisting of A and R.
  • (CC) 28 is an amino acid selected from the group consisting of V, Q, and A.
  • (CC) 29 is an amino acid selected from the group consisting of P and A.
  • (CC) 30 is an amino acid selected from the group consisting of K, A, and P.
  • (CC) 31 is an amino acid selected from the group consisting of A, L, and F.
  • (CC) 32 is an amino acid selected from the group consisting of L and W.
  • (CC) 33 is an amino acid selected from the group consisting of P and Q.
  • (CC) 34 is an amino acid selected from the group consisting of L, T, and Q.
  • (CC) 35 is an amino acid selected from the group consisting of C, L, and A.
  • (CC)36 is an amino acid selected from the group consisting of C, A, and L.
  • (CC) 37 is an amino acid selected from the group consisting of L, A, and S.
  • (CC) 38 is an amino acid selected from the group consisting of C, L, and F.
  • (CC) 39 is an amino acid selected from the group consisting of C, A, and L.
  • (CC) 40 is an amino acid selected from the group consisting of L and A.
  • (CC) 41 is an amino acid selected from the group consisting of L and S.
  • (CC) 42 is an amino acid ACTIVE/131743364.1 123 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT selected from the group consisting of V, S, and L.
  • (CC) 43 is an amino acid selected from the group consisting of A, S, and P.
  • (CC) 44 is an amino acid selected from the group consisting of A, V, and L.
  • (CC) 45 is alanine (A).
  • (CC) 46 is an amino acid selected from the group consisting of L, E, and S.
  • (CC) 47 is alanine (A).
  • a variant of SEQ ID NO: 29 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XXIX.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 2 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 3 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 4 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 5 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 6 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 7 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 8 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 9 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 10 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 11 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 12 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 13 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 14 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 15 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 16 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 17 of SEQ ID NO: 29.
  • the signal peptide comprises the amino ACTIVE/131743364.1 124 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT acid sequence of SEQ ID NO: 29 and a substitution at position 18 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 19 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 20 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 21 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 22 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 23 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 24 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 25 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 26 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 27 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 28 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 29 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 30 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 31 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 32 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 33 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 34 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 35 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 36 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 37 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 38 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a ACTIVE/131743364.1 125 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT substitution at position 39 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 40 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 41 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 42 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 43 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 44 of SEQ ID NO: 29. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at position 46 of SEQ ID NO: 29.
  • the variant may also comprise any number of substitutions as provided by Formula XXIX.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at at least one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 46 of SEQ ID NO: 29.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 29 and a substitution at more than one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, or 46 of SEQ ID NO: 29.
  • the signal peptide comprises an amino acid sequence represented by: (DD) 1 -(DD) 2 -(DD) 3 -(DD) 4 -(DD) 5 -(DD) 6 -(DD) 7 -(DD) 8 -(DD) 9 -(DD) 10 -(DD) 11 -(DD) 12 -(DD) 13 - (DD) 14 -(DD) 15 -(DD) 16 -(DD) 17 -(DD) 18 -(DD) 19 -(DD) 20 -(DD) 21 -(DD) 22 -(DD) 23 -(DD) 24 -(DD) 25 - (DD) 26 -(DD) 27 -(DD) 28 -(DD) 29 -(DD) 30 -(DD) 31 -(DD) 32 -(DD) 33 -(DD) 34 -(DD) 35 -(DD) 30 -(DD) 31 -(DD) 32 -(DD) 33 -(DD) 34 -(
  • (DD) 1 is methionine (M).
  • (DD) 2 is an amino acid selected from the group consisting of G and H.
  • (DD) 3 is an amino acid selected from the group consisting of K and P.
  • (DD) 4 is an amino acid selected from the group consisting of I and P.
  • (DD) 5 is an amino acid selected from the group consisting of S and K.
  • (DD) 6 is an amino acid selected from the group consisting of S and T.
  • (DD) 7 is an amino acid selected from the group consisting of L and P.
  • (DD) 8 is an amino acid selected from the group consisting of P and S.
  • (DD) 9 is an amino acid selected from the group consisting of T and G.
  • (DD)10 is an amino acid selected from the group consisting of Q and A.
  • (DD)11 is leucine (L).
  • (DD) 12 is an amino acid selected from the group consisting of F and H.
  • (DD) 13 is an amino acid selected from the group consisting of K and R.
  • (DD) 14 is an amino acid selected from the group consisting of C and K.
  • (DD) 15 is an amino acid selected from the group consisting of C and R.
  • (DD) 16 is an amino acid selected from the group consisting of F and K.
  • (DD) 17 is an amino acid selected from the group consisting ACTIVE/131743364.1 128 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT of C and M.
  • (DD) 18 is an amino acid selected from the group consisting of D and A.
  • (DD) 19 is an amino acid selected from the group consisting of F and A.
  • (DD) 20 is an amino acid selected from the group consisting of L and W.
  • (DD) 21 is an amino acid selected from the group consisting of K and P.
  • (DD) 22 is an amino acid selected from the group consisting of V and F.
  • (DD) 23 is an amino acid selected from the group consisting of K and S.
  • (DD) 24 is an amino acid selected from the group consisting of M and R.
  • (DD)25 is an amino acid selected from the group consisting of H and L.
  • (DD) 26 is an amino acid selected from the group consisting of T and W.
  • (DD) 27 is an amino acid selected from the group consisting of M and K.
  • (DD) 28 is an amino acid selected from the group consisting of S and V.
  • (DD) 29 is serine (S).
  • (DD) 30 is an amino acid selected from the group consisting of S and D.
  • (DD) 31 is an amino acid selected from the group consisting of H and P.
  • (DD) 32 is an amino acid selected from the group consisting of L and I.
  • (DD) 33 is an amino acid selected from the group consisting of F and L.
  • (DD) 34 is an amino acid selected from the group consisting of Y and F.
  • (DD) 35 is an amino acid selected from the group consisting of L and Q.
  • (DD)36 is an amino acid selected from the group consisting of A and M.
  • (DD) 37 is an amino acid selected from the group consisting of L and T.
  • (DD) 38 is an amino acid selected from the group consisting of C and L.
  • (DD) 39 is an amino acid selected from the group consisting of L and I.
  • (DD) 40 is an amino acid selected from the group consisting of L and A.
  • (DD) 41 is an amino acid selected from the group consisting of T and A.
  • (DD) 42 is an amino acid selected from the group consisting of F and L.
  • (DD) 43 is an amino acid selected from the group consisting of T and L.
  • (DD) 44 is an amino acid selected from the group consisting of S and P.
  • (DD) 45 is an amino acid selected from the group consisting of S and A.
  • (DD)46 is an amino acid selected from the group consisting of A and V.
  • (DD) 47 is an amino acid selected from the group consisting of T and L.
  • (DD) 48 is an amino acid selected from the group consisting of A and G.
  • the ACTIVE/131743364.1 129 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 2 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 3 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 4 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 5 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 6 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 7 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 8 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 9 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 10 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 12 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 13 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 14 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 15 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 16 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 17 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 18 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 19 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 20 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 21 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 22 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 23 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino ACTIVE/131743364.1 130 Attorney Docket No.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 24 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 25 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 26 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 27 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 28 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 30 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 31 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 32 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 33 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 34 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 35 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 36 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 37 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 38 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 39 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 40 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 41 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 42 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 43 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 44 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 45 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a ACTIVE/131743364.1 131 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT substitution at position 46 of SEQ ID NO: 30. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 47 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at position 48 of SEQ ID NO: 30.
  • the variant may also comprise any number of substitutions as provided by Formula XXX.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 of SEQ ID NO: 30.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 30 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 of SEQ ID NO: 30.
  • the signal peptide comprises an amino acid sequence represented by: (EE) 1 -(EE) 2 -(EE) 3 -(EE) 4 -(EE) 5 -(EE) 6 -(EE) 7 -(EE) 8 -(EE) 9 -(EE) 10 -(EE) 11 -(EE) 12 -(EE) 13 -(EE) 14 - (EE)15-(EE)16-(EE)17-(EE)18-(EE)19-(EE)20-(EE)21-(EE)22-(EE)23-(EE)24-(EE)25-(EE)26-(EE)27- (EE) 28 -(EE) 29 -(EE) 30 -(EE) 31 -(EE) 32 -(EE) 33 -(EE) 34 -(EE) 35 -(EE) 36 -(EE) 37 -(EE) 30 -(EE) 31 -(EE) 32 -(EE) 33 -(EE) 34 -(EE
  • (EE) 1 is methionine (M).
  • (EE) 2 is an amino acid selected from the group consisting of A, Q, and Y.
  • (EE) 3 is an amino acid selected from the group consisting of P, R, and K.
  • (EE) 4 is an amino acid selected from the group consisting of A and R.
  • (EE) 5 is an amino acid selected from the group consisting of G, V, and R.
  • (EE)6 is an amino acid selected from the group consisting of P and C.
  • (EE) 7 is an amino acid selected from the group consisting of A, E, and P.
  • (EE) 8 is an amino acid selected from the group consisting of G and A.
  • (EE) 9 is an amino acid selected from the group consisting of H, F, and G.
  • (EE) 10 is an amino acid selected from the group consisting of P, G, and S.
  • (EE) 11 is an amino acid selected from the group consisting of P, R, and G.
  • (EE) 12 is an amino acid selected from the group consisting of P, R, and G.
  • (EE) 13 is an amino acid selected from the group consisting of P and K.
  • (EE) 14 is an amino acid selected from the group consisting of S, L, and G.
  • (EE)15 is an amino acid selected from the group consisting of P, G, and A.
  • (EE)16 is an amino acid selected from the group consisting of Q, S, and E.
  • (EE) 17 is an amino acid selected from the group consisting of A, D, and P.
  • (EE) 18 is an amino acid selected from the group consisting of C, M, and P.
  • (EE) 19 is an amino acid selected from the group consisting of V, G, and A.
  • (EE) 20 is an amino acid selected from the group consisting of C, N, and M.
  • (EE) 21 is an amino acid selected from the group consisting of A and P.
  • (EE) 22 is an amino ACTIVE/131743364.1 134 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT acid selected from the group consisting of G, E, and A.
  • (EE) 23 is an amino acid selected from the group consisting of K, R, and P.
  • (EE) 24 is an amino acid selected from the group consisting of M, A, and R.
  • (EE) 25 is an amino acid selected from the group consisting of L, P, and G.
  • (EE) 26 is an amino acid selected from the group consisting of A, G, and R.
  • (EE) 27 is an amino acid selected from the group consisting of M, S, and A.
  • (EE) 28 is an amino acid selected from the group consisting of G, R, and A.
  • (EE)29 is an amino acid selected from the group consisting of A, S, and P.
  • (EE) 30 is an amino acid selected from the group consisting of L, F, and W.
  • (EE) 31 is an amino acid selected from the group consisting of A, G, and T.
  • (EE) 32 is an amino acid selected from the group consisting of G, P, and T.
  • (EE) 33 is an amino acid selected from the group consisting of F, V, and A.
  • (EE) 34 is an amino acid selected from the group consisting of W, P, and L.
  • (EE) 35 is an amino acid selected from the group consisting of I, T, and L.
  • (EE) 36 is leucine (L).
  • (EE) 37 is an amino acid selected from the group consisting of L and C.
  • (EE) 38 is leucine (L).
  • (EE) 39 is an amino acid selected from the group consisting of L and A.
  • (EE)40 is an amino acid selected from the group consisting of T, A, and S.
  • (EE) 41 is an amino acid selected from the group consisting of Y, A, and Q.
  • (EE) 42 is an amino acid selected from the group consisting of G, A, and V.
  • (EE) 43 is an amino acid selected from the group consisting of L and Y.
  • (EE) 44 is an amino acid selected from the group consisting of L and S.
  • (EE) 45 is an amino acid selected from the group consisting of S, A, and P.
  • (EE) 46 is an amino acid selected from the group consisting of W, V, and G.
  • (EE) 47 is an amino acid selected from the group consisting of S and G.
  • (EE) 48 is an amino acid selected from the group consisting of Q, D, and C.
  • (EE)49 is alanine (A). [0191] It is to be understood that a variant of SEQ ID NO: 31 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one substitution to be within the scope of Formula XXXI.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 2 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 3 of SEQ ID NO: 31. In some ACTIVE/131743364.1 135 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 4 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 5 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 6 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 7 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 8 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 9 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 10 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 11 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 12 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 13 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 14 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 15 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 16 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 17 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 18 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 19 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 20 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 21 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 22 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 23 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 24 of SEQ ID NO: 31. In some embodiments, the signal peptide ACTIVE/131743364.1 136 Attorney Docket No.
  • PATENT comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 25 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 26 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 27 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 28 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 29 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 30 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 31 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 32 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 33 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 34 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 35 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 37 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 39 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 40 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 41 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 42 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 43 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 44 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 45 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 46 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at position 47 of SEQ ID NO: 31. In some embodiments, the signal peptide comprises the amino acid sequence of ACTIVE/131743364.1 137 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT SEQ ID NO: 31 and a substitution at position 48 of SEQ ID NO: 31. The variant may also comprise any number of substitutions as provided by Formula XXXI.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at at least one position corresponding to position 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, 31, 32, 33, 34, 35, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 of SEQ ID NO: 31.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 31 and a substitution at more than one position corresponding to position 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, 31, 32, 33, 34, 35, 37, 39, 40, 41, 42, 43, 44, 45, 46, 47, or 48 of SEQ ID NO: 31.
  • the signal peptide comprises an amino acid sequence represented by: (FF) 1 -(FF) 2 -(FF) 3 -(FF) 4 -(FF) 5 -(FF) 6 -(FF) 7 -(FF) 8 -(FF) 9 -(FF) 10 -(FF) 11 -(FF) 12 -(FF) 13 -(FF) 14 - (FF) 15 -(FF) 16 -(FF) 17 -(FF) 18 -(FF) 19 -(FF) 20 -(FF) 21 -(FF) 22 -(FF) 23 -(FF) 24 -(FF) 25 -(FF) 26 -(FF) 27 - (FF) 28 -(FF) 29 -(FF) 30 -(FF) 31 -(FF) 32 -(FF) 33 -(FF) 34 -(FF) 35 -(FF) 30 -(FF) 31 -(FF) 32 -(FF) 33 -(FF) 34 -(
  • (FF) 1 is methionine (M).
  • (FF) 2 is an amino acid selected from the group consisting of Q and S.
  • (FF) 3 is an amino acid selected from the group consisting of R and T.
  • (FF) 4 is an amino acid selected from the group consisting of L and F.
  • (FF)5 is an amino acid selected from the group consisting of R and P.
  • (FF) 6 is an amino acid selected from the group consisting of W and V.
  • (FF) 7 is leucine (L).
  • (FF) 8 is an amino acid selected from the group consisting of R and A.
  • (FF) 9 is an amino acid selected from the group consisting of D and E.
  • (FF) 10 is an amino acid selected from the group consisting of W and D.
  • (FF) 11 is an amino acid selected from the group consisting of K and I.
  • (FF) 12 is an amino acid selected from the group consisting of S and P.
  • (FF) 13 is an amino acid selected from the group consisting of S and L.
  • (FF) 14 is an amino acid selected from the group consisting of G and R.
  • (FF)15 is an amino acid selected from the group consisting of R and E.
  • (FF) 16 is an amino acid selected from the group consisting of G and R.
  • (FF) 17 is an amino acid selected from the group consisting of L and H.
  • (FF) 18 is an amino acid selected from the group consisting of T and V.
  • (FF) 19 is an amino acid selected from the group consisting of A and K.
  • (FF) 20 is an amino acid selected from the group consisting of A and G.
  • (FF) 21 is an amino acid selected from the group consisting of K and R.
  • (FF) 22 is an amino acid selected from the group consisting of E and V.
  • (FF) 23 is an amino acid selected from the group consisting of P and D.
  • (FF) 24 is an amino acid selected from the group consisting of G and P.
  • (FF)25 is an amino acid selected from the group consisting ACTIVE/131743364.1 140 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT of A and H.
  • (FF) 26 is an amino acid selected from the group consisting of R and F.
  • (FF) 27 is an amino acid selected from the group consisting of S and R.
  • (FF) 28 is an amino acid selected from the group consisting of S and A.
  • (FF) 29 is proline (P).
  • (FF) 30 is an amino acid selected from the group consisting of L and K.
  • (FF) 31 is an amino acid selected from the group consisting of Q and M.
  • (FF) 32 is an amino acid selected from the group consisting of A and E.
  • (FF) 33 is methionine (M).
  • (FF)34 is an amino acid selected from the group consisting of R and F.
  • (FF) 35 is an amino acid selected from the group consisting of I and Q.
  • (FF) 36 is an amino acid selected from the group consisting of L and R.
  • (FF) 37 is an amino acid selected from the group consisting of Q and L.
  • (FF) 38 is leucine (L).
  • (FF) 39 is an amino acid selected from the group consisting of I and L.
  • (FF) 40 is leucine (L).
  • (FF) 41 is leucine (L).
  • (FF) 42 is an amino acid selected from the group consisting of A and L.
  • (FF) 43 is leucine (L).
  • (FF) 44 is an amino acid selected from the group consisting of A and S.
  • (FF) 45 is an amino acid selected from the group consisting of T and M.
  • (FF)46 is glycine (G).
  • (FF) 47 is an amino acid selected from the group consisting of L and G.
  • (FF) 48 is an amino acid selected from the group consisting of V and T.
  • (FF) 49 is an amino acid selected from the group consisting of G and W.
  • (FF) 50 is an amino acid selected from the group consisting of G and A.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 2 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 3 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 4 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 5 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 6 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at ACTIVE/131743364.1 141 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT position 8 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 9 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 15 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 16 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 17 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 18 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 19 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 20 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 21 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 22 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 23 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 24 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 25 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 26 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 27 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 28 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 30 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 31 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 32 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 34 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 35 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 36 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 37 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 39 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 42 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 44 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 45 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 47 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 48 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 49 of SEQ ID NO: 32. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at position 50 of SEQ ID NO: 32.
  • the variant may also comprise any number of substitutions as provided by Formula XXXII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at at least one position corresponding to position 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 34, 35, 36, 37, 39, 42, 44, 45, 47, 48, 49, or 50 of SEQ ID NO: 32.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 32 and a substitution at more than one position corresponding to position 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 30, 31, 32, 34, 35, 36, 37, 39, 42, 44, 45, 47, 48, 49, or 50 of SEQ ID NO: 32.
  • Variants of SEQ ID NO: 33 (Formula XXXIII)
  • the signal peptide comprises an amino acid sequence represented by: ACTIVE/131743364.1 143 Attorney Docket No.
  • (GG) 1 is methionine (M).
  • (GG) 2 is an amino acid selected from the group consisting of N, Q, and S.
  • (GG) 3 is an amino acid selected from the group consisting of F, A, and Q.
  • (GG) 4 is an amino acid selected from the group consisting of Q, P, and T.
  • ACTIVE/131743364.1 145 Attorney Docket No.
  • GG 5 is an amino acid selected from the group consisting of G and Q.
  • (GG) 6 is an amino acid selected from the group consisting of R and S.
  • (GG) 7 is an amino acid selected from the group consisting of L, G, and H.
  • (GG) 8 is an amino acid selected from the group consisting of P and Q.
  • (GG) 9 is an amino acid selected from the group consisting of S, L, and G.
  • (GG) 10 is an amino acid selected from the group consisting of L, G, and R.
  • (GG) 11 is an amino acid selected from the group consisting of W, L, and G.
  • (GG)12 is an amino acid selected from the group consisting of T, R, and L.
  • (GG) 13 is an amino acid selected from the group consisting of L and A.
  • (GG) 14 is an amino acid selected from the group consisting of A, M, and G.
  • (GG) 15 is an amino acid selected from the group consisting of R and M.
  • (GG) 16 is an amino acid selected from the group consisting of P and W.
  • (GG) 17 is an amino acid selected from the group consisting of F, G, and L.
  • (GG) 18 is an amino acid selected from the group consisting of C, R, and W.
  • (GG) 19 is an amino acid selected from the group consisting of P, R, and G.
  • (GG) 20 is an amino acid selected from the group consisting of P, G, and A.
  • (GG) 21 is an amino acid selected from the group consisting of L, A, and Q.
  • (GG)22 is an amino acid selected from the group consisting of L and P.
  • (GG) 23 is an amino acid selected from the group consisting of A, R, and C.
  • (GG) 24 is an amino acid selected from the group consisting of T, E, and L.
  • (GG) 25 is an amino acid selected from the group consisting of A, P, and L.
  • (GG) 26 is an amino acid selected from the group consisting of S, G, and L.
  • (GG) 27 is an amino acid selected from the group consisting of Q, G, and P.
  • (GG) 28 is an amino acid selected from the group consisting of M, C, and I.
  • (GG) 29 is an amino acid selected from the group consisting of Q, G, and V.
  • (GG) 30 is an amino acid selected from the group consisting of M, S, and P.
  • (GG)31 is an amino acid selected from the group consisting of V, C, and L.
  • (GG) 32 is an amino acid selected from the group consisting of V, L, and S.
  • (GG) 33 is an amino acid selected from the group consisting of L, G, and W.
  • (GG) 34 is an amino acid selected from the group consisting of P, V, and L.
  • (GG) 35 is an amino acid selected from the group consisting of C, A, and V.
  • (GG) 36 is an amino acid selected from the group consisting of L and W.
  • (GG) 37 is an amino acid ACTIVE/131743364.1 146 Attorney Docket No.
  • (GG) 38 is an amino acid selected from the group consisting of L and F.
  • (GG) 39 is an amino acid selected from the group consisting of L and T.
  • (GG) 40 is leucine (L).
  • (GG) 41 is leucine (L).
  • (GG) 42 is leucine (L).
  • (GG) 43 is an amino acid selected from the group consisting of W, L, and A.
  • (GG) 44 is an amino acid selected from the group consisting of S and P.
  • (GG) 45 is an amino acid selected from the group consisting of Q, A, and L.
  • (GG)46 is an amino acid selected from the group consisting of V, C, and L.
  • (GG) 47 is an amino acid selected from the group consisting of S, C, and P.
  • (GG) 48 is an amino acid selected from the group consisting of G, P, and S.
  • (GG) 49 is an amino acid selected from the group consisting of A and V.
  • (GG) 50 is an amino acid selected from the group consisting of R and Q.
  • (GG) 51 is an amino acid selected from the group consisting of G, A, and L.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 2 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 3 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 4 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 5 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 6 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 7 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 8 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 9 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 10 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 11 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at ACTIVE/131743364.1 147 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT position 12 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 13 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 14 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 15 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 16 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 17 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 18 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 19 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 20 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 21 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 22 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 23 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 24 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 25 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 26 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 27 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 28 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 29 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 30 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 31 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 32 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 33 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 34 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 35 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 36 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 37 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 38 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 39 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 43 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 44 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 45 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 46 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 47 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 48 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 49 of SEQ ID NO: 33. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 50 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at position 51 of SEQ ID NO: 33.
  • the variant may also comprise any number of substitutions as provided by Formula XXXIII.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at at least one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 43, 44, 45, 47, 48, 49, 50, or 51 of SEQ ID NO: 33.
  • the signal peptide comprises the amino acid sequence of SEQ ID NO: 33 and a substitution at more than one position corresponding to position 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, 31, 32, 33, 34, 35, 36, 37, 38, 39, 43, 44, 45, 47, 48, 49, 50, or 51 of SEQ ID NO: 33.
  • ACTIVE/131743364.1 149 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT [0200]
  • the signal peptide is a novel signal peptide.
  • a “novel” signal peptide is understood to comprise an amino acid sequence not found in nature or not yet known to exist in nature. Accordingly, if an embodiment references a novel signal peptide, it is understood to exclude any corresponding native sequence.
  • a novel signal peptide is provided, wherein the novel signal peptide comprises an amino acid sequence corresponding to Formula X. In such an embodiment, if a native signal peptide could be construed from the formula of Formula X, the embodiment is understood to exclude said native signal peptide. [0201] In some embodiments, a novel signal peptide is provided.
  • the novel signal peptide comprises an amino acid sequence selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XVII, Formula XXVIII, Formula XXIX, Formula XXX, Formula XX, Formula XXI, Formula XII, or Formula XXXIII.
  • the novel signal peptide comprises an amino acid sequence of Formula I. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula II. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula III. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula IV. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula V. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula VI. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula VII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula VIII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula IX.
  • the novel signal peptide comprises an amino acid sequence of Formula X. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XI. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XIII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XIV. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XV. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XVI. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XVII.
  • the novel ACTIVE/131743364.1 150 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT signal peptide comprises an amino acid sequence of Formula XVIII.
  • the novel signal peptide comprises an amino acid sequence of Formula XIX.
  • the novel signal peptide comprises an amino acid sequence of Formula XX.
  • the novel signal peptide comprises an amino acid sequence of Formula XXI.
  • the novel signal peptide comprises an amino acid sequence of Formula XXIII.
  • the novel signal peptide comprises an amino acid sequence of Formula XXIV. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXV. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXVI. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXVII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXVIII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXIX. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXX. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXI.
  • the novel signal peptide comprises an amino acid sequence of Formula XXXII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXXIII. [0202] While novel signal peptide sequences of any one of Formula I – Formula XXXIII are contemplated herein, in some embodiments, specific sequence identities are not contemplated. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula II, provided that the sequence of Formula II is not SEQ ID NO: 34 (MLLLLLLLLLAAVAA).
  • the novel signal peptide comprises an amino acid sequence of Formula III, provided that the sequence of Formula III is not SEQ ID NO: 35 (MKVLLLLLFLLLLTLA), SEQ ID NO: 55 (MWVLLLLLFLLLLTLA), SEQ ID NO: 56 (MKVLLLLLLLLTLA), SEQ ID NO: 57 (MKVLLLLLFLLLLTSA), SEQ ID NO: 58 (MWVLLLLLLLLTLA), SEQ ID NO: 59 (MWVLLLLLFLLLLTSA), SEQ ID NO: 60 (MKVLLLLLLLLLLTSA), or SEQ ID NO: 61 (MWVLLLLLLLLLLTSA).
  • the novel signal peptide comprises an amino acid sequence of Formula IV, provided that the sequence of Formula IV is not SEQ ID NO: 36 (MWLLLALLLLLAGAAAA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula V, provided that the sequence of Formula V is not SEQ ID NO: 37 (MKLLLLLLLLLLLSGADA) or SEQ ID NO: 62 (MKLLLLLLLLLLLSGALA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula VI, ACTIVE/131743364.1 151 Attorney Docket No.
  • the novel signal peptide comprises an amino acid sequence of Formula VII, provided that the sequence of Formula VII is not SEQ ID NO: 39 (MALLLLLLLLLLLALALA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula VIII, provided that the sequence of Formula VIII is not SEQ ID NO: 40 (MALLALLLLLLLLLLLALAQA).
  • the novel signal peptide comprises an amino acid sequence of Formula IX, provided that the sequence of Formula IX is not SEQ ID NO: 41 (MALLRLLLLLLLLLLLLAGVLG), SEQ ID NO: 63 (MAPLRLLLLLLLLLLLLAGVLG), SEQ ID NO: 64 (MALLRLLLLLLLLLLLLGGVLG), or SEQ ID NO: 65 (MAPLRLLLLLLLLLLLLLLGGVLG).
  • the novel signal peptide comprises an amino acid sequence of Formula X, provided that the sequence of Formula X is not SEQ ID NO: 42 (MALSFALLLLLLLLLLLSSCSLA).
  • the novel signal peptide comprises an amino acid sequence of Formula XI, provided that the sequence of Formula XI is not SEQ ID NO: 43 (MARLALLLLLLLLLLLLLLPAVEA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XII, provided that the sequence of Formula XII is not SEQ ID NO: 44 (MGSLGLLLLLLLLLLLLLLLGGALA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XIII, provided that the sequence of Formula XIII is not SEQ ID NO: 45 (MAAPLRSALLLLALLLLLLLLLLGEASA).
  • the novel signal peptide comprises an amino acid sequence of Formula XIV, provided that the sequence of Formula XIV is not SEQ ID NO: 46 (MALARLLLLLLLLLLLLLLLLLGGVLA), SEQ ID NO: 66 (MAPARLLLLLLLLLLLLLLLLLGGVLA), SEQ ID NO: 67 (MALARLLLLLLLLLLLLLLPGGVLA), SEQ ID NO: 68 (MALARLLLLLLLLLLLLLLLLLGGVRA), SEQ ID NO: 69 (MAPARLLLLLLLLLLLLLLLLPGGVLA), SEQ ID NO: 70 (MAPARLLLLLLLLLLLLLLLLLGGVRA), SEQ ID NO: 71 (MALARLLLLLLLLLLLLLLLLPGGVRA), or SEQ ID NO: 72 (MAPARLLLLLLLLLLLLLLPGGVRA).
  • the novel signal peptide comprises an amino acid sequence of Formula XV, provided that the sequence of Formula XV is not SEQ ID NO: 47 (MAPGRTPLLALLLLLLLLLLLLPAAALA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XVI, provided that the sequence of Formula XVI is not SEQ ID NO: 48 ACTIVE/131743364.1 152 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT (MPARGLRALLLLLLLLLLLLLLPLRPAQA).
  • the novel signal peptide comprises an amino acid sequence of Formula XVII, provided that the sequence of Formula XVII is not SEQ ID NO: 49 (MAAARSRGARWLKLLLLLLLLLPPGALA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XVIII, provided that the sequence of Formula XVIII is not SEQ ID NO: 50 (MALASRGSAALALLALLLLLLLALLLAGAAA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XIX, provided that the sequence of Formula XIX is not SEQ ID NO: 51 (MRAGPALAVRAALRALLLLLLLGLLLLDGSDA).
  • the novel signal peptide comprises an amino acid sequence of Formula XX, provided that the sequence of Formula XX is not SEQ ID NO: 52 (MAALAPKVSPAAAGVLLLLLLLLLLPGGAAA). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXI, provided that the sequence of Formula XXI is not SEQ ID NO: 53 (MARATLSAAPSNPRLLRVALLLLLLLAALRRAAG). In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXII, provided that the sequence of Formula XII is not SEQ ID NO: 54 (MAGWRRMAKALPAPAGGPACALLLLLLLLAAGAQA).
  • the novel signal peptide comprises an amino acid sequence having at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 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, 31, 32, or 33.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 1. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 2. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 3. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 4. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 5.
  • the novel signal peptide comprises an ACTIVE/131743364.1 153 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 6.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 7.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 8.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 9.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 10. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 11. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 12. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 13. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 14.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 15. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 16. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 17. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 18. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 19.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 20. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 21. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 22. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 23. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 24.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 25. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino ACTIVE/131743364.1 154 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT acid sequence of SEQ ID NO: 26. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 27. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 28.
  • the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 29. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 30. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 31. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 32. In some embodiments, the novel signal peptide comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 33.
  • a recombinant polypeptide comprising a formula of X 1 -Z 1 , wherein X 1 is a signal peptide as provided for herein and Z1 is a payload protein.
  • the recombinant polypeptide comprises a formula of X 1 -Z 1 , wherein X 1 is a novel signal peptide as provided for herein and Z 1 is a payload protein.
  • X 1 comprises an amino acid sequence selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, Formula XXIV, Formula XXV, Formula XXVI, Formula XXVII, Formula XXVIII, Formula XXIX, Formula XXX, Formula XX, Formula XXI, Formula XII, or Formula XXXIII.
  • X 1 comprises an amino acid sequence of Formula I. In some embodiments, X1 comprises an amino acid sequence of Formula II. In some embodiments, X 1 comprises an amino acid sequence of Formula III. In some embodiments, X 1 comprises an amino acid sequence of Formula IV. In some embodiments, X 1 comprises an amino acid sequence of Formula V. In some embodiments, X 1 comprises an amino acid sequence of Formula VI. In some embodiments, X 1 comprises an amino acid sequence of Formula VII. In some embodiments, X 1 comprises an amino acid sequence of Formula VIII. In some embodiments, X 1 comprises an amino acid sequence of Formula IX. ACTIVE/131743364.1 155 Attorney Docket No.
  • X 1 comprises an amino acid sequence of Formula X. In some embodiments, X 1 comprises an amino acid sequence of Formula XI. In some embodiments, X 1 comprises an amino acid sequence of Formula XII. In some embodiments, X 1 comprises an amino acid sequence of Formula XIII. In some embodiments, X 1 comprises an amino acid sequence of Formula XIV. In some embodiments, X 1 comprises an amino acid sequence of Formula XV. In some embodiments, X 1 comprises an amino acid sequence of Formula XVI. In some embodiments, X 1 comprises an amino acid sequence of Formula XVII.
  • X1 comprises an amino acid sequence of Formula XVIII. In some embodiments, X 1 comprises an amino acid sequence of Formula XIX. In some embodiments, X 1 comprises an amino acid sequence of Formula XX. In some embodiments, X 1 comprises an amino acid sequence of Formula XXI. In some embodiments, X 1 comprises an amino acid sequence of Formula XXII. In some embodiments, X 1 comprises an amino acid sequence of Formula XXIII. In some embodiments, X 1 comprises an amino acid sequence of Formula XXIV. In some embodiments, X 1 comprises an amino acid sequence of Formula XXV. In some embodiments, X 1 comprises an amino acid sequence of Formula XXVI.
  • X 1 comprises an amino acid sequence of Formula XXVII. In some embodiments, X 1 comprises an amino acid sequence of Formula XXVIII. In some embodiments, X 1 comprises an amino acid sequence of Formula XXIX. In some embodiments, X1 comprises an amino acid sequence of Formula XXX. In some embodiments, X 1 comprises an amino acid sequence of Formula XXXI. In some embodiments, X 1 comprises an amino acid sequence of Formula XXXII. In some embodiments, X 1 comprises an amino acid sequence of Formula XXXIII.
  • X 1 comprises an amino acid sequence having at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 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, 31, 32, or 33.
  • X1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 1. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 2. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 3. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 4. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 5. In ACTIVE/131743364.1 156 Attorney Docket No.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 6. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 7. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 8. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 9. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 10.
  • X1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 11. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 12. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 13. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 14. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 15. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 16.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 17. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 18. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 19. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 20. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 21. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 22.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 23. In some embodiments, X1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 24. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 25. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 26. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 27.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino ACTIVE/131743364.1 157 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT acid sequence of SEQ ID NO: 28.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 29.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 30.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 31.
  • X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 32. In some embodiments, X 1 comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 33.
  • the payload protein, Z 1 may be any peptide or protein. In some embodiments, the payload protein, Z 1 , is any peptide or protein that is useful in the treatment of a disease or disorder. In some embodiments, the payload protein, Z 1 , is any peptide or protein that, once secreted from the cell, is useful in the treatment of a disease or disorder.
  • the payload protein, Z 1 is any peptide or protein that is useful in the treatment of cancer.
  • X 1 is linked directly to Z 1 .
  • X 1 is linked indirectly to Z 1 through, for example, a polypeptide linker.
  • Polypeptide linkers are known in the art, and any such linker may be incorporated into the recombinant polypeptide of the present disclosure.
  • the recombinant polypeptide may be represented by the formula X 1 -(Y 1 ) a -Z 1 , wherein X 1 is a signal peptide as provided for herein, Y 1 is a linker, such as but not limited to a polypeptide linker, Z 1 is a payload protein as provided for herein, and a is an integer selected from 0 or 1.
  • X 1 is a novel signal peptide as provided for herein.
  • Nucleic Acid Molecules [0209]
  • a nucleic acid molecule is provided.
  • the nucleic acid molecule encodes for a signal peptide as provided for herein.
  • the nucleic acid molecule encodes for a novel signal peptide as provided for herein.
  • the nucleic acid molecule is a deoxyribonucleotide sequence (DNA).
  • the nucleic acid molecule is a ribonucleic acid sequence (RNA).
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence selected from the group consisting of Formula I, Formula II, Formula III, Formula IV, Formula V, Formula VI, Formula VII, Formula VIII, Formula IX, Formula X, Formula XI, Formula XII, Formula XIII, Formula XIV, ACTIVE/131743364.1 158 Attorney Docket No.
  • a signal peptide e.g., a novel signal peptide
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula II. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula III. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula IV. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula V.
  • a signal peptide e.g., a novel signal peptide
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula X. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XI. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XII. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XIII.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XIV. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XV. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XVI. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XVII.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence ACTIVE/131743364.1 159 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT of Formula XVIII.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XIX.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XX.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXI. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXII. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXIII.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXIV. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXV. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXVI.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXVII. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXVIII. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXIX.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXX. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXXI. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXXII.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence of Formula XXXIII.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% (e.g., at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%) identity to an amino acid sequence selected from the group consisting of SEQ ID NO: 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, 31, 32, or 33.
  • the ACTIVE/131743364.1 160 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 1.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 2.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 3. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 4. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 5.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 6. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 7. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 8.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 9. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 10. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 11.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 12. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 13. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 14.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 17. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 18. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 19.
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 23. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 24. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 25.
  • a signal peptide e.g., a novel signal peptide
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 26. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 27. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 28.
  • a signal peptide e.g., a novel signal peptide
  • the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 31. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 32. In some embodiments, the nucleic acid molecule encodes for a signal peptide (e.g., a novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 33.
  • a signal peptide e.g., a novel signal peptide
  • the nucleic acid molecule encodes for a recombinant polypeptide comprising a formula of X 1 -(Y 1 ) a -Z 1 , wherein X 1 is a signal peptide (e.g., a novel signal peptide) as provided for herein, Y1 is a linker, such as but not limited to a polypeptide linker, Z 1 is a payload protein as provided for herein, and a is an integer selected from 0 or 1. [0213] The skilled artisan will readily be able to deduce an appropriate DNA or RNA sequence based on the amino acid sequences and variations provided for herein.
  • X 1 is a signal peptide (e.g., a novel signal peptide) as provided for herein
  • Y1 is a linker, such as but not limited to a polypeptide linker
  • Z 1 is a payload protein as provided for herein
  • a is an integer selected from 0 or 1.
  • nucleic acid sequences capable of encoding for the amino acid sequences provided for herein are within the scope of the present disclosure.
  • a nucleic acid molecule as provided for here disclosed may further comprise one or more elements selected from, but not limited to, a promoter, an enhancer, a leader, a transcription start site (TSS), a linker, 5’ and 3’ untranslated regions (UTRs), Kozak sequence, an intron, a polyadenylation signal, cap sequences, enhancers, viral sequences, IRES sequences or a termination region or any element, that is suitable or necessary for regulating or allowing expression of the recombinant polypeptide as provided for herein in a cell.
  • TSS transcription start site
  • UTRs untranslated regions
  • the 5’ UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3’ UTR starts immediately following ACTIVE/131743364.1 163 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT the stop codon and continues until the transcriptional termination signal.
  • the regulatory features of a UTR can be incorporated into the polynucleotides of the present disclosure to, for example, enhance the stability of the molecule.
  • the specific features can also be incorporated to ensure controlled down-regulation of the transcript in case they are misdirected to undesired organs sites.
  • any suitable naturally occurring or synthetic UTR sequence can be incorporated into the nucleic acid molecules disclosed herein.
  • Other non-UTR sequences may also be incorporated within the nucleic acid molecules.
  • introns or portions of intron sequences may be incorporated into regions of the nucleic acid molecules of the disclosure. Incorporation of intronic sequences may increase protein production as well as polynucleotide levels. Combinations of features may be included in flanking regions and may be contained within other features.
  • the ORF may be flanked by a 5’ UTR which may contain a strong Kozak translational initiation signal and/or a 3’ UTR which may include an oligo(dT) sequence for templated addition of a poly-A tail.
  • UTR may comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and/or different genes.
  • the nucleic acid molecules disclosed herein may be assembled inside a cell.
  • the nucleic acid molecules may be synthesized in vivo.
  • the nucleic acid molecules may be synthesized in vitro using methods known in the art for example in vitro transcription, DNA, RNA and cDNA synthesis methods.
  • the nucleic acid molecules disclosed herein may be incorporated into a suitable viral vector, expression cassette, expression vector, transposon, extrachromosomal element, integrated into the chromosome, host cell, delivery systems.
  • the nucleic acid molecule is a chemically modified nucleic acid molecule.
  • the nucleic acid molecule e may comprise one or more modified nucleosides comprising a modified sugar moiety.
  • modified sugar moieties are substituted sugar moieties.
  • modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of substituted sugar moieties.
  • the modified nucleic acid molecule may comprise a modified backbone, for example, phosphorothioates, phosphotriesters, morpholinos, methyl phosphonates, short chain alkyl or cycloalkyl intersugar linkages or short chain heteroatomic or heterocyclic inter sugar linkages.
  • modified sugar moieties are substituted sugar moieties comprising one or more non-bridging sugar substituent, including but not limited to substituents at the 2’ and/or 5’ positions.
  • sugar substituents suitable for the 2’- position include, but are not limited to: 2’-F, 2-OCH 3 (“OMe” or “O-methyl”), and 2’- O(CH 2 ) 2 OCH 3 (“MOE”).
  • sugar substituents at the 5’-position include, but are not limited to: 5’- methyl (R or S); 5’- vinyl, and 5’-methoxy.
  • substituted sugars comprise more than one non- bridging sugar substituent, for example, T-F-5’-methyl sugar moieties.
  • Nucleosides comprising 2’-substituted sugar moieties are referred to as 2’-substituted nucleosides.
  • These 2’-substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO 2 ), thiol, thioalkoxy (S-alkyl), halogen, alkyl, aryl, alkenyl and alkynyl.
  • a 2’-substituted nucleoside comprises a sugar moiety comprising a 2’- substituent group selected from F, O—CH 3 , and OCH 2 CH 2 OCH 3 .
  • Certain modified sugar moieties comprise a bridging sugar substituent that forms a second ring resulting in a bicyclic sugar moiety.
  • the bicyclic sugar moiety comprises a bridge between the 4’ and the 2’ furanose ring atoms. Examples of such 4’ to 2’ ACTIVE/131743364.1 165 Attorney Docket No.
  • PATENT sugar substituents include, but are not limited to: —[C(Ra)(Rb)]—, —[C(Ra)(Rb)]n—O—, —C(RaRb)— N(R)—O— or, —C(RaRb)—O—N(R)—; 4’-CH 2 -2’, 4’-(CH 2 ) 2 -2’, 4’-(CH 2 )— 0-2’ (LNA); 4’-(CH 2 )— S-2’; 4’-(CH 2 ) 2 —0-2’ (ENA); 4’-CH(CH 3 )—0-2’ (cEt) and 4’- CH(CH 2 OCH 3 )—0-2’, and analogs thereof (see, e.g., U.S.
  • Bicyclic nucleosides comprising bicyclic sugar moieties are referred to as bicyclic nucleosides or BNAs.
  • Bicyclic nucleosides include, but are not limited to, (A) ⁇ -L-Methyleneoxy (4- CH2—O- 2’) BNA, (B) ⁇ -D-Methyleneoxy (4-CH2—0-2’) BNA (also referred to as locked nucleic acid or LNA), (C) Ethyleneoxy (4’-(CH2)2—0-2’) BNA, (D) Aminooxy (4’-CH2— O—N(R)-2’) BNA, (E) Oxyamino (4’-CH2—N(R)—0-2’) BNA, (F) Methyl (methyleneoxy) (4’-CH(CH3)—0-2’) BNA (also referred to as constrained ethyl or cEt), (G) methylene-thio (4-CH2—S-2’) BNA,
  • bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration.
  • a nucleoside comprising a 4’-2’ methylene-oxy bridge may be in the .alpha.-L configuration or in the .beta.-D configuration.
  • substituted sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent.
  • modified sugar moieties are sugar surrogates.
  • the oxygen atom of the naturally occurring sugar is substituted, e.g., with a sulfur, carbon or nitrogen atom.
  • such modified sugar moiety also comprises bridging and/or non-bridging substituents as described above.
  • sugar surrogates comprise a 4’-sulfur atom and a substitution at the 2’-position and/or the 5’ position.
  • carbocyclic bicyclic nucleosides having a 4-2’ bridge have been described.
  • sugar surrogates comprise rings having other than 5-atoms.
  • a sugar surrogate comprises a six-membered tetrahydropyran (THP). Such tetrahydropyrans may be further modified or substituted.
  • Nucleosides comprising such modified tetrahydropyrans include, but are not limited to, hexitol nucleic acid (HNA), anitol nucleic acid (ANA), mannitol nucleic acid (MNA), and fluoro HNA (F-HNA).
  • HNA hexitol nucleic acid
  • ANA anitol nucleic acid
  • MNA mannitol nucleic acid
  • F-HNA fluoro HNA
  • the ACTIVE/131743364.1 167 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT nucleic acid molecules comprise one or more RNA-like nucleosides. In some embodiments, the nucleic acid molecules comprise one or more DNA- like nucleotides. [0230] In some embodiments, nucleosides of the present disclosure comprise one or more unmodified nucleobases. In some embodiments, nucleosides of the present disclosure comprise one or more modified nucleobases.
  • modified nucleobases are selected from: universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases as defined herein.5- substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2- aminopropyladenine, 5-propynyluracil; 5-propynylcytosine; 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2- propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2- thiocytosine, 5-halouracil and cytosine, 5-propynyl CH3, uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytos
  • nucleobases include tricyclic pyrimidines such as phenoxazine cytidine([5,4-b][1,4]benzoxazin-2(3H)- one), phenothiazine cytidine (1H- pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g., 9-(2-aminoethoxy)-H-pyrimido[5,4- 13][1,4]benzoxazin-2(3H)-one), carbazole cytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H-pyrido[3’,2’:4,5]pyrrolo[2,3- d]pyrimidin-2-one).
  • tricyclic pyrimidines such as phenox
  • Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2- aminopyridine and 2- pyridone.
  • the present disclosure provides nucleic acid molecules comprising linked nucleosides.
  • the nucleosides may be linked together using any internucleoside linkage.
  • the two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom.
  • Representative non-phosphorus containing internucleoside linking groups include, but are not ACTIVE/131743364.1 168 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT limited to, methylenemethylimino (—CH2— N(CH3)—O—CH2—), thiodiester (—O— C(O)—S—).
  • internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers.
  • Representative chiral linkages include, but are not limited to, alkylphosphonates and phosphorothioates.
  • nucleic acid molecules described herein may comprise one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), such as for sugar anomers, or as (D) or (L) such as for amino acids etc. Included in the antisense compounds provided herein are all such possible isomers, as well as their racemic and optically pure forms.
  • Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides.
  • Such moieties include but are not limited to lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-5-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl- rac-glycerol or triethylammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety.
  • lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e
  • a vector is provided.
  • the vector comprises a nucleic acid molecule as provided for herein.
  • the nucleic acid molecule encodes for a signal peptide as provided for herein.
  • the nucleic acid molecule encodes for a novel signal peptide as provided for herein.
  • the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein.
  • Cells [0237] In some embodiments, a cell is provided.
  • the cell comprises a nucleic acid molecule encoding for a signal peptide as provided for herein. In some embodiments, the cell comprises a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein. In some embodiments, the cell comprises a vector as provided for herein. In some embodiments, the cell is any appropriate cell. In some embodiments, the cell is a mammalian cell. In some embodiments, the cell is a human cell. In some embodiments, the cell is a mammalian cell used in a method of manufacturing a protein product. In some embodiments, the cell is any in vitro cell line. In some embodiments, the cell is any ex vivo cell.
  • compositions [0238] In some embodiments, a composition is provided. In some embodiments, the composition comprises a vector encoding for a signal peptide as provided for herein and a delivery system. In some embodiments, the composition comprises a vector encoding for a recombinant polypeptide as provided for herein and a delivery system. [0239] In some embodiments, the delivery system may be a viral vector. In some embodiments, the viral vector is an RNA viral vector. In some embodiments, the viral vector is a DNA viral vector.
  • Non-limiting examples of suitable viral vectors include adenovirus, adeno associated virus (AAV), retrovirus, herpesvirus, lentivirus, poxvirus, or papilloma virus vector.
  • the delivery system is a non-viral delivery system.
  • Non-limiting examples of non-viral delivery systems include polymers, polyplexes, lipids, lipidoids, lipoplexes, liposomes, lipid fusion constructs, polymer nanoparticles, nanoparticles, lipid nanoparticles (LNPs), core-shell nanoparticles, solid lipid nanoparticles, metal nanoparticles, self-assembled nucleic acid nanoparticles, hyaluronidase, nanoparticle mimics, ribonucleoproteins, positively charged peptides, small molecule RNA-conjugates, aptamer- RNA chimeras, RNA-fusion protein complexes and any combination thereof.
  • ACTIVE/131743364.1 170 Attorney Docket No.
  • UTSD 4319 (106546-823037)(SIGY-005WO) PATENT [0241]
  • the above exemplary delivery systems are not to be construed to be limiting in any way. Appropriate delivery systems are known in the art and any such delivery system is within the scope of the present disclosure.
  • the method comprises administering to a subject in need thereof a vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein, thereby treating the disease or disorder.
  • the payload protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the disease or disorder.
  • the signal peptide directs the payload protein to be expressed at a particular cellular localization useful for the treatment of the disease or disorder.
  • the subject in need thereof is administered an effective amount of the vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein.
  • the subject in need thereof is administered a therapeutically effective amount of the vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein.
  • diseases or disorders, or therapeutic fields for which the recombinant polypeptides disclosed herein may be useful include, but are not limited to, oncology, inflammatory diseases or disorders, autoimmune disease or disorders, immunotherapeutics, enzyme replacement therapeutics, protein replacement therapeutics, biologics manufacturing, diabetes, blood disorders (e.g., hemophilia), hormone replacement therapies, or peptide-based drugs (e.g., GLP-1 for obesity).
  • the disease or disorder is cancer.
  • the disease or disorder is an inflammatory disease or disorder.
  • the disease or disorder is an autoimmune disease or disorder.
  • the disease or disorder is diabetes.
  • the disease or disorder is a blood disorder.
  • the disease or disorder is any disease or disorder for which immunotherapies would be beneficial.
  • the disease or disorder is any disease or disorder for which enzyme replacement therapies would be beneficial.
  • the disease or disorder is any disease or disorder for which protein replacement therapies would be beneficial.
  • the disease or disorder is any disease or disorder for which ACTIVE/131743364.1 171 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT hormone replacement therapies would be beneficial.
  • the disease or disorder is any disease or disorder for which a peptide based drug would be beneficial.
  • a method of treating a cancer comprising administering to a subject in need thereof a vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein, thereby treating the cancer.
  • the payload protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the cancer.
  • the signal peptide directs the payload protein to be secreted by the cell, providing the payload protein into circulation whereby it is useful in treating the cancer.
  • the subject in need thereof is administered an effective amount of the vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein. In some embodiments, the subject in need thereof is administered a therapeutically effective amount of the vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein.
  • a method of treating a disease or disorder comprises administering to a subject in need thereof a composition comprising a vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein, thereby treating the disease or disorder.
  • the payload protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the disease or disorder.
  • the signal peptide directs the payload protein to be expressed at a particular cellular localization useful for the treatment of the disease or disorder.
  • the subject in need thereof is administered an effective amount of the composition. In some embodiments, the subject in need thereof is administered a therapeutically effective amount of the composition.
  • Non-limiting examples of diseases or disorders, or therapeutic fields for which the recombinant polypeptides disclosed herein may be useful include, but are not limited to, oncology, inflammatory diseases or disorders, autoimmune disease or disorders, immunotherapeutics, enzyme replacement therapeutics, protein replacement therapeutics, biologics manufacturing, diabetes, blood disorders (e.g., hemophilia), hormone replacement therapies, or peptide-based drugs (e.g., GLP-1 for obesity).
  • the disease or disorder is cancer.
  • the disease or disorder is an inflammatory disease or disorder.
  • the disease or disorder is an autoimmune disease or disorder.
  • the disease or disorder is diabetes.
  • the disease or disorder is a blood disorder.
  • the disease or disorder is any disease or disorder for which immunotherapies would be beneficial.
  • the disease or disorder ACTIVE/131743364.1 172 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT is any disease or disorder for which enzyme replacement therapies would be beneficial.
  • the disease or disorder is any disease or disorder for which protein replacement therapies would be beneficial.
  • the disease or disorder is any disease or disorder for which hormone replacement therapies would be beneficial.
  • the disease or disorder is any disease or disorder for which a peptide based drug would be beneficial.
  • a method of treating a cancer comprising administering to a subject in need thereof a composition comprising a vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein, thereby treating the cancer.
  • the payload protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the cancer.
  • the signal peptide directs the payload protein to be secreted by the cell, providing the payload protein into circulation whereby it is useful in treating the cancer.
  • the subject in need thereof is administered an effective amount of the composition.
  • a method of producing a payload protein comprising administering to a cell a vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein and culturing the cell under conditions sufficient to produce the payload protein.
  • the payload protein is secreted from the cell, and the method further comprises collecting a cell supernatant containing the payload protein and purifying the payload protein from the cell supernatant.
  • the payload protein is not secreted, and the method further comprises collecting the cells comprising the payload protein, lysing the cells, and purifying the payload protein from the cell lysate.
  • a method of manufacturing a payload protein comprising administering to a cell a vector comprising a nucleic acid molecule encoding for a recombinant polypeptide as provided for herein and culturing the cell under conditions sufficient to produce the payload protein.
  • the payload protein is secreted from the cell, and the method further comprises collecting a cell supernatant containing the payload protein and purifying the payload protein from the cell supernatant.
  • the payload protein is not secreted, and the method further comprises collecting the cells comprising the payload protein, lysing the cells, and purifying the payload protein from the cell lysate.
  • ACTIVE/131743364.1 173 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT [0249]
  • the present disclosure is directed, in part, toward novel recombinant polypeptides comprising a novel signal peptide and a payload protein.
  • the novel recombinant polypeptides of the disclosure are useful in the treatment of a cancer by using the subject’s own cells to produce and secrete the payload protein that is useful for the treatment of cancer.
  • the present disclosure is also directed, in part, toward methods of producing or manufacturing a payload protein using the novel signal peptides as provided for herein.
  • the novel signal peptides as provided for herein direct the payload protein to a particular cellular or extracellular location, such as but not limited to, secreting the payload protein from the cell.
  • SP-mCherry coding region were obtained directly by PCR with well-designed primers.
  • the SPs of the following examples are as provided in Table 35 below: Table 35 ACTIVE/131743364.1 174 Attorney Docket No. UTSD 4319 (106546-823037)(SIGY-005WO) PATENT Enzyme digested SP-mCherry products were cloned into pCS2-MT vector based on standard protocols. After validation by sequencing, SP-mCherry plasmids were ready for in vitro screening. In vitro SP screening by pDNA transfection [0253] To perform SPs screening, pDNA transfection was executed in cells.
  • pDNAs were encapsulated in Lipfectamine2000 and administered to HeLa cells at 50 ng/well in 96 well plates and allowed to incubate for 24 hours. Cell lysates and media were collected an mCherry signal was quantified via plate reader.
  • Example 1 Use of novel signal peptides to drive export of mCherry.
  • the ability of the novel signal peptides provided for herein to secrete a payload protein was tested by constructing signal peptide modified mCherry plasmids containing an encoded novel secretory signal peptide directly upstream of the mCherry sequence. As a control, unmodified mCherry plasmids containing no signal peptide sequence were also used.
  • each of the novel secretory signal peptides tested were able to drive export of mCherry protein to the cell media, whereas mCherry protein without the secretory signal peptides was not secreted from the cell.
  • Example 2 Use of novel signal peptides to secret therapeutic antibodies from a cell. [0257] Example 2 is carried out using similar methods to Example 1, with the exception that the payload protein is an antibody. As a control, plasmids encoding antibodies without the secretory signal peptides are also used. In lieu of mCherry assessment, proper antibody secretion is determined via Western Blot or ELISA analysis using a proper secondary antibody and detection reagent.
  • Example 3 mRNA synthesis and mRNA-Nanoparticle formulation [0258] mRNA are produced by in vitro transcription as described in Cheng, Qiang et al.
  • mRNA-loaded LNP formulations are formed using the ethanol dilution method as described in Cheng, Qiang et al. Proceedings of the National Academy of Sciences of the United States of America vol.120,52 (2023); Cheng, Qiang et al. Nature Nanotechnology 15, 313-320 (2020); and International Patent Publication Serial No. WO2024064874A2, each of which is hereby incorporated by reference in their entirety. Briefly, all lipids with specified molar ratios were dissolved in ethanol and RNA was dissolved in 10 mM citrate buffer (pH 4.0) first.
  • HeLa cells were transfected with wild type (WT) mCherry pDNA containing no SP and gLuc-mCherry pDNA via Lipofectamine2000, and both intracellular and extracellular fluorescence were quantified via fluorescent microscopy at 24-, 48-, and 72-hours post transfection, wherein the gLuc SP induced high levels of mCherry expression into media.
  • WT wild type
  • mCherry protein content present in cell medium and cell lysates were quantified via a fluorescent plate reader individually at 24-, 48-, and 72-hours revealing an increase in mCherry fluorescence in the gLuc SP group (FIG. 2A).

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Abstract

L'invention concerne de nouveaux peptides signal sécrétoire, des polypeptides recombinants les comprenant, des molécules d'acide nucléique codant pour ceux-ci, des compositions pharmaceutiques les comprenant, et leurs procédés d'utilisation.
PCT/US2024/047828 2023-09-22 2024-09-20 Nouveaux peptides signal sécrétoires et leurs utilisations Pending WO2025064926A1 (fr)

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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030177535A1 (en) * 2002-01-10 2003-09-18 Maureen Hanson Genes for altering mitochondrial function and for hybrid seed production
US20040029789A1 (en) * 2001-07-05 2004-02-12 Anderson David W. Novel proteins and nucleic acids encoding same
US20190382462A1 (en) * 2017-01-13 2019-12-19 Pietro P. Sanna Methods and compositions for treating hpa hyperactivity
US20210205415A1 (en) * 2010-04-22 2021-07-08 Longevity Biotech, Inc. Highly active polypeptides and methods of making and using the same
US20220133808A1 (en) * 2019-02-01 2022-05-05 Avrobio, Inc. Compositions and methods for treating neurocognitive disorders
WO2022198019A1 (fr) * 2021-03-19 2022-09-22 Tenza, Inc. Peptides signaux de pré-protéines synthétiques pour diriger la sécrétion de protéines hétérologues dans des bactéries bacillus
US20220332774A1 (en) * 2019-08-12 2022-10-20 Cohbar, Inc. Therapeutic mitochondrial peptides

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040029789A1 (en) * 2001-07-05 2004-02-12 Anderson David W. Novel proteins and nucleic acids encoding same
US20030177535A1 (en) * 2002-01-10 2003-09-18 Maureen Hanson Genes for altering mitochondrial function and for hybrid seed production
US20210205415A1 (en) * 2010-04-22 2021-07-08 Longevity Biotech, Inc. Highly active polypeptides and methods of making and using the same
US20190382462A1 (en) * 2017-01-13 2019-12-19 Pietro P. Sanna Methods and compositions for treating hpa hyperactivity
US20220133808A1 (en) * 2019-02-01 2022-05-05 Avrobio, Inc. Compositions and methods for treating neurocognitive disorders
US20220332774A1 (en) * 2019-08-12 2022-10-20 Cohbar, Inc. Therapeutic mitochondrial peptides
WO2022198019A1 (fr) * 2021-03-19 2022-09-22 Tenza, Inc. Peptides signaux de pré-protéines synthétiques pour diriger la sécrétion de protéines hétérologues dans des bactéries bacillus

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