Novel lysosome targeting signal peptides and uses thereof

Abstract

Provided for herein are novel signal peptides that direct an encoded protein to the lysosome of a cell, recombinant polypeptides comprising the same, nucleic acid molecules encoding the same, pharmaceutical compositions comprising the same, and methods of use thereof.

Description

Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT NOVEL LYSOSOME TARGETING SIGNAL PEPTIDES AND USES THEREOF Related Applications

[0001] This application claims the benefit of U.S. Provisional Application Ser. No. 63 / 594,198 filed October 30, 2023, and of U.S. Provisional Application Ser. No.63 / 606,494 filed December 05, 2023, each of which is hereby incorporated by reference in its entirety. 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 “827226_sequencelisting”, file size 28,672 bytes, created on October 30, 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 signal peptides for targeting an encoded protein to the lysosome of a cell. Background

[0004] Recent scientific discoveries have highlighted the innumerable therapeutic applications of mRNA due to its modular nature and ability to provide customizable “instructions” to create functional proteins. Clinical studies continue to confirm its favorable efficacy, further underscoring its potential as a next-generation genetic medicine wherein scientists have only begun to scratch the surface of potential applications. Most of the research focus so far has been on amplifying intracellular expression of the encoded polypeptide. However, less focus has been placed on post-translational control of encoded proteins and targeted localization and / or secretion of the protein within the body.

[0005] Within the cell, a variety of unique avenues and processes exist that allow for the shuttling of proteins to various organelles as well as the export of proteins into the extracellular space via excretion pathways. However, in order to take advantage of these transport systems, the mRNA encoding each protein must also contain a metaphorical shipping label upstream from the protein sequence known as a signal peptide (SP). Design of novel SP for therapeutic mRNA could greatly IPTS / 128757636.1 1Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT benefit delivery, localization, and clearance of an encoded therapeutic protein. The present disclosure addresses these needs and others. Summary

[0006] In some embodiments, a signal peptide is provided. In some embodiments, 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, XX, XXI, XXII, XXIII, and XXIV; wherein Formula I is represented as: A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16(Formula I) and the identities of A1-A16are as provided in Table 2; wherein Formula II is represented as: B1-B2-B3-B4-B5-B6-B7-B8-B9-B10-B11-B12-B13-B14-B15-B16-B17(Formula II) and the identities of B1-B17are as provided in Table 3; wherein Formula III is represented as: C1-C2-C3-C4-C5-C6-C7-C8-C9-C10-C11-C12-C13-C14-C15-C16-C17-C18(Formula III) and the identities of C1-C18are as provided in Table 4; wherein Formula IV is represented as: D1-D2-D3-D4-D5-D6-D7-D8-D9-D10-D11-D12-D13-D14-D15-D16-D17-D18-D19(Formula IV) and the identities of D1-D19are as provided in Table 5; wherein Formula V is represented as: E1-E2-E3-E4-E5-E6-E7-E8-E9-E10-E11-E12-E13-E14-E15-E16-E17-E18-E19-E20(Formula V) and the identities of E1-E20are as provided in Table 6; wherein Formula VI is represented as: F1-F2-F3-F4-F5-F6-F7-F8-F9-F10-F11-F12-F13-F14-F15-F16-F17-F18-F19-F20-F21(Formula VI) and the identities of F1-F21are as provided in Table 7; wherein Formula VII is represented as: G1-G2-G3-G4-G5-G6-G7-G8-G9-G10-G11-G12-G13-G14-G15-G16-G17-G18-G19-G20-G21-G22(Formula VII) and the identities of G1-G22are as provided in Table 8; wherein Formula VIII is represented as: IPTS / 128757636.1 2Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT H1-H2-H3-H4-H5-H6-H7-H8-H9-H10-H11-H12-H13-H14-H15-H16-H17-H18-H19-H20-H21-H22-H23(Formula VIII) and the identities of H1-H23are as provided in Table 9; wherein Formula IX is represented as: I1-I2-I3-I4-I5-I6-I7-I8-I9-I10-I11-I12-I13-I14-I15-I16-I17-I18-I19-I20-I21-I22-I23-I24(Formula IX) and the identities of I1-I24are as provided in Table 10; wherein Formula X is represented as: J1-J2-J3-J4-J5-J6-J7-J8-J9-J10-J11-J12-J13-J14-J15-J16-J17-J18-J19-J20-J21-J22-J23-J24-J25(Formula X) and the identities of J1-J25are as provided in Table 11; wherein Formula XI is represented as: K1-K2-K3-K4-K5-K6-K7-K8-K9-K10-K11-K12-K13-K14-K15-K16-K17-K18-K19-K20-K21-K22-K23-K24- K25-K26(Formula XI) and the identities of K1-K26are as provided in Table 12; wherein Formula XII is represented as: L1-L2-L3-L4-L5-L6-L7-L8-L9-L10-L11-L12-L13-L14-L15-L16-L17-L18-L19-L20-L21-L22-L23-L24-L25-L26- L27(Formula XII) and the identities of L1-L27are as provided in Table 13; wherein Formula XIII is represented as: M1-M2-M3-M4-M5-M6-M7-M8-M9-M10-M11-M12-M13-M14-M15-M16-M17-M18-M19-M20-M21-M22- M23-M24-M25-M26-M27-M28(Formula XIII) and the identities of M1-M28are as provided in Table 14; wherein Formula XIV is represented as: N1-N2-N3-N4-N5-N6-N7-N8-N9-N10-N11-N12-N13-N14-N15-N16-N17-N18-N19-N20-N21-N22-N23-N24- N25-N26-N27-N28-N29(Formula XIV) and the identities of N1-N29are as provided in Table 15; wherein Formula XV is represented as: O1-O2-O3-O4-O5-O6-O7-O8-O9-O10-O11-O12-O13-O14-O15-O16-O17-O18-O19-O20-O21-O22-O23-O24- O25-O26-O27-O28-O29-O30(Formula XV) and the identities of O1-O30are as provided in Table 16; wherein Formula XVI is represented as: IPTS / 128757636.1 3Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-P15-P16-P17-P18-P19-P20-P21-P22-P23-P24-P25-P26- P27-P28-P29-P30-P31(Formula XVI) and the identities of P1-P31are as provided in Table 17; wherein Formula XVII is represented as: Q1-Q2-Q3-Q4-Q5-Q6-Q7-Q8-Q9-Q10-Q11-Q12-Q13-Q14-Q15-Q16-Q17-Q18-Q19-Q20-Q21-Q22-Q23-Q24- Q25-Q26-Q27-Q28-Q29-Q30-Q31-Q32(Formula XVII) and the identities of Q1-Q32are as provided in Table 18; wherein Formula XVIII is represented as: R1-R2-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22-R23-R24-R25- R26-R27-R28-R29-R30-R31-R32-R33(Formula XVIII) and the identities of R1-R33are as provided in Table 19; wherein Formula XIX is represented as: S1-S2-S3-S4-S5-S6-S7-S8-S9-S10-S11-S12-S13-S14-S15-S16-S17-S18-S19-S20-S21-S22-S23-S24-S25-S26- S27-S28-S29-S30-S31-S32-S33-S34-S35(Formula XIX) and the identities of S1-S35are as provided in Table 20; wherein Formula XX is represented as: T1-T2-T3-T4-T5-T6-T7-T8-T9-T10-T11-T12-T13-T14-T15-T16-T17-T18-T19-T20-T21-T22-T23-T24-T25-T26- T27-T28-T29-T30-T31-T32-T33-T34-T35-T36(Formula XX) and the identities of T1-T36are as provided in Table 21; wherein Formula XXI is represented as: U1-U2-U3-U4-U5-U6-U7-U8-U9-U10-U11-U12-U13-U14-U15-U16-U17-U18-U19-U20-U21-U22-U23-U24- U25-U26-U27-U28-U29-U30-U31-U32-U33-U34-U35-U36-U37(Formula XXI) and the identities of U1-U37are as provided in Table 22; wherein Formula XXII is represented as: V1-V2-V3-V4-V5-V6-V7-V8-V9-V10-V11-V12-V13-V14-V15-V16-V17-V18-V19-V20-V21-V22-V23-V24- V25-V26-V27-V28-V29-V30-V31-V32-V33-V34-V35-V36-V37-V38(Formula XXII) and the identities of V1-V38are as provided in Table 23; wherein Formula XXIII is represented as: W1-W2-W3-W4-W5-W6-W7-W8-W9-W10-W11-W12-W13-W14-W15-W16-W17-W18-W19-W20-W21- W22-W23-W24-W25-W26-W27-W28-W29-W30-W31-W32-W33-W34-W35-W36-W37-W38-W39-W40-W41- W42(Formula XXIII) IPTS / 128757636.1 4Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT and the identities of W1-W42are as provided in Table 24; and wherein Formula XXIV is represented as: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24- X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-X43-X44-X45-X46(Formula XXIV) and the identities of X1-X46are as provided in Table 25.

[0007] In some embodiments, 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, or 25.

[0008] In some embodiments, a signal peptide is provided, the 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, or 25.

[0009] In some embodiments, a signal peptide as provided for herein is a novel signal peptide.

[0010] In some embodiments, a recombinant polypeptide is provided. In some embodiments, the recombinant polypeptide comprises a formula of X1-(Y1)a-Z1, wherein X1is a signal peptide, Y1is a peptide linker, and Z1is a payload protein, wherein a is an integer selected from 0 and 1.

[0011] In some embodiments, the signal peptide X1comprises 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, XX, XXI, XXII, XXIII, and XXIV; wherein Formula I is represented as: A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16(Formula I) and the identities of A1-A16are as provided in Table 2; wherein Formula II is represented as: B1-B2-B3-B4-B5-B6-B7-B8-B9-B10-B11-B12-B13-B14-B15-B16-B17(Formula II) and the identities of B1-B17are as provided in Table 3; wherein Formula III is represented as: C1-C2-C3-C4-C5-C6-C7-C8-C9-C10-C11-C12-C13-C14-C15-C16-C17-C18(Formula III) and the identities of C1-C18are as provided in Table 4; IPTS / 128757636.1 5Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT wherein Formula IV is represented as: D1-D2-D3-D4-D5-D6-D7-D8-D9-D10-D11-D12-D13-D14-D15-D16-D17-D18-D19(Formula IV) and the identities of D1-D19are as provided in Table 5; wherein Formula V is represented as: E1-E2-E3-E4-E5-E6-E7-E8-E9-E10-E11-E12-E13-E14-E15-E16-E17-E18-E19-E20(Formula V) and the identities of E1-E20are as provided in Table 6; wherein Formula VI is represented as: F1-F2-F3-F4-F5-F6-F7-F8-F9-F10-F11-F12-F13-F14-F15-F16-F17-F18-F19-F20-F21(Formula VI) and the identities of F1-F21are as provided in Table 7; wherein Formula VII is represented as: G1-G2-G3-G4-G5-G6-G7-G8-G9-G10-G11-G12-G13-G14-G15-G16-G17-G18-G19-G20-G21-G22(Formula VII) and the identities of G1-G22are as provided in Table 8; wherein Formula VIII is represented as: H1-H2-H3-H4-H5-H6-H7-H8-H9-H10-H11-H12-H13-H14-H15-H16-H17-H18-H19-H20-H21-H22-H23(Formula VIII) and the identities of H1-H23are as provided in Table 9; wherein Formula IX is represented as: I1-I2-I3-I4-I5-I6-I7-I8-I9-I10-I11-I12-I13-I14-I15-I16-I17-I18-I19-I20-I21-I22-I23-I24(Formula IX) and the identities of I1-I24are as provided in Table 10; wherein Formula X is represented as: J1-J2-J3-J4-J5-J6-J7-J8-J9-J10-J11-J12-J13-J14-J15-J16-J17-J18-J19-J20-J21-J22-J23-J24-J25(Formula X) and the identities of J1-J25are as provided in Table 11; wherein Formula XI is represented as: K1-K2-K3-K4-K5-K6-K7-K8-K9-K10-K11-K12-K13-K14-K15-K16-K17-K18-K19-K20-K21-K22-K23-K24- K25-K26(Formula XI) and the identities of K1-K26are as provided in Table 12; wherein Formula XII is represented as: L1-L2-L3-L4-L5-L6-L7-L8-L9-L10-L11-L12-L13-L14-L15-L16-L17-L18-L19-L20-L21-L22-L23-L24-L25-L26- L27(Formula XII) and the identities of L1-L27are as provided in Table 13; IPTS / 128757636.1 6Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT wherein Formula XIII is represented as: M1-M2-M3-M4-M5-M6-M7-M8-M9-M10-M11-M12-M13-M14-M15-M16-M17-M18-M19-M20-M21-M22- M23-M24-M25-M26-M27-M28(Formula XIII) and the identities of M1-M28are as provided in Table 14; wherein Formula XIV is represented as: N1-N2-N3-N4-N5-N6-N7-N8-N9-N10-N11-N12-N13-N14-N15-N16-N17-N18-N19-N20-N21-N22-N23-N24- N25-N26-N27-N28-N29(Formula XIV) and the identities of N1-N29are as provided in Table 15; wherein Formula XV is represented as: O1-O2-O3-O4-O5-O6-O7-O8-O9-O10-O11-O12-O13-O14-O15-O16-O17-O18-O19-O20-O21-O22-O23-O24- O25-O26-O27-O28-O29-O30(Formula XV) and the identities of O1-O30are as provided in Table 16; wherein Formula XVI is represented as: P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-P15-P16-P17-P18-P19-P20-P21-P22-P23-P24-P25-P26- P27-P28-P29-P30-P31(Formula XVI) and the identities of P1-P31are as provided in Table 17; wherein Formula XVII is represented as: Q1-Q2-Q3-Q4-Q5-Q6-Q7-Q8-Q9-Q10-Q11-Q12-Q13-Q14-Q15-Q16-Q17-Q18-Q19-Q20-Q21-Q22-Q23-Q24- Q25-Q26-Q27-Q28-Q29-Q30-Q31-Q32(Formula XVII) and the identities of Q1-Q32are as provided in Table 18; wherein Formula XVIII is represented as: R1-R2-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22-R23-R24-R25- R26-R27-R28-R29-R30-R31-R32-R33(Formula XVIII) and the identities of R1-R33are as provided in Table 19; wherein Formula XIX is represented as: S1-S2-S3-S4-S5-S6-S7-S8-S9-S10-S11-S12-S13-S14-S15-S16-S17-S18-S19-S20-S21-S22-S23-S24-S25-S26- S27-S28-S29-S30-S31-S32-S33-S34-S35(Formula XIX) and the identities of S1-S35are as provided in Table 20; wherein Formula XX is represented as: T1-T2-T3-T4-T5-T6-T7-T8-T9-T10-T11-T12-T13-T14-T15-T16-T17-T18-T19-T20-T21-T22-T23-T24-T25-T26- T27-T28-T29-T30-T31-T32-T33-T34-T35-T36(Formula XX) IPTS / 128757636.1 7Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT and the identities of T1-T36are as provided in Table 21; wherein Formula XXI is represented as: U1-U2-U3-U4-U5-U6-U7-U8-U9-U10-U11-U12-U13-U14-U15-U16-U17-U18-U19-U20-U21-U22-U23-U24- U25-U26-U27-U28-U29-U30-U31-U32-U33-U34-U35-U36-U37(Formula XXI) and the identities of U1-U37are as provided in Table 22; wherein Formula XXII is represented as: V1-V2-V3-V4-V5-V6-V7-V8-V9-V10-V11-V12-V13-V14-V15-V16-V17-V18-V19-V20-V21-V22-V23-V24- V25-V26-V27-V28-V29-V30-V31-V32-V33-V34-V35-V36-V37-V38(Formula XXII) and the identities of V1-V38are as provided in Table 23; wherein Formula XXIII is represented as: W1-W2-W3-W4-W5-W6-W7-W8-W9-W10-W11-W12-W13-W14-W15-W16-W17-W18-W19-W20-W21- W22-W23-W24-W25-W26-W27-W28-W29-W30-W31-W32-W33-W34-W35-W36-W37-W38-W39-W40-W41- W42(Formula XXIII) and the identities of W1-W42are as provided in Table 24; and wherein Formula XXIV is represented as: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24- X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-X43-X44-X45-X46(Formula XXIV) and the identities of X1-X46are as provided in Table 25.

[0012] In some embodiments, the signal peptide X1comprises 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, or 25.

[0013] In some embodiments, the payload protein is a therapeutic peptide or protein.

[0014] In some embodiments, a nucleic acid molecule is provided. In some embodiments, the nucleic acid molecule encodes for a signal peptide as provided for herein.

[0015] In some embodiments, a nucleic acid molecule is provided. In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein.

[0016] In some embodiments, 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 IPTS / 128757636.1 8Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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.

[0017] In some embodiments, 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. In some embodiments, the composition 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.

[0019] In some embodiments, a method for treating a disease or disorder in a subject in need thereof is provided. In some embodiments, 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. In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein. In some embodiments, the disease or disorder is a lysosomal disease or disorder.

[0020] In some embodiments, a method for treating a lysosomal disease or disorder in a subject in need thereof is provided. In some embodiments, the method comprises administering to the subject a vector comprising a nucleic acid molecule encoding for a signal peptide fused or linked to a payload 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 the lysosomal disease or disorder. Brief Description of the Drawings

[0021] 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.

[0022] FIG. 1B illustrates representative images of signal peptide tagged mCherry colocalized with LysoTracker Green DND-26. Top: SP is Nov-EMI-21-1 (SEQ ID NO: 6). Bottom: SP is Nov-EMI-29-1 (SEQ ID NO: 25). IPTS / 128757636.1 9Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0023] FIG. 1C illustrates representative images of signal peptide tagged mCherry colocalized with LysoTracker Green DND-26. Top: SP is Nov-EMI-23-1 (SEQ ID NO: 8). Bottom: SP is Nov-EMI-32-1 (SEQ ID NO: 17).

[0024] FIG. 1D illustrates representative images of signal peptide tagged mCherry colocalized with LysoTracker Green DND-26. Top: SP is Nov-EMI-27-1 (SEQ ID NO: 12). Bottom: No SP control.

[0025] FIG. 1E illustrates the quantification of the experiments corresponding to the representative images of FIGs.1B, 1C, and 1D.

[0026] FIG. 1F illustrates the quantification of the experiments corresponding to the representative images of FIGs.1B, 1C, and 1D.

[0027] 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.

[0028] FIG.2B provides quantification of mCherry fluorescence in Hela cell lysate and medium after 72 hours.

[0029] FIG.2C provides quantification of mCherry fluorescence in Huh7 cell lysates and medium at 72h after transfection.

[0030] 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.

[0031] 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. Detailed Description

[0032] Before the present compositions and methods are described, it is to be understood that the scope of the disclosure is not limited to the particular processes, compositions, or methodologies described herein, as these may vary. It is also to be understood that the terminology used in the description is for the purpose of describing the particular versions or embodiments only, and is not intended to limit the scope of the present disclosure. Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art. It is further to be understood that any methods and materials similar or equivalent IPTS / 128757636.1 10Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT to those described herein can be used in the practice or testing of embodiments of the methods and systems disclosed herein, and such equivalents are within the scope of the present disclosure. Definitions

[0033] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art in the practice of the present disclosure.

[0034] As used herein, “comprising” means “including” and the singular forms “a” or “an” or “the” include plural references unless the context clearly dictates otherwise. For example, reference to “comprising a therapeutic agent” includes one or a plurality of such therapeutic agents. The term “or” refers to a single element of stated alternative elements, unless the context clearly indicates otherwise. For example, the phrase “A or B” refers to A alone or B alone. The phrase “A, B, or a combination thereof” refers to A alone, B alone, or a combination of A and B. Similarly, “one or more of A and B” refers to A, B, or a combination of both A and B. The phrase “A and B” refers to a combination of A and B. Furthermore, the various elements, features and steps discussed herein, as well as other known equivalents for each such element, feature or step, can be mixed and matched by one of ordinary skill in this art to perform methods in accordance with principles described herein. Among the various elements, features, and steps some will be specifically included and others specifically excluded in particular examples.

[0035] In some examples, 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." For example, "about" or "approximately" can indicate + / - 10%, + / - 5%, or + / - 1% variation of the value it describes. Accordingly, in some embodiments, 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.

[0036] As used herein, the terms “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, IPTS / 128757636.1 11Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT lipofection (e.g., using commercially available reagents such as, for example, LIPOFECTIN® (Invitrogen Corp., San Diego, CA), LIPOFECTAMINE® (Invitrogen), FUGENE® (Roche Applied Science, Basel, Switzerland), JETPEI™ (Polyplus-transfection Inc., New York, NY), EFFECTENE® (Qiagen, Valencia, CA), DREAMFECT™ (OZ Biosciences, France) and the like), or electroporation (e.g., in vivo electroporation). 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.

[0037] 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., TRANSFECTAM™ and LIPOFECTIN™). Cationic and neutral lipids that are suitable for efficient receptor-recognition lipofection of polynucleotides include those disclosed in WO91 / 17424 and WO 91 / 16024.

[0038] 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.

[0039] As used herein, “payload protein” or “protein of interest” refers to the protein that will be generated by the host cell and chaperoned to the desired intracellular location, e.g., chaperoned to the lysosome of a cell. Upon translocation to the proper intracellular space, all, some, or none of the novel signal peptide may be fused to the payload protein. Optionally, a payload protein still being attached partially or fully to the novel signal peptide may be further processed, for example, to remove the remaining novel signal peptide. A payload protein may be any protein known or yet to be known, for example, an enzyme, enzyme inhibitor, growth factor, hormone, antibody, antigen, vaccine, a therapeutic agent, or any combination thereof. More specific examples follow herein below. IPTS / 128757636.1 12Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0040] As used herein, 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. In some embodiments, 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.

[0041] “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.

[0042] By “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.

[0043] 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). Such software matches identical or similar sequences by assigning degrees of homology to various substitutions, deletions, and / or IPTS / 128757636.1 13Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT other modifications. 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. In an exemplary approach to determining the degree of identity, a BLAST program may be used, with a probability score between e3 and e100 indicating a closely related sequence. In some embodiments, sequence identity is determined by using BLAST with the default settings. In some embodiments, sequence identity is determined using Clustal Omega.

[0044] To the extent embodiments provided for herein, includes 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. Identity between polypeptides can be determined by the Smith- Waterman homology search algorithm as implemented in the MPSRCH program (Oxford Molecular), using an affine gap search with parameters gap open penalty – 12 and gap extension penalty = 1.

[0045] These proteins may, compared to the disclosed proteins, include one or more (e.g., 1, 2, 3,4, 5, 6, 7, 8, 9, 10, etc.) conservative amino acid replacements i.e., replacements of one amino acid with another which has a related side chain. Genetically-encoded amino acids are generally divided into four families: (1) acidic i.e., aspartate, glutamate; (2) basic i.e., lysine, arginine, histidine; (3) non polar i.e., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan; and (4) uncharged polar i.e., glycine, asparagine, glutamine, cysteine, serine, threonine, tyrosine. Phenylalanine, tryptophan, and tyrosine are sometimes classified jointly as aromatic amino acids. In general, substitution of single amino acids within these families does not have a major effect on the biological activity. 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.

[0046] “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 IPTS / 128757636.1 14Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. Thus, 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.

[0047] 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.

[0048] 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. The phrase 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).

[0049] The term “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 “T.”

[0050] The term “polynucleotide” as used herein is defined as a chain of nucleotides. Furthermore, nucleic acids are polymers of nucleotides. Thus, the terms “nucleic acids” or “nucleic acid molecules” and “polynucleotides” as used herein are interchangeable. As used herein 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.

[0051] 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. IPTS / 128757636.1 15Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT “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.

[0052] As used herein, unless otherwise indicated, “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. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, and Fv fragments; diabodies; linear antibodies; single-chain antibody molecules, e.g., sc-Fv; nanobodies (single domain antibody) and multispecific antibodies formed from antibody fragments.

[0053] A “Fab fragment” is comprised of one light chain and the CH1 and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule.

[0054] An “Fc” region contains two heavy chain fragments comprising the CH2 and CH3 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.

[0055] A “Fab' fragment” contains one light chain and a portion or fragment of one heavy chain that contains the VHdomain and the CH1 domain and also the region between the CH1 and CH2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab')2molecule.

[0056] A “F(ab')2fragment” contains two light chains and two heavy chains containing a portion of the constant region between the CH1 and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab')2fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains.

[0057] The “Fv region” comprises the variable regions from both the heavy and light chains, but lacks the constant regions.

[0058] The term “single-chain Fv” or “scFv” antibody refers to antibody fragments comprising the VHand VLdomains of an antibody, wherein these domains are present in a single polypeptide chain. Generally, the Fv polypeptide further comprises a polypeptide linker between the VHand VLdomains which enables the scFv to form the desired structure for antigen binding. For a review IPTS / 128757636.1 16Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT of scFv, see Pluckthun (1994) THE PHARMACOLOGY OF MONOCLONAL ANTIBODIES, vol. 113, Rosenburg and Moore eds. Springer-Verlag, New York, pp. 269-315. See also, International Patent Application Publication No. WO 88 / 01649 and U.S. Pat. Nos.4,946, 778 and 5,260,203.

[0059] 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.

[0060] As used herein, the terms “comprising” (and any form of comprising, such as “comprise”, “comprises”, and “comprised”), “having” (and any form of having, such as “have” and “has”), “including” (and any form of including, such as “includes” and “include”), or “containing” (and any form of containing, such as “contains” and “contain”), are inclusive or open-ended and do not exclude additional, unrecited elements or method steps. 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.”

[0061] As used herein, the term “contacting” means bringing together of two elements in an in vitro system or an in vivo system. For example, “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.

[0062] As used herein, 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. In some embodiments, 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.

[0063] The compositions disclosed herein may be provided to a subject in a variety of ways through administration of the composition to the subject. As used herein, administer or administration means to provide or the providing of a composition to a subject. Oral administration, as used herein, refers to delivery of an active agent through the mouth. Topical IPTS / 128757636.1 17Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT administration, as used herein, 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).

[0064] 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. In contrast, 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.

[0065] “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 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.

[0066] Ranges: throughout this disclosure, various aspects of the embodiments can be presented in a range format. It should be understood that the description in 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. IPTS / 128757636.1 18Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Novel Signal Peptides

[0067] Without being bound to any particular theory, the embodiments provided for herein have been found to show that novel signal peptides may direct payload proteins as provided for herein to be expressed in the lysosomes of a 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., the lysosomes. Accordingly, the provided novel signal peptides can direct enhanced expression of a native lysosomal protein in the lysosomes, or can direct expression of a payload protein, e.g., a therapeutic protein to the lysosomes for expression.

[0068] In some embodiments, a signal peptide is provided. In some embodiments, the signal peptide comprises an amino acid sequence as recited in Table 1 below: Table 1: Exemplary Novel Signal Peptides SEQ ID NO: Amino Acid Sequence 1IPTS / 128757636.1 19Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT SEQ ID NO: Amino Acid Sequence 18MATLWRGLRRLGSLLSLLCLLLSLLLLAQLSDP, hat is substantially similar to an amino acid sequence as recited in Table 1. 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 as recited in Table 1. 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: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 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: 1. 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: 2. 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: 3. 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: 4. 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 IPTS / 128757636.1 20Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. 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: 6. 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: 7. 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: 8. 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: 9. 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: 10. 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: 11. 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: 12. 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: 13. 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: 14. 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%) IPTS / 128757636.1 21Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT identical to an amino acid sequence of SEQ ID NO: 15. 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: 16. 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: 17. 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: 18. 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: 19. 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: 20. 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: 21. 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: 22. 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: 23. 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: 24. 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: 25. IPTS / 128757636.1 22Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0070] In some embodiments, the signal peptide is a variant of an amino acid sequence as provided in Table 1. In some embodiments, the signal peptide comprises an amino acid sequence as defined by Formula I-XXIV below. Variants of SEQ ID NO: 1 (Formula I)

[0071] In some embodiments, the signal peptide comprises an amino acid sequence represented by: A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16(Formula I); wherein the identity of each of A1– A16are as provided for in Table 2 below. Table 2 Position Suitable Amino Acids A M

[0072] In some embodiments, A1is methionine (M). In some embodiments, A2is an amino acid selected from the group consisting of L, C, G, K, and Y. In some embodiments, A3is an amino acid selected from the group consisting of R, W, L, T, and A. In some embodiments, A4is an IPTS / 128757636.1 23Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT amino acid selected from the group consisting of L and V. In some embodiments, A5is an amino acid selected from the group consisting of A, F, V, and T. In some embodiments, A6is an amino acid selected from the group consisting of L, A, C, and S. In some embodiments, A7is an amino acid selected from the group consisting of A, K, V, Y, M, and L. In some embodiments, A8is an amino acid selected from the group consisting of L, V, F, and A. In some embodiments, A9is an amino acid selected from the group consisting of L, F, and S. In some embodiments, A10is an amino acid selected from the group consisting of L, G, V, and S. In some embodiments, A11is an amino acid selected from the group consisting of L, F, A, C, and S. In some embodiments, A12is an amino acid selected from the group consisting of R, G, S, and T. In some embodiments, A13is an amino acid selected from the group consisting of S, G, V, L, and A. In some embodiments, A14is an amino acid selected from the group consisting of A, L, S, and P. In some embodiments, A15is an amino acid selected from the group consisting of L, F, V, and E. In some embodiments, A16is an amino acid selected from the group consisting of A, G, and S.

[0073] It is to be understood that 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 substitution to be within the scope of Formula I. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 1 and a substitution at position 2 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 position 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 position 4 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 position 5 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 position 6 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 position 7 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 position 8 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 position 9 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 position 10 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 position 11 of SEQ ID NO: 1. In some embodiments, the IPTS / 128757636.1 24Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT signal peptide comprises the amino acid sequence of SEQ ID NO: 1 and a substitution at position 12 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 position 13 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 position 14 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 position 15 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 position 16 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, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 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, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 of SEQ ID NO: 1. Variants of SEQ ID NO: 2 (Formula II)

[0074] In some embodiments, the signal peptide comprises an amino acid sequence represented by: B1-B2-B3-B4-B5-B6-B7-B8-B9-B10-B11-B12-B13-B14-B15-B16-B17(Formula II); wherein the identity of each of B1– B17are as provided for in Table 3 below. Table 3 Position Suitable Amino AcidsIPTS / 128757636.1 25Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids B10 L, G, F, A, S, C, . embodiments, B2is an amino acid selected from the group consisting of R, L, N, A, V, and W. In some embodiments, B3is an amino acid selected from the group consisting of L, P, W, and Q. In some embodiments, B4is an amino acid selected from the group consisting of A, L, K, S, T, and H. In some embodiments, B5is an amino acid selected from the group consisting of L, V, T, and W. In some embodiments, B6 is an amino acid selected from the group consisting of L, A, V, and I. In some embodiments, B7is an amino acid selected from the group consisting of L, S, Y, W, F, and V. In some embodiments, B8is an amino acid selected from the group consisting of L, A, Y, C, S, and F. In some embodiments, B9is an amino acid selected from the group consisting of L, A, F, G, and C. In some embodiments, B10is an amino acid selected from the group consisting of L, G, F, A, S, and C. In some embodiments, B11is an amino acid selected from the group consisting of L, C, W, H, and V. In some embodiments, B12is an amino acid selected from the group consisting of L, S, V, C, and A. In some embodiments, B13is an amino acid selected from the group consisting of G, T, F, A, L, and V. In some embodiments, B14is an amino acid selected from the group consisting of Q, I, A, L, S, and G. In some embodiments, B15 is an amino acid selected from the group consisting of A, G, P, T, V, L, and I. In some embodiments, B16is an amino acid selected from the group consisting of S, E, L, A, T, G, and N. In some embodiments, B17is an amino acid selected from the group consisting of A, M, P, and T.

[0076] It is to be understood that a variant of SEQ ID NO: 2 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 II. Accordingly, in some embodiments, the signal IPTS / 128757636.1 26Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 2 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 3 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 4 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 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. In some embodiments, 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 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 2 and a substitution at position 16 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 17 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, 15, 16, or 17 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 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: 2. IPTS / 128757636.1 27Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Variants of SEQ ID NO: 3 (Formula III)

[0077] In some embodiments, the signal peptide comprises an amino acid sequence represented by: C1-C2-C3-C4-C5-C6-C7-C8-C9-C10-C11-C12-C13-C14-C15-C16-C17-C18(Formula III); wherein the identity of each of C1– C18are as provided for in Table 4 below. Table 4 Position Suitable Amino Acids C M

[0078] In some embodiments, C1is methionine (M). In some embodiments, C2is an amino acid selected from the group consisting of I, L, and R. In some embodiments, C3is an amino acid selected from the group consisting of L, P, and T. In some embodiments, C4is an amino acid selected from the group consisting of L, F, A, and P. In some embodiments, C5is an amino acid IPTS / 128757636.1 28Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT selected from the group consisting of L and V. In some embodiments, C6is an amino acid selected from the group consisting of L and P. In some embodiments, C7is an amino acid selected from the group consisting of L, A, and Y. In some embodiments, C8is an amino acid selected from the group consisting of A, L, C, and V. In some embodiments, C9is an amino acid selected from the group consisting of L and F. In some embodiments, C10is an amino acid selected from the group consisting of L, G, and A. In some embodiments, C11is an amino acid selected from the group consisting of C, L, W, and S. In some embodiments, C12is an amino acid selected from the group consisting of V and S. In some embodiments, C13is an amino acid selected from the group consisting of P, L, F, and I. In some embodiments, C14is an amino acid selected from the group consisting of A, G, Q, and P. In some embodiments, C15is an amino acid selected from the group consisting of G, C, and T. In some embodiments, C16is an amino acid selected from the group consisting of A, T, and S. In some embodiments, C17is an amino acid selected from the group consisting of L, G, A, and V. In some embodiments, C18is an amino acid selected from the group consisting of T, A, G, and L.

[0079] It is to be understood that a variant of SEQ ID NO: 3 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 III. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 2 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 3 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 4 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 5 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 6 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 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 SEQ ID NO: 3 and a substitution at position 10 of SEQ ID NO: 3. In some embodiments, the signal peptide comprises the amino acid sequence of IPTS / 128757636.1 29Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT SEQ ID NO: 3 and a substitution at position 11 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 3 and a substitution at position 17 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 18 of SEQ ID NO: 3. The variant may also comprise any number of substitutions as provided by Formula III. Accordingly, in some embodiments, 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, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 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 more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18 of SEQ ID NO: 3. Variants of SEQ ID NO: 4 (Formula IV)

[0080] In some embodiments, the signal peptide comprises an amino acid sequence represented by: D1-D2-D3-D4-D5-D6-D7-D8-D9-D10-D11-D12-D13-D14-D15-D16-D17-D18-D19(Formula IV); wherein the identity of each of D1– D19are as provided for in Table 5 below. Table 5 Position Suitable Amino AcidsIPTS / 128757636.1 30Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids D6 L, Y, Q, F, C, P

[0081] In some embodiments, D1is methionine (M). In some embodiments, D2is an amino acid selected from the group consisting of A, G, K, L, and R. In some embodiments, D3is an amino acid selected from the group consisting of L, G, P, S, T, and F. In some embodiments, D4is an amino acid selected from the group consisting of I, L, W, Q, and H. In some embodiments, D5is an amino acid selected from the group consisting of L, F, and A. In some embodiments, D6is an amino acid selected from the group consisting of L, Y, Q, F, C, and P. In some embodiments, D7is an amino acid selected from the group consisting of L, F, and S. In some embodiments, D8is an amino acid selected from the group consisting of L, A, V, and F. In some embodiments, D9is an amino acid selected from the group consisting of L, S, V, and G. In some embodiments, D10 is an amino acid selected from the group consisting of L, F, N, V, S, and A. In some embodiments, D11is an amino acid selected from the group consisting of L, S, and F. In some embodiments, D12is an amino acid selected from the group consisting of C, G, T, A, L, and M. In some embodiments, D13is an amino acid selected from the group consisting of L, C, E, M, and G. In some embodiments, D14is an amino acid selected from the group consisting of L, A, F, I, and V. In some embodiments, D15is an amino acid selected from the group consisting of G, L, P, and M. In IPTS / 128757636.1 31Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT some embodiments, D16is an amino acid selected from the group consisting of I, G, L, S, E, Q, and T. In some embodiments, D17is an amino acid selected from the group consisting of A, V, C, G, and T. In some embodiments, D18is an amino acid selected from the group consisting of D, V, H, K, Q, S, and A. In some embodiments, D19is an amino acid selected from the group consisting of A, G, and C.

[0082] It is to be understood that a variant of SEQ ID NO: 4 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 IV. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 4 and a substitution at position 2 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 3 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 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence IPTS / 128757636.1 32Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT of SEQ ID NO: 4 and a substitution at position 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 position 18 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 19 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, 17, 18, or 19 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, 17, 18, or 19 of SEQ ID NO: 4. Variants of SEQ ID NO: 5 (Formula V)

[0083] In some embodiments, the signal peptide comprises an amino acid sequence represented by: E1-E2-E3-E4-E5-E6-E7-E8-E9-E10-E11-E12-E13-E14-E15-E16-E17-E18-E19-E20(Formula V); wherein the identity of each of E1– E20are as provided for in Table 6 below. Table 6 Position Suitable Amino AcidsIPTS / 128757636.1 33Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids E12 L, C, V, F,1. embodiments, E2is an amino acid selected from the group consisting of K, D, P, Q, and S. In some embodiments, E3is an amino acid selected from the group consisting of L, T, R, P, and C. In some embodiments, E4is an amino acid selected from the group consisting of R, L, N, Q, S, and P. In some embodiments, E5is an amino acid selected from the group consisting of V, S, F, and L. In some embodiments, E6is an amino acid selected from the group consisting of L, S, A, and P. In some embodiments, E7 is an amino acid selected from the group consisting of A, T, V, I, and L. In some embodiments, E8is an amino acid selected from the group consisting of A, P, V, and C. In some embodiments, E9is an amino acid selected from the group consisting of L, T, V, A, and C. In some embodiments, E10is an amino acid selected from the group consisting of A, L, V, and S. In some embodiments, E11is an amino acid selected from the group consisting of L, M, and G. In some embodiments, E12is an amino acid selected from the group consisting of L, C, V, and F. In some embodiments, E13is an amino acid selected from the group consisting of L, A, and T. In some embodiments, E14is an amino acid selected from the group consisting of L, I, H, S, and V. In some embodiments, E15is an amino acid selected from the group consisting of L, V, F, and A. In some embodiments, E16is an amino acid selected from the group consisting of S, A, P, and G. In some embodiments, E17is an amino acid selected from the group consisting of P, S, I, V, and L. In some embodiments, E18is an amino acid selected from the group consisting of A, S, V, I, and C. In some embodiments, E19is an amino acid selected from the group consisting of L, E, S, and R. In some embodiments, E20is an amino acid selected from the group consisting of A, T, and H. IPTS / 128757636.1 34Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0085] 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. Accordingly, in some embodiments, 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 3 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 5 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. In some embodiments, 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 10 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 12 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 5 and a substitution at position 19 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 IPTS / 128757636.1 35Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 20 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, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 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 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, or 20 of SEQ ID NO: 5. Variants of SEQ ID NO: 6 (Formula VI)

[0086] In some embodiments, the signal peptide comprises an amino acid sequence represented by: F1-F2-F3-F4-F5-F6-F7-F8-F9-F10-F11-F12-F13-F14-F15-F16-F17-F18-F19-F20-F21(Formula VI); wherein the identity of each of F1– F21are as provided for in Table 7 below. Table 7 Position Suitable Amino AcidsIPTS / 128757636.1 36Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids F16 L, V, P, . embodiments, F2is an amino acid selected from the group consisting of G, P, and A. In some embodiments, F3is an amino acid selected from the group consisting of G and S. In some embodiments, F4is an amino acid selected from the group consisting of R, A, and G. In some embodiments, F5 is an amino acid selected from the group consisting of L, A, W, and S. In some embodiments, F6is an amino acid selected from the group consisting of C, A, L, and V. In some embodiments, F7is an amino acid selected from the group consisting of V, L, and P. In some embodiments, F8is an amino acid selected from the group consisting of L, A, and W. In some embodiments, F9is an amino acid selected from the group consisting of L and V. In some embodiments, F10is an amino acid selected from the group consisting of L and V. In some embodiments, F11is an amino acid selected from the group consisting of F, L, and A. In some embodiments, F12is an amino acid selected from the group consisting of L and A. In some embodiments, F13is an amino acid selected from the group consisting of L, F, and A. In some embodiments, F14is an amino acid selected from the group consisting of L, A, and V. In some embodiments, F15 is an amino acid selected from the group consisting of L, A, G, and N. In some embodiments, F16is an amino acid selected from the group consisting of L, V, and P. In some embodiments, F17is an amino acid selected from the group consisting of S and T. In some embodiments, F18is an amino acid selected from the group consisting of A and C. In some embodiments, F19is an amino acid selected from the group consisting of A and L. In some embodiments, F20is an amino acid selected from the group consisting of S, D, and V. In some embodiments, F21is an amino acid selected from the group consisting of A, G, and S.

[0088] It is to be understood that a variant of SEQ ID NO: 6 is not required to comprise a substitution at each position where a substitution is provided, but rather need only contain one IPTS / 128757636.1 37Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT substitution to be within the scope of Formula VI. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 2 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 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. In some embodiments, 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 10 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. In some embodiments, the signal peptide comprises the amino acid sequence of 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 6 and a substitution at position 20 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 21 of SEQ ID NO: 6. The variant may also IPTS / 128757636.1 38Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, or 21 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 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, or 21 of SEQ ID NO: 6. Variants of SEQ ID NO: 7 (Formula VII)

[0089] In some embodiments, the signal peptide comprises an amino acid sequence represented by: G1-G2-G3-G4-G5-G6-G7-G8-G9-G10-G11-G12-G13-G14-G15-G16-G17-G18-G19-G20-G21-G22(Formula VII); wherein the identity of each of G1– G22are as provided for in Table 8 below. Table 8 Position Suitable Amino AcidsIPTS / 128757636.1 39Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids G15 L, K, A, . embodiments, G2is an amino acid selected from the group consisting of G, T, A, I, and W. In some embodiments, G3is an amino acid selected from the group consisting of R, L, A, and S. In some embodiments, G4is an amino acid selected from the group consisting of R, G, Q, N, S, and T. In some embodiments, G5is an amino acid selected from the group consisting of S, A, V, W, G, R, and L. In some embodiments, G6is an amino acid selected from the group consisting of L, A, C, and P. In some embodiments, G7is an amino acid selected from the group consisting of L, T, V, A, and W. In some embodiments, G8is an amino acid selected from the group consisting of L, A, V, I, and F. In some embodiments, G9is an amino acid selected from the group consisting of G, W, T, F, S, and C. In some embodiments, G10is an amino acid selected from the group consisting of L, A, and I. In some embodiments, G11is an amino acid selected from the group consisting of L, A, F, M, and G. In some embodiments, G12is an amino acid selected from the group consisting of L, A, and F. In some embodiments, G13is an amino acid selected from the group consisting of L, A, G, P, and W. In some embodiments, G14is an amino acid selected from the group consisting of L, P, I, M, and A. In some embodiments, G15 is an amino acid selected from the group consisting of L, K, and A. In some embodiments, G16is an amino acid selected from the group consisting of L, S, C, F, and G. In some embodiments, G17is an amino acid selected from the group consisting of V, W, G, T, P, and A. In some embodiments, G18is an amino acid selected from the group consisting of G, P, K, E, and A. In some embodiments, G19is an amino acid selected from the group consisting of C, V, K, Q, and R. In some embodiments, G20is an amino acid selected from the group consisting of A, C, S, and V. In some embodiments, G21is an amino acid selected from the group consisting IPTS / 128757636.1 40Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT of E, L, Y, F, T, and G. In some embodiments, G22is an amino acid selected from the group consisting of S, G, and A.

[0091] It is to be understood that a variant of SEQ ID NO: 7 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 VII. Accordingly, in some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 7 and a substitution at position 6 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 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 9 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 11 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 13 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. In some embodiments, 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 IPTS / 128757636.1 41Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT of SEQ ID NO: 7 and a substitution at position 19 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 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 position 21 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 22 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, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 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, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 of SEQ ID NO: 7. Variants of SEQ ID NO: 8 (Formula VIII)

[0092] In some embodiments, the signal peptide comprises an amino acid sequence represented by: H1-H2-H3-H4-H5-H6-H7-H8-H9-H10-H11-H12-H13-H14-H15-H16-H17-H18-H19-H20-H21-H22-H23(Formula VIII); wherein the identity of each of H1– H23are as provided for in Table 9 below. Table 9 Position Suitable Amino AcidsIPTS / 128757636.1 42Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids H11 A, L

[0093] n some embod ments,1s met on ne ( ). n some embodiments, H2is isoleucine (I). In some embodiments, H3is an amino acid selected from the group consisting of L and R. In some embodiments, H4is an amino acid selected from the group consisting of N and L. In some embodiments, H5is lysine (K). In some embodiments, H6is alanine (A). In some embodiments, H7is an amino acid selected from the group consisting of L and A. In some embodiments, H8is an amino acid selected from the group consisting of M and L. In some embodiments, H9is leucine (L). In some embodiments, H10is an amino acid selected from the group consisting of G, L, and P. In some embodiments, H11is an amino acid selected from the group consisting of A and L. In some embodiments, H12is an amino acid selected from the group consisting of L and A. In some embodiments, H13is an amino acid selected from the group consisting of A and L. In some embodiments, H14is leucine (L). In some embodiments, H15is an amino acid selected from the group consisting of T and L. In some embodiments, H16is an amino acid selected from the group consisting of T and L. In some embodiments, H17is an amino acid selected from the group consisting of V and L. In some embodiments, H18is an amino acid selected from the group consisting of M, A, and L. In some embodiments, H19is an amino acid selected from the group consisting of S and G. In some embodiments, H20is an amino acid selected from the group IPTS / 128757636.1 43Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT consisting of P, G, and L. In some embodiments, H21is an amino acid selected from the group consisting of C and A. In some embodiments, H22is an amino acid selected from the group consisting of G and Q. In some embodiments, H23is an amino acid selected from the group consisting of G and A.

[0094] It is to be understood that a variant of SEQ ID NO: 8 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 VIII. Accordingly, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 7 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 10 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 11 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 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 comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 15 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 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 position 22 of SEQ ID NO: 8. In some embodiments, the IPTS / 128757636.1 44Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT signal peptide comprises the amino acid sequence of SEQ ID NO: 8 and a substitution at position 23 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 3, 4, 7, 8, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, or 23 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 3, 4, 7, 8, 10, 11, 12, 13, 15, 16, 17, 18, 19, 20, 21, 22, or 23 of SEQ ID NO: 8. Variants of SEQ ID NO: 9 (Formula IX)

[0095] In some embodiments, the signal peptide comprises an amino acid sequence represented by: I1-I2-I3-I4-I5-I6-I7-I8-I9-I10-I11-I12-I13-I14-I15-I16-I17-I18-I19-I20-I21-I22-I23-I24(Formula IX); wherein the identity of each of I1– I24are as provided for in Table 10 below. Table 10 Position Suitable Amino AcidsIPTS / 128757636.1 45Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids I15 V, L, Pso e e o e s,1s e o e . so e embodiments, I2is an amino acid selected from the group consisting of G, H, K, S. In some embodiments, I3is an amino acid selected from the group consisting of A and P. In some embodiments, I4is an amino acid selected from the group consisting of G, A, M, and P. In some embodiments, I5is an amino acid selected from the group consisting of P, A, L, and K. In some embodiments, I6is an amino acid selected from the group consisting of S, F, K, and L. In some embodiments, I7is an amino acid selected from the group consisting of L, P, and D. In some embodiments, I8is an amino acid selected from the group consisting of L, F, and S. In some embodiments, I9is an amino acid selected from the group consisting of L, P, and S. In some embodiments, I10is an amino acid selected from the group consisting of A, V, N, and G. In some embodiments, I11is an amino acid selected from the group consisting of A, V, L, and C. In some embodiments, I12is an amino acid selected from the group consisting of L, V, and I. In some embodiments, I13is an amino acid selected from the group consisting of L, A, and F. In some embodiments, I14is an amino acid selected from the group consisting of L, A, V, and F. In some embodiments, I15is an amino acid selected from the group consisting of V, L, and P. In some embodiments, I16is leucine (L). In some embodiments, I17is an amino acid selected from the group consisting of S, W, C, and L. In some embodiments, I18is an amino acid selected from the group consisting of G, D, and L. In some embodiments, I19is an amino acid selected from the group consisting of D, A, Y, and F. In some embodiments, I20is an amino acid selected from the group consisting of G, A, V, and Q. In some embodiments, I21IPTS / 128757636.1 46Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT is an amino acid selected from the group consisting of A, P, L, and Q. In some embodiments, I22is an amino acid selected from the group consisting of V, T, G, A. In some embodiments, I23is an amino acid selected from the group consisting of R and E. In some embodiments, I24is an amino acid selected from the group consisting of A, C, and G.

[0097] It is to be understood that a variant of SEQ ID NO: 9 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 IX. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 2 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 3 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 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. In some embodiments, 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 12 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 13 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. 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 IPTS / 128757636.1 47Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 19 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 9 and a substitution at position 23 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 24 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, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, or 24 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 more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 20, 21, 22, 23, or 24 of SEQ ID NO: 9. Variants of SEQ ID NO: 10 (Formula X)

[0098] In some embodiments, the signal peptide comprises an amino acid sequence represented by: J1-J2-J3-J4-J5-J6-J7-J8-J9-J10-J11-J12-J13-J14-J15-J16-J17-J18-J19-J20-J21-J22-J23-J24-J25(Formula X); wherein the identity of each of J1– J25are as provided for in Table 11 below. Table 11 Position Suitable Amino AcidsIPTS / 128757636.1 48Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids J8 V, I, S, P, R

[0099] In some embodiments, J1is methionine (M). In some embodiments, J2is an amino acid selected from the group consisting of A, F, G, K, and P. In some embodiments, J3 is an amino acid selected from the group consisting of I, P, L, and H. In some embodiments, J4is an amino acid selected from the group consisting of S, R, I, Q, L, and P. In some embodiments, J5is an amino acid selected from the group consisting of R, G, A, and F. In some embodiments, J6is an amino acid selected from the group consisting of V, G, A, R, and T. In some embodiments, J7is an amino acid selected from the group consisting of L, P, V, E, and G. In some embodiments, J8is an amino acid selected from the group consisting of V, I, S, P, and R. In some embodiments, J9is an amino acid selected from the group consisting of L, P, A, and G. In some embodiments, J10is an amino acid selected from the group consisting of G, R, A, I, and L. In some embodiments, J11is an amino acid selected from the group consisting of F, A, G, and L. In some embodiments, J12is an amino IPTS / 128757636.1 49Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT acid selected from the group consisting of L, F, H, A, and W. In some embodiments, J13is an amino acid selected from the group consisting of S, I, T, A, and L. In some embodiments, J14is an amino acid selected from the group consisting of L, I, A, and G. In some embodiments, J15is an amino acid selected from the group consisting of A, L, M, and F. In some embodiments, J16is an amino acid selected from the group consisting of L, T, F, W, A, and V. In some embodiments, J17is an amino acid selected from the group consisting of L, G, and M. In some embodiments, J18is an amino acid selected from the group consisting of L, M, F, T, and S. In some embodiments, J19is an amino acid selected from the group consisting of S and L. In some embodiments, J20is an amino acid selected from the group consisting of L, A, P, T, and V. In some embodiments, J21is an amino acid selected from the group consisting of Q, R, G, and C. In some embodiments, J22is an amino acid selected from the group consisting of E, G, L, P, and V. In some embodiments, J23is an amino acid selected from the group consisting of A, S, T, and L. In some embodiments, J24is an amino acid selected from the group consisting of G, W, A, T, and L. In some embodiments, J25is an amino acid selected from the group consisting of A, T, and G.

[0100] It is to be understood that a variant of SEQ ID NO: 10 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 X. Accordingly, in some embodiments, 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 4 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. In some embodiments, 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 8 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 IPTS / 128757636.1 50Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT sequence of SEQ ID NO: 10 and a substitution at position 11 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 12 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 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 10 and a substitution at position 23 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 24 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 25 of SEQ ID NO: 10. The variant may also comprise any number of substitutions as provided by Formula X. Accordingly, in some embodiments, 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, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25 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 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, or 25 of SEQ ID NO: 10. IPTS / 128757636.1 51Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Variants of SEQ ID NO: 11 (Formula XI)

[0101] In some embodiments, the signal peptide comprises an amino acid sequence represented by: K1-K2-K3-K4-K5-K6-K7-K8-K9-K10-K11-K12-K13-K14-K15-K16-K17-K18-K19-K20-K21-K22-K23-K24- K25-K26(Formula XI); wherein the identity of each of K1– K26are as provided for in Table 12 below. Table 12 Position Suitable Amino Acids K MIPTS / 128757636.1 52Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids K22 M, C, R, P, S, . embodiments, K2is an amino acid selected from the group consisting of G, A, E, and F. In some embodiments, K3is an amino acid selected from the group consisting of A, N, P, H, and S. In some embodiments, K4is an amino acid selected from the group consisting of V, M, F, E, and G. In some embodiments, K5is an amino acid selected from the group consisting of V, F, Y, Q, and W. In some embodiments, K6is an amino acid selected from the group consisting of A, L, S, N, and V. In some embodiments, K7is an amino acid selected from the group consisting of Q, A, C, and P. In some embodiments, K8is an amino acid selected from the group consisting of W, T, S, and G. In some embodiments, K9is an amino acid selected from the group consisting of R, S, A, and V. In some embodiments, K10is an amino acid selected from the group consisting of W, M, T, A, and V. In some embodiments, K11is an amino acid selected from the group consisting of L, W, G, and A. In some embodiments, K12is an amino acid selected from the group consisting of L, Q, and T. In some embodiments, K13 is an amino acid selected from the group consisting of L, C, and Q. In some embodiments, K14is an amino acid selected from the group consisting of L, I, M, and V. In some embodiments, K15is an amino acid selected from the group consisting of L, F, and N. In some embodiments, K16is an amino acid selected from the group consisting of L, V, and P. In some embodiments, K17is an amino acid selected from the group consisting of L and T. In some embodiments, K18is an amino acid selected from the group consisting of S, I, A, L, and R. In some embodiments, K19is an amino acid selected from the group consisting of A, S, V, W, and L. In some embodiments, K20is an amino acid selected from the group consisting of A, G, L, and D. In some embodiments, K21is an amino acid selected from the group consisting of S, G, V, and L. In some embodiments, K22is an amino acid selected from the group consisting of M, C, R, P, and S. In some embodiments, K23 is an amino acid selected from the group consisting of E, G, H, and M. In some embodiments, K24is an amino acid selected from the group consisting of S, A, L, and T. In some IPTS / 128757636.1 53Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT embodiments, K25is an amino acid selected from the group consisting of W, S, C, and Q. In some embodiments, K26is an amino acid selected from the group consisting of G, A, and Q.

[0103] 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 15 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. In some embodiments, the IPTS / 128757636.1 54Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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 SEQ ID NO: 11 and a substitution at position 22 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 11 and a substitution at position 25 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 26 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, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26 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 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, or 26 of SEQ ID NO: 11. Variants of SEQ ID NO: 12 (Formula XII)

[0104] In some embodiments, the signal peptide comprises an amino acid sequence represented by: L1-L2-L3-L4-L5-L6-L7-L8-L9-L10-L11-L12-L13-L14-L15-L16-L17-L18-L19-L20-L21-L22-L23-L24-L25-L26- L27(Formula XII); wherein the identity of each of L1– L27are as provided for in Table 13 below. Table 13 Position Suitable Amino AcidsIPTS / 128757636.1 55Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids L4 V, L, R, K

[0105] In some embodiments, L1is methionine (M). In some embodiments, L2is an amino acid selected from the group consisting of G, K, L, and R. In some embodiments, L3is an amino acid selected from the group consisting of V, S, Q, and P. In some embodiments, L4is an amino acid selected from the group consisting of V, L, R, and K. In some embodiments, L5is an amino acid selected from the group consisting of G and Q. In some embodiments, L6is an amino acid selected IPTS / 128757636.1 56Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT from the group consisting of A, P, and G. In some embodiments, L7is an amino acid selected from the group consisting of L, P, and G. In some embodiments, L8is an amino acid selected from the group consisting of L, R, and A. In some embodiments, L9is an amino acid selected from the group consisting of L, S, V, and A. In some embodiments, L10is an amino acid selected from the group consisting of L and P. In some embodiments, L11is an amino acid selected from the group consisting of A, R, C, and S. In some embodiments, L12is an amino acid selected from the group consisting of L, A, and T. In some embodiments, L13is an amino acid selected from the group consisting of L, V, and A. In some embodiments, L14is an amino acid selected from the group consisting of L and A. In some embodiments, L15is an amino acid selected from the group consisting of L, V, and A. In some embodiments, L16is an amino acid selected from the group consisting of L, T, and P. In some embodiments, L17is an amino acid selected from the group consisting of L and A. In some embodiments, L18is an amino acid selected from the group consisting of L and V. In some embodiments, L19is an amino acid selected from the group consisting of L, S, and P. In some embodiments, L20is an amino acid selected from the group consisting of A and L. In some embodiments, L21is an amino acid selected from the group consisting of L, S, and V. In some embodiments, L22is an amino acid selected from the group consisting of L and P. In some embodiments, L23is an amino acid selected from the group consisting of G and L. In some embodiments, L24is an amino acid selected from the group consisting of L, A, V, and T. In some embodiments, L25is an amino acid selected from the group consisting of L, P, A, and S. In some embodiments, L26is an amino acid selected from the group consisting of L, H, and E. In some embodiments, L27is an amino acid selected from the group consisting of G, V, A, and L.

[0106] 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. Accordingly, in some embodiments, 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 IPTS / 128757636.1 57Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 6 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 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 9 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 13 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 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 15 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. In some embodiments, 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 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. In some embodiments, 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. In some embodiments, the signal IPTS / 128757636.1 58Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT peptide comprises the amino acid sequence of SEQ ID NO: 12 and a substitution at position 26 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 27 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, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27 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 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, or 27 of SEQ ID NO: 12. Variants of SEQ ID NO: 13 (Formula XIII)

[0107] In some embodiments, the signal peptide comprises an amino acid sequence represented by: M1-M2-M3-M4-M5-M6-M7-M8-M9-M10-M11-M12-M13-M14-M15-M16-M17-M18-M19-M20-M21-M22- M23-M24-M25-M26-M27-M28(Formula XIII); wherein the identity of each of M1– M28are as provided for in Table 14 below. Table 14 Position Suitable Amino AcidsIPTS / 128757636.1 59Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids M12 A, L, P, R, V

[0108] In some embodiments, M1 is methionine (M). In some embodiments, M2 is an amino acid selected from the group consisting of A, C, I, R, S, and V. In some embodiments, M3is an amino acid selected from the group consisting of L, R, T, and A. In some embodiments, M4is an amino acid selected from the group consisting of Q, R, A, and K. In some embodiments, M5is an amino acid selected from the group consisting of I, F, A, D, L, and V. In some embodiments, M6is an amino acid selected from the group consisting of P, R, and S. In some embodiments, M7is an amino acid selected from the group consisting of G, P, E, V, and A. In some embodiments, M8is an amino acid selected from the group consisting of G, A, P, and L. In some embodiments, M9is an amino acid selected from the group consisting of L, S, F, R, and P. In some embodiments, M10is an amino acid selected from the group consisting of R, P, W, C, and F. In some embodiments, M11 is an amino acid selected from the group consisting of A, M, L, G, P, and T. In some embodiments, M12is an amino acid selected from the group consisting of A, L, P, R, and V. In IPTS / 128757636.1 60Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT some embodiments, M13is an amino acid selected from the group consisting of A, T, L, P, and W. In some embodiments, M14is an amino acid selected from the group consisting of L, V, S, and P. In some embodiments, M15is an amino acid selected from the group consisting of T, L, and R. In some embodiments, M16is an amino acid selected from the group consisting of L, V, and A. In some embodiments, M17is an amino acid selected from the group consisting of L, M, and T. In some embodiments, M18is leucine (L). In some embodiments, M19is an amino acid selected from the group consisting of L, M, V, and A. In some embodiments, M20is an amino acid selected from the group consisting of V, M, L, and S. In some embodiments, M21is an amino acid selected from the group consisting of L, S, and A. In some embodiments, M22is an amino acid selected from the group consisting of S, L, W, and G. In some embodiments, M23is an amino acid selected from the group consisting of T, A, S, and L. In some embodiments, M24is an amino acid selected from the group consisting of P, S, G, and L. In some embodiments, M25is an amino acid selected from the group consisting of V, L, R, and G. In some embodiments, M26is an amino acid selected from the group consisting of A, G, S, and V. In some embodiments, M27is an amino acid selected from the group consisting of E, L, A, V, and Q. In some embodiments, M28is an amino acid selected from the group consisting of A, G, and P.

[0109] 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. In some embodiments, 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. In some embodiments, the IPTS / 128757636.1 61Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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 embodiments, 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. 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 21 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 13 and a substitution at position 27 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 28 of SEQ ID NO: 13. The variant may also comprise any number of substitutions as provided by Formula XIII. Accordingly, in some embodiments, 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, 19, IPTS / 128757636.1 62Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 20, 21, 22, 23, 24, 25, 26, 27, or 28 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 more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 of SEQ ID NO: 13. Variants of SEQ ID NO: 14 (Formula XIV)

[0110] In some embodiments, the signal peptide comprises an amino acid sequence represented by: N1-N2-N3-N4-N5-N6-N7-N8-N9-N10-N11-N12-N13-N14-N15-N16-N17-N18-N19-N20-N21-N22-N23-N24- N25-N26-N27-N28-N29(Formula XIV); wherein the identity of each of N1– N29are as provided for in Table 15 below. Table 15 Position Suitable Amino AcidsIPTS / 128757636.1 63Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids N18 T, L[ ] n some em o men s,1s me on ne ( ). n some embodiments, N2is valine (V). In some embodiments, N3is cysteine (C). In some embodiments, N4is leucine (L). In some embodiments, N5is an amino acid selected from the group consisting of K and R. In some embodiments, N6is an amino acid selected from the group consisting of L, V, and F. In some embodiments, N7is proline (P). In some embodiments, N8is glycine (G). In some embodiments, N9is glycine (G). In some embodiments, N10is serine (S). In some embodiments, N11is an amino acid selected from the group consisting of C and Y. In some embodiments, N12is methionine (M). In some embodiments, N13 is an amino acid selected from the group consisting of A, V, and T. In some embodiments, N14is an amino acid selected from the group consisting of A and V. In some embodiments, N15is leucine (L). In some embodiments, N16is threonine (T). In some embodiments, N17is valine (V). In some embodiments, N18is an amino acid selected from the group consisting of T and L. In some embodiments, N19is leucine (L). In some embodiments, N20is methionine (M). In some embodiments, N21is valine (V). In some embodiments, N22is leucine (L). In some embodiments, N23is serine (S). In some embodiments, N24is serine (S). In some embodiments, N25is proline (P). In some embodiments, N26is leucine (L). In some embodiments, N27is an amino acid selected from the group consisting of A and V. In some IPTS / 128757636.1 64Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT embodiments, N28is an amino acid selected from the group consisting of L and Q. In some embodiments, N29is an amino acid selected from the group consisting of A and G.

[0112] It is to be understood that a variant of SEQ ID NO: 14 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 XIV. Accordingly, in some embodiments, 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 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 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 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 position 28 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 29 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 5, 6, 11, 13, 14, 18, 27, 28, or 29 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 corresponding to position 5, 6, 11, 13, 14, 18, 27, 28, or 29 of SEQ ID NO: 14.

[0113] In some non-limiting embodiments, the variant of SEQ ID NO: 14 comprises the amino acid sequence of SEQ ID NO: 25. In some embodiments, the sequence of SEQ ID NO: 25 is derived from Formula XIV as follows: N1is methionine (M), N2is valine (V), N3is cysteine (C), N4is leucine (L), N5is lysine (K), N6is leucine (L), N7is proline (P), N8is glycine (G), N9is glycine (G), N10is serine (S), N11is cysteine (C), N12is methionine (M), N13is alanine (A), N14is alanine (A), N15is leucine (L), N16is threonine (T), N17is valine (V), N18is threonine (T), N19is IPTS / 128757636.1 65Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT leucine (L), N20is methionine (M), N21is valine (V), N22is leucine (L), N23is serine (S), N24is serine (S), N25is proline (G), N26is leucine (L), N27is alanine (A), N28is leucine (L), and N29is alanine (A). Variants of SEQ ID NO: 15 (Formula XV)

[0114] In some embodiments, the signal peptide comprises an amino acid sequence represented by: O1-O2-O3-O4-O5-O6-O7-O8-O9-O10-O11-O12-O13-O14-O15-O16-O17-O18-O19-O20-O21-O22-O23-O24- O25-O26-O27-O28-O29-O30(Formula XV); wherein the identity of each of O1– O30are as provided for in Table 16 below. Table 16 Position Suitable Amino Acids MIPTS / 128757636.1 66Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids O19 T, L, G, M, F[ ] n some em o men s,1s me on ne ( ). n some embodiments, O2is an amino acid selected from the group consisting of S, T, A, G, and K. In some embodiments, O3is an amino acid selected from the group consisting of W, G, C, K, A, and P. In some embodiments, O4is an amino acid selected from the group consisting of K, L, A, D, and V. In some embodiments, O5is an amino acid selected from the group consisting of K, R, G, L, E, and P. In some embodiments, O6is an amino acid selected from the group consisting of S, R, K, A, and N. In some embodiments, O7is an amino acid selected from the group consisting of L, G, R, I, K, and Y. In some embodiments, O8 is an amino acid selected from the group consisting of R, W, M, P, G, and Q. In some embodiments, O9is an amino acid selected from the group consisting of I, S, G, R, and A. In some embodiments, O10is an amino acid selected from the group consisting of P, R, L, G, M, and H. In some embodiments, O11is an amino acid selected from the group consisting of G, A, N, L, and Q. In some embodiments, O12is an amino acid selected from the group consisting of D, A, K, R, L, and S. In some embodiments, O13is an amino acid selected from the group consisting of L, A, Q, and R. In some embodiments, O14is an amino acid selected from the group consisting of R, L, P, A, and V. In some embodiments, O15is an amino acid selected from the group consisting of V, T, Q, L, and C. In some embodiments, O16is an amino acid selected from the group consisting of L, A, V, and M. In some embodiments, O17is an amino acid selected from the IPTS / 128757636.1 67Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT group consisting of T, L, G, and I. In some embodiments, O18is an amino acid selected from the group consisting of L, V, A, and G. In some embodiments, O19is an amino acid selected from the group consisting of T, L, G, M, and F. In some embodiments, O20is an amino acid selected from the group consisting of L, V, A, and F. In some embodiments, O21is an amino acid selected from the group consisting of M, L, A, and N. In some embodiments, O22is an amino acid selected from the group consisting of L, T, M, and E. In some embodiments, O23is an amino acid selected from the group consisting of A, L, V, T, and I. In some embodiments, O24is an amino acid selected from the group consisting of V, I, S, M, L, and E. In some embodiments, O25is an amino acid selected from the group consisting of L, M, T, S, and W. In some embodiments, O26is an amino acid selected from the group consisting of S, P, G, and V. In some embodiments, O27is an amino acid selected from the group consisting of S, P, V, K, and L. In some embodiments, O28is an amino acid selected from the group consisting of S, C, T, A, and L. In some embodiments, O29is an amino acid selected from the group consisting of L, R, G, E, S, and T. In some embodiments, O30is an amino acid selected from the group consisting of A, G, and Y.

[0116] 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. In some embodiments, 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. In some embodiments, 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 IPTS / 128757636.1 68Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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 14 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 16 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 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 18 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. In some embodiments, the signal peptide 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 15 and a substitution at position 29 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 30 of SEQ ID NO: 15. The variant may also comprise any number of IPTS / 128757636.1 69Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 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 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, or 30 of SEQ ID NO: 15. Variants of SEQ ID NO: 16 (Formula XVI)

[0117] In some embodiments, the signal peptide comprises an amino acid sequence represented by: P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-P15-P16-P17-P18-P19-P20-P21-P22-P23-P24-P25-P26- P27-P28-P29-P30-P31(Formula XVI); wherein the identity of each of P1– P31are as provided for in Table 17 below. Table 17 Position Suitable Amino AcidsIPTS / 128757636.1 70Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids P15 L, P, A, V

[0118] In some embodiments, P1 is methionine (M). In some embodiments, P2 is an amino acid selected from the group consisting of Q, R, E, and M. In some embodiments, P3is an amino acid selected from the group consisting of P, V, L, S, and A. In some embodiments, P4is an amino acid selected from the group consisting of G, L, R, P, and E. In some embodiments, P5is an amino acid selected from the group consisting of P, Q, N, C, G, and D. In some embodiments, P6is an amino acid selected from the group consisting of V, T, P, M, and R. In some embodiments, P7is an amino acid selected from the group consisting of A, S, E, L, R, and M. In some embodiments, P8is an amino acid selected from the group consisting of A, L, E, S, and F. In some embodiments, P9is an amino acid selected from the group consisting of H, Q, A, L, and R. In some embodiments, P10is an amino acid selected from the group consisting of R, P, L, and I. In some embodiments, P11 is an amino acid selected from the group consisting of R, G, N, and A. In some embodiments, P12is an amino acid selected from the group consisting of C, A, T, and G. In some embodiments, IPTS / 128757636.1 71Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT P13is an amino acid selected from the group consisting of V, S, A, G, and P. In some embodiments, P14is an amino acid selected from the group consisting of L, A, and I. In some embodiments, P15is an amino acid selected from the group consisting of L, P, A, and V. In some embodiments, P16is an amino acid selected from the group consisting of L, P, M, A, and R. In some embodiments, P17is an amino acid selected from the group consisting of A, W, R, C, and L. In some embodiments, P18is an amino acid selected from the group consisting of L and F. In some embodiments, P19is an amino acid selected from the group consisting of L, P, A, and S. In some embodiments, P20is an amino acid selected from the group consisting of L, M, and A. In some embodiments, P21is an amino acid selected from the group consisting of G, V, L, I, F, and A. In some embodiments, P22is an amino acid selected from the group consisting of L, V, T, and F. In some embodiments, P23is an amino acid selected from the group consisting of L, S, V, and G. In some embodiments, P24is an amino acid selected from the group consisting of L, T, W, F, and A. In some embodiments, P25is an amino acid selected from the group consisting of S, W, D, V, and A. In some embodiments, P26is an amino acid selected from the group consisting of S, V, I, A, E, and L. In some embodiments, P27is an amino acid selected from the group consisting of G, V, P, E, S, and R. In some embodiments, P28is an amino acid selected from the group consisting of G, L, Q, C, and V. In some embodiments, P29is an amino acid selected from the group consisting of A, G, C, and R. In some embodiments, P30is an amino acid selected from the group consisting of R, L, Y, and G. In some embodiments, P31is an amino acid selected from the group consisting of A and G.

[0119] It is to be understood that a variant of SEQ ID NO: 16 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 XVI. Accordingly, in some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence IPTS / 128757636.1 72Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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 IPTS / 128757636.1 73Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 16 and a substitution at position 30 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 31 of SEQ ID NO: 16. The variant may also comprise any number of substitutions as provided by Formula XVI. Accordingly, in some embodiments, 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, 29, 30, or 31 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 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, or 31 of SEQ ID NO: 16. Variants of SEQ ID NO: 17 (Formula XVII)

[0120] In some embodiments, the signal peptide comprises an amino acid sequence represented by: Q1-Q2-Q3-Q4-Q5-Q6-Q7-Q8-Q9-Q10-Q11-Q12-Q13-Q14-Q15-Q16-Q17-Q18-Q19-Q20-Q21-Q22-Q23-Q24- Q25-Q26-Q27-Q28-Q29-Q30-Q31-Q32(Formula XVII); wherein the identity of each of Q1– Q32are as provided for in Table 18 below. Table 18 Position Suitable Amino AcidsIPTS / 128757636.1 74Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids Q8 R

[0121] In some embodiments, Q1is methionine (M). In some embodiments, Q2is serine (S). In some embodiments, Q3is tryptophan (W). In some embodiments, Q4is lysine (K). In some embodiments, Q5is lysine (K). In some embodiments, Q6is alanine (A). In some embodiments, IPTS / 128757636.1 75Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Q7is leucine (L). In some embodiments, Q8is arginine (R). In some embodiments, Q9is isoleucine (I). In some embodiments, Q10is proline (P). In some embodiments, Q11is glycine (G). In some embodiments, Q12is glycine (G). In some embodiments, Q13is leucine (L). In some embodiments, Q14is arginine (R). In some embodiments, Q15is an amino acid selected from the group consisting of A and V. In some embodiments, Q16is alanine (A). In some embodiments, Q17is threonine (T). In some embodiments, Q18is valine (V). In some embodiments, Q19is threonine (T). In some embodiments, Q20is leucine (L). In some embodiments, Q21is methionine (M). In some embodiments, Q22is leucine (L). In some embodiments, Q23is an amino acid selected from the group consisting of A and S. In some embodiments, Q24is methionine (M). In some embodiments, Q25is leucine (L). In some embodiments, Q26is serine (S). In some embodiments, Q27is threonine (T). In some embodiments, Q28is proline (P). In some embodiments, Q29is valine (V). In some embodiments, Q30is alanine (A). In some embodiments, Q31is glutamate (E). In some embodiments, Q32is glycine (G).

[0122] It is to be understood that a variant of SEQ ID NO: 17 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 XVII. Accordingly, 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 23 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 15 or 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 more than one position corresponding to position 15 or 23 of SEQ ID NO: 17. Variants of SEQ ID NO: 18 (Formula XVIII)

[0123] In some embodiments, the signal peptide comprises an amino acid sequence represented by: R1-R2-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22-R23-R24-R25- R26-R27-R28-R29-R30-R31-R32-R33(Formula XVIII); wherein the identity of each of R1– R33are as provided for in Table 19 below. IPTS / 128757636.1 76Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Table 19 Position Suitable Amino Acids R1MIPTS / 128757636.1 77Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids R29 Q, D, K, . embodiments, R2is an amino acid selected from the group consisting of A, G, and R. In some embodiments, R3is an amino acid selected from the group consisting of T, L, and S. In some embodiments, R4is an amino acid selected from the group consisting of L, H, and A. In some embodiments, R5is an amino acid selected from the group consisting of W, L, and A. In some embodiments, R6is an amino acid selected from the group consisting of R and G. In some embodiments, R7is an amino acid selected from the group consisting of G, P, and R. In some embodiments, R8is an amino acid selected from the group consisting of L, Y, and G. In some embodiments, R9is an amino acid selected from the group consisting of R and L. In some embodiments, R10is an amino acid selected from the group consisting of R, V, and A. In some embodiments, R11is an amino acid selected from the group consisting of L, G, and A. In some embodiments, R12is an amino acid selected from the group consisting of G, L, and P. In some embodiments, R13is an amino acid selected from the group consisting of S, L, and A. In some embodiments, R14 is an amino acid selected from the group consisting of L, P, and A. In some embodiments, R15is an amino acid selected from the group consisting of L, D, and R. In some embodiments, R16is an amino acid selected from the group consisting of S, G, and D. In some embodiments, R17is an amino acid selected from the group consisting of L and S. In some embodiments, R18is an amino acid selected from the group consisting of L and S. In some embodiments, R19is an amino acid selected from the group consisting of C, F, and P. In some embodiments, R20is an amino acid selected from the group consisting of L and V. In some embodiments, R21is an amino acid selected from the group consisting of L and A. In some embodiments, R22is leucine (L). In some embodiments, R23is an amino acid selected from the group consisting of S, L, and F. In some embodiments, R24is an amino acid selected from the group consisting of L and V. In some embodiments, R25 is an amino acid selected from the group consisting of L, M, and C. In some embodiments, R26is leucine (L). IPTS / 128757636.1 78Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT In some embodiments, R27is leucine (L). In some embodiments, R28is an amino acid selected from the group consisting of A and L. In some embodiments, R29is an amino acid selected from the group consisting of Q, D, and K. In some embodiments, R30is an amino acid selected from the group consisting of L, P, and T. In some embodiments, R31is an amino acid selected from the group consisting of S, A, and C. In some embodiments, R32is an amino acid selected from the group consisting of D, L, and E. In some embodiments, R33is an amino acid selected from the group consisting of P and A.

[0125] It is to be understood that a variant of SEQ ID NO: 18 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 XVIII. Accordingly, in some embodiments, 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. In some embodiments, 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. In some embodiments, 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 IPTS / 128757636.1 79Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 21 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 18 and a substitution at position 32 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 33 of SEQ ID NO: 18. The variant may also comprise any number of substitutions as provided by Formula XVIII. Accordingly, in some embodiments, 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, 21, 23, 24, 25, 28, 29, 30, 31, 32, or 33 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 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, 28, 29, 30, 31, 32, or 33 of SEQ ID NO: 18. IPTS / 128757636.1 80Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Variants of SEQ ID NO: 19 (Formula XIX)

[0126] In some embodiments, the signal peptide comprises an amino acid sequence represented by: S1-S2-S3-S4-S5-S6-S7-S8-S9-S10-S11-S12-S13-S14-S15-S16-S17-S18-S19-S20-S21-S22-S23-S24-S25-S26- S27-S28-S29-S30-S31-S32-S33-S34-S35(Formula XIX); wherein the identity of each of S1– S35are as provided for in Table 20 below. Table 20 Position Suitable Amino Acids S MIPTS / 128757636.1 81Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids S22 L, G, W

[0127] In some embodiments, S1is methionine (M). In some embodiments, S2is an amino acid selected from the group consisting of A, L, and R. In some embodiments, S3is an amino acid selected from the group consisting of A, L, and G. In some embodiments, S4is an amino acid selected from the group consisting of P, R, and S. In some embodiments, S5is an amino acid selected from the group consisting of K, S, and V. In some embodiments, S6is an amino acid selected from the group consisting of G, K, and E. In some embodiments, S7is an amino acid selected from the group consisting of S, P, and C. In some embodiments, S8is an amino acid selected from the group consisting of L, A, and T. In some embodiments, S9is an amino acid selected from the group consisting of W and L. In some embodiments, S10 is an amino acid selected from the group consisting of V, P, and G. In some embodiments, S11is an amino acid selected from the group consisting of R, P, and W. In some embodiments, S12is an amino acid selected from the group consisting of T, P, and G. In some embodiments, S13is an amino acid selected from the group consisting of Q, L, and H. In some embodiments, S14is an amino acid selected from the group consisting of L, M, and C. In some embodiments, S15is an amino acid selected from the group consisting of G, L, and A. In some embodiments, S16is an amino acid IPTS / 128757636.1 82Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT selected from the group consisting of L and P. In some embodiments, S17is an amino acid selected from the group consisting of P, L, and S. In some embodiments, S18is an amino acid selected from the group consisting of P and L. In some embodiments, S19is an amino acid selected from the group consisting of L and G. In some embodiments, S20is an amino acid selected from the group consisting of L and P. In some embodiments, S21is leucine (L). In some embodiments, S22is an amino acid selected from the group consisting of L, G, and W. In some embodiments, S23is an amino acid selected from the group consisting of T and P. In some embodiments, S24is an amino acid selected from the group consisting of L and M. In some embodiments, S25is an amino acid selected from the group consisting of A, S, and L. In some embodiments, S26is an amino acid selected from the group consisting of L and P. In some embodiments, S27is an amino acid selected from the group consisting of A, G, and F. In some embodiments, S28is an amino acid selected from the group consisting of A and G. In some embodiments, S29is an amino acid selected from the group consisting of G, L, and A. In some embodiments, S30is an amino acid selected from the group consisting of P and S. In some embodiments, S31is an amino acid selected from the group consisting of G, R, and F. In some embodiments, S32is an amino acid selected from the group consisting of T, P, and G. In some embodiments, S33is an amino acid selected from the group consisting of A and L. In some embodiments, S34is an amino acid selected from the group consisting of S, Q, and L. In some embodiments, S35is an amino acid selected from the group consisting of A and G.

[0128] 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. Accordingly, in some embodiments, 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. In some embodiments, 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 IPTS / 128757636.1 83Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 12 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 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. In some embodiments, 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 comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 22 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 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. In some embodiments, 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 IPTS / 128757636.1 84Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 19 and a substitution at position 32 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 33 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 34 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 35 of SEQ ID NO: 19. The variant may also comprise any number of substitutions as provided by Formula XIX. Accordingly, in some embodiments, 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, 12, 13, 14, 15, 16, 17, 18, 19, 20, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35 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 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, 31, 32, 33, 34, or 35 of SEQ ID NO: 19. Variants of SEQ ID NO: 20 (Formula XX)

[0129] In some embodiments, the signal peptide comprises an amino acid sequence represented by: T1-T2-T3-T4-T5-T6-T7-T8-T9-T10-T11-T12-T13-T14-T15-T16-T17-T18-T19-T20-T21-T22-T23-T24-T25-T26- T27-T28-T29-T30-T31-T32-T33-T34-T35-T36(Formula XX); wherein the identity of each of T1– T36are as provided for in Table 21 below. Table 21 Position Suitable Amino AcidsIPTS / 128757636.1 85Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids T4 R, LIPTS / 128757636.1 86Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids T33 A, Gembodiments, T2is an amino acid selected from the group consisting of G and R. In some embodiments, T3is an amino acid selected from the group consisting of P and L. In some embodiments, T4is an amino acid selected from the group consisting of R and L. In some embodiments, T5is an amino acid selected from the group consisting of G and P. In some embodiments, T6is an amino acid selected from the group consisting of A and L. In some embodiments, T7is alanine (A). In some embodiments, T8is an amino acid selected from the group consisting of S and P. In some embodiments, T9is an amino acid selected from the group consisting of L and G. In some embodiments, T10is an amino acid selected from the group consisting of P and R. In some embodiments, T11is an amino acid selected from the group consisting of R and L. In some embodiments, T12is an amino acid selected from the group consisting of G and R. In some embodiments, T13is an amino acid selected from the group consisting of P and R. In some embodiments, T14is glycine (G). In some embodiments, T15is an amino acid selected from the group consisting of P and S. In some embodiments, T16is an amino acid selected from the group consisting of R and P. In some embodiments, T17is arginine (R). In some embodiments, T18is an amino acid selected from the group consisting of L and H. In some embodiments, T19is leucine (L). In some embodiments, T20is an amino acid selected from the group consisting of L and P. In some embodiments, T21is an amino acid selected from the group consisting of P and S. In some embodiments, T22is an amino acid selected from the group consisting of V and C. In some embodiments, T23is an amino acid selected from the group consisting of V and S. In some embodiments, T24is an amino acid selected from the group consisting of L and P. In some embodiments, T25is an amino acid selected from the group consisting of P and A. In some embodiments, T26is leucine (L). In some embodiments, T27is leucine (L). In some embodiments, T28is leucine (L). In some embodiments, T29is leucine (L). In some embodiments, T30is an amino acid selected from the group consisting of L and V. In some embodiments, T31is leucine (L). In some embodiments, T32is an amino acid selected from IPTS / 128757636.1 87Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT the group consisting of L and G. In some embodiments, T33is an amino acid selected from the group consisting of A and G. In some embodiments, T34is an amino acid selected from the group consisting of P and C. In some embodiments, T35is an amino acid selected from the group consisting of P and L. In some embodiments, T36is glycine (G).

[0131] It is to be understood that a variant of SEQ ID NO: 20 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 XX. Accordingly, in some embodiments, 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. In some embodiments, 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 10 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 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 15 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 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 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 20 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 21 of IPTS / 128757636.1 88Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, 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 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 20 and a substitution at position 34 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 35 of SEQ ID NO: 20. The variant may also comprise any number of substitutions as provided by Formula XX. Accordingly, in some embodiments, 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, 8, 9, 10, 11, 12, 13, 15, 16, 18, 20, 21, 22, 23, 24, 25, 30, 32, 33, 34, or 35 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 more than one position corresponding to position 2, 3, 4, 5, 6, 8, 9, 10, 11, 12, 13, 15, 16, 18, 20, 21, 22, 23, 24, 25, 30, 32, 33, 34, or 35 of SEQ ID NO: 20. Variants of SEQ ID NO: 21 (Formula XXI)

[0132] In some embodiments, the signal peptide comprises an amino acid sequence represented by: U1-U2-U3-U4-U5-U6-U7-U8-U9-U10-U11-U12-U13-U14-U15-U16-U17-U18-U19-U20-U21-U22-U23-U24- U25-U26-U27-U28-U29-U30-U31-U32-U33-U34-U35-U36-U37(Formula XXI); wherein the identity of each of U1– U37are as provided for in Table 22 below. Table 22 Position Suitable Amino AcidsIPTS / 128757636.1 89Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids U2 E, PIPTS / 128757636.1 90Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids U31 L, C, . embodiments, U2is an amino acid selected from the group consisting of E and P. In some embodiments, U3is an amino acid selected from the group consisting of F and G. In some embodiments, U4is an amino acid selected from the group consisting of S and R. In some embodiments, U5is an amino acid selected from the group consisting of S and A. In some embodiments, U6is proline (P). In some embodiments, U7is an amino acid selected from the group consisting of S and L. In some embodiments, U8is arginine (R). In some embodiments, U9is an amino acid selected from the group consisting of E and T. In some embodiments, U10is an amino acid selected from the group consisting of E and V. In some embodiments, U11is an amino acid selected from the group consisting of C and P. In some embodiments, U12is an amino acid selected from the group consisting of P and G. In some embodiments, U13is an amino acid selected from the group consisting of K and A. In some embodiments, U14is an amino acid selected from the group consisting of P and L. In some embodiments, U15is an amino acid selected from the group consisting of S and G. In some embodiments, U16is an amino acid selected from the group consisting of G and A. In some embodiments, U17is an amino acid selected from the group consisting of R and W. In some embodiments, U18is an amino acid selected from the group consisting of V and L. In some embodiments, U19is an amino acid selected from the group consisting of S and L. In some embodiments, U20is an amino acid selected from the group consisting of I and G. In some embodiments, U21is an amino acid selected from the group consisting of M and G. In some embodiments, U22is an amino acid selected from the group consisting of A and L. In some embodiments, U23is an amino acid selected from the group consisting of G and W. In some embodiments, U24is an amino acid selected from the group consisting of S and A. In some IPTS / 128757636.1 91Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT embodiments, U25is an amino acid selected from the group consisting of L and W. In some embodiments, U26is threonine (T). In some embodiments, U27is an amino acid selected from the group consisting of G and L. In some embodiments, U28is an amino acid selected from the group consisting of L and C. In some embodiments, U29is an amino acid selected from the group consisting of L and G. In some embodiments, U30is leucine (L). In some embodiments, U31is an amino acid selected from the group consisting of L and C. In some embodiments, U32is an amino acid selected from the group consisting of Q and S. In some embodiments, U33is an amino acid selected from the group consisting of A and L. In some embodiments, U34is an amino acid selected from the group consisting of V and G. In some embodiments, U35is an amino acid selected from the group consisting of S and A. In some embodiments, U36is an amino acid selected from the group consisting of W and V. In some embodiments, U37is an amino acid selected from the group consisting of A and G.

[0134] It is to be understood that 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. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 2 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 3 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 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 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 IPTS / 128757636.1 92Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 17 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 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 20 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 24 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 25 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 21 and a substitution at position 35 of SEQ ID NO: 21. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID IPTS / 128757636.1 93Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT NO: 21 and a substitution at position 36 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 37 of SEQ ID NO: 21. The variant may also comprise any number of substitutions as provided by Formula XXI. Accordingly, in some embodiments, 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, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 31, 32, 33, 34, 35, 36, or 37 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 more than one position corresponding to position 2, 3, 4, 5, 7, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 31, 32, 33, 34, 35, 36, or 37 of SEQ ID NO: 21. Variants of SEQ ID NO: 22 (Formula XXII)

[0135] In some embodiments, the signal peptide comprises an amino acid sequence represented by: V1-V2-V3-V4-V5-V6-V7-V8-V9-V10-V11-V12-V13-V14-V15-V16-V17-V18-V19-V20-V21-V22-V23-V24- V25-V26-V27-V28-V29-V30-V31-V32-V33-V34-V35-V36-V37-V38(Formula XXII); wherein the identity of each of V1– V38are as provided for in Table 23 below. Table 23 Position Suitable Amino AcidsIPTS / 128757636.1 94Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids V12 R, V, LIPTS / 128757636.1 95Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0136] In some embodiments, V1is methionine (M). In some embodiments, V2is an amino acid selected from the group consisting of G, S, and T. In some embodiments, V3is an amino acid selected from the group consisting of R and P. In some embodiments, V4is an amino acid selected from the group consisting of P and G. In some embodiments, V5is an amino acid selected from the group consisting of P, Q, and G. In some embodiments, V6is an amino acid selected from the group consisting of G, L, and P. In some embodiments, V7is an amino acid selected from the group consisting of A, R, and G. In some embodiments, V8is an amino acid selected from the group consisting of G and R. In some embodiments, V9is an amino acid selected from the group consisting of V, W, and R. In some embodiments, V10is an amino acid selected from the group consisting of S, R, and P. In some embodiments, V11is an amino acid selected from the group consisting of C, L, and G. In some embodiments, V12is an amino acid selected from the group consisting of R, V, and L. In some embodiments, V13is an amino acid selected from the group consisting of G, S, and P. In some embodiments, V14is an amino acid selected from the group consisting of G, S, and Q. In some embodiments, V15is an amino acid selected from the group consisting of P and C. In some embodiments, V16is an amino acid selected from the group consisting of P and G. In some embodiments, V17is an amino acid selected from the group consisting of F, S, and P. In some embodiments, V18is an amino acid selected from the group consisting of S, G, and L. In some embodiments, V19is an amino acid selected from the group consisting of R, V, and L. In some embodiments, V20is an amino acid selected from the group consisting of L and P. In some embodiments, V21is an amino acid selected from the group consisting of L and G. In some embodiments, V22is an amino acid selected from the group consisting of L and A. In some embodiments, V23is an amino acid selected from the group consisting of W, A, and L. In some embodiments, V24is an amino acid selected from the group consisting of L and C. In some embodiments, V25is an amino acid selected from the group consisting of L and F. In some embodiments, V26is an amino acid selected from the group consisting of L, A, and P. In some embodiments, V27is leucine (L). In some embodiments, V28is an amino acid selected from the group consisting of L and A. In some embodiments, V29is an amino acid selected from the group consisting of L and A. In some embodiments, V30is an amino acid selected from the group consisting of S, L, and V. In some embodiments, V31is an amino acid selected from the group consisting of P, L, and T. In some embodiments, V32is an amino acid selected from the group consisting of A and Q. In some embodiments, V33is an amino acid IPTS / 128757636.1 96Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT selected from the group consisting of A, L, and E. In some embodiments, V34is an amino acid selected from the group consisting of P and R. In some embodiments, V35is an amino acid selected from the group consisting of G, L, and P. In some embodiments, V36is an amino acid selected from the group consisting of S, A, and K. In some embodiments, V37is an amino acid selected from the group consisting of R, A, and P. In some embodiments, V38is an amino acid selected from the group consisting of G and A.

[0137] It is to be understood that a variant of SEQ ID NO: 22 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 XXII. Accordingly, in some embodiments, 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. In some embodiments, 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. In some embodiments, 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 embodiments, 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 IPTS / 128757636.1 97Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, 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. In some embodiments, 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 25 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 26 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 28 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 22 and a substitution at position 36 of SEQ ID NO: 22. In some embodiments, the signal peptide comprises the amino acid sequence of IPTS / 128757636.1 98Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT SEQ ID NO: 22 and a substitution at position 37 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 38 of SEQ ID NO: 22. The variant may also comprise any number of substitutions as provided by Formula XXII. Accordingly, in some embodiments, 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, 23, 24, 25, 26, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38 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 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, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, or 38 of SEQ ID NO: 22. Variants of SEQ ID NO: 23 (Formula XXIII)

[0138] In some embodiments, 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-W21- W22-W23-W24-W25-W26-W27-W28-W29-W30-W31-W32-W33-W34-W35-W36-W37-W38-W39-W40-W41- W42(Formula XXIII); wherein the identity of each of W1– W42are as provided for in Table 24 below. Table 24 Position Suitable Amino AcidsIPTS / 128757636.1 99Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids W11 Q, PIPTS / 128757636.1 100Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids W40 G, Aembodiments, W2is an amino acid selected from the group consisting of A and E. In some embodiments, W3 is an amino acid selected from the group consisting of E and L. In some embodiments, W4is an amino acid selected from the group consisting of W and C. In some embodiments, W5is an amino acid selected from the group consisting of L and G. In some embodiments, W6is leucine (L). In some embodiments, W7is an amino acid selected from the group consisting of S and G. In some embodiments, W8is an amino acid selected from the group consisting of A and L. In some embodiments, W9is an amino acid selected from the group consisting of S and P. In some embodiments, W10is an amino acid selected from the group consisting of W and R. In some embodiments, W11is an amino acid selected from the group consisting of Q and P. In some embodiments, W12is an amino acid selected from the group consisting of R and P. In some embodiments, W13is an amino acid selected from the group consisting of R and M. In some embodiments, W14 is an amino acid selected from the group consisting of A and L. In some embodiments, W15is an amino acid selected from the group consisting of K and L. In some embodiments, W16is alanine (A). In some embodiments, W17is an amino acid selected from the group consisting of M and L. In some embodiments, W18is an amino acid selected from the group consisting of T and L. In some embodiments, W19is an amino acid selected from the group consisting of A and L. In some embodiments, W20is alanine (A). In some embodiments, W21is an amino acid selected from the group consisting of A and T. In some embodiments, W22is an amino acid selected from the group consisting of G and L. In some embodiments, W23is an amino acid selected from the group consisting of S and L. In some embodiments, W24is alanine (A). In some embodiments, W25is an amino acid selected from the group consisting of G and A. In some embodiments, W26is an amino acid selected from the group consisting of R and M. In some embodiments, W27is an amino acid selected from the group consisting of A and L. In some embodiments, W28is alanine (A). In some embodiments, W29is an amino acid selected from the group consisting of V and L. In some embodiments, W30is an amino acid selected from the group consisting of P and L. In some IPTS / 128757636.1 101Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT embodiments, W31is an amino acid selected from the group consisting of L and T. In some embodiments, W32is an amino acid selected from the group consisting of L and Q. In some embodiments, W33is an amino acid selected from the group consisting of L and V. In some embodiments, W34is an amino acid selected from the group consisting of C and A. In some embodiments, W35is an amino acid selected from the group consisting of A and L. In some embodiments, W36is an amino acid selected from the group consisting of L and V. In some embodiments, W37is an amino acid selected from the group consisting of L and V. In some embodiments, W38is an amino acid selected from the group consisting of A and Q. In some embodiments, W39is an amino acid selected from the group consisting of P and V. In some embodiments, W40is an amino acid selected from the group consisting of G and A. In some embodiments, W41is an amino acid selected from the group consisting of G and E. In some embodiments, W42is alanine (A).

[0140] It is to be understood that a variant of 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. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a substitution at position 2 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 3 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 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 7 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 8 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 9 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 10 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 11 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 12 of SEQ ID NO: 23. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 and a IPTS / 128757636.1 102Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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 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 21 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 22 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 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 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. 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 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. In some embodiments, 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 23 IPTS / 128757636.1 103Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT and a substitution at position 37 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 38 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 39 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 40 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 41 of SEQ ID NO: 23. The variant may also comprise any number of substitutions as provided by Formula XXIII. Accordingly, in some embodiments, 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, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 21, 22, 23, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 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 more than one position corresponding to position 2, 3, 4, 5, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18, 19, 21, 22, 23, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, or 41 of SEQ ID NO: 23. Variants of SEQ ID NO: 24 (Formula XXIV)

[0141] In some embodiments, the signal peptide comprises an amino acid sequence represented by: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24- X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-X43-X44-X45-X46(Formula XXIV); wherein the identity of each of X1– X46are as provided for in Table 25 below. Table 25 Position Suitable Amino AcidsIPTS / 128757636.1 104Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids X7 T, SIPTS / 128757636.1 105Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Position Suitable Amino Acids X36 A, Vn some em o men s,1s me on ne . n some embodiments, X2is an amino acid selected from the group consisting of A and P. In some embodiments, X3is an amino acid selected from the group consisting of Q and R. In some embodiments, X4is an amino acid selected from the group consisting of E and Y. In some embodiments, X5is an amino acid selected from the group consisting of V and G. In some embodiments, X6is an amino acid selected from the group consisting of D and A. In some embodiments, X7is an amino acid selected from the group consisting of T and S. In some embodiments, X8 is an amino acid selected from the group consisting of A and L. In some embodiments, X9is an amino acid selected from the group consisting of Q and R. In some embodiments, X10is an amino acid selected from the group consisting of G and Q. In some embodiments, X11is an amino acid selected from the group consisting of A and S. In some embodiments, X12is an amino acid selected from the group consisting of E and C. In some embodiments, X13is an amino acid selected from the group consisting of M and P. In some embodiments, X14is arginine (R). In some embodiments, X15is an amino acid selected from the group consisting of R and S. In some embodiments, X16is glycine (G). In some embodiments, X17is an amino acid selected from the group consisting of A and R. In some embodiments, X18is an amino acid selected from the group consisting of G and E. In some embodiments, X19 is an amino acid selected from the group consisting of A and Q. In some embodiments, X20is an amino acid selected from the group consisting of A and G. In some IPTS / 128757636.1 106Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT embodiments, X21is an amino acid selected from the group consisting of R and Q. In some embodiments, X22is an amino acid selected from the group consisting of G and D. In some embodiments, X23is an amino acid selected from the group consisting of R and G. In some embodiments, X24is an amino acid selected from the group consisting of A and T. In some embodiments, X25is an amino acid selected from the group consisting of S and A. In some embodiments, X26is an amino acid selected from the group consisting of W and G. In some embodiments, X27is an amino acid selected from the group consisting of C and A. In some embodiments, X28is an amino acid selected from the group consisting of W and P. In some embodiments, X29is an amino acid selected from the group consisting of A and G. In some embodiments, X30is leucine (L). In some embodiments, X31is an amino acid selected from the group consisting of A and L. In some embodiments, X32is an amino acid selected from the group consisting of L and W. In some embodiments, X33is an amino acid selected from the group consisting of L and M. In some embodiments, X34is an amino acid selected from the group consisting of W and G. In some embodiments, X35is leucine (L). In some embodiments, X36is an amino acid selected from the group consisting of A and V. In some embodiments, X37is an amino acid selected from the group consisting of V and L. In some embodiments, X38is an amino acid selected from the group consisting of V and A. In some embodiments, X39is an amino acid selected from the group consisting of P and L. In some embodiments, X40is an amino acid selected from the group consisting of G and A. In some embodiments, X41is an amino acid selected from the group consisting of W and L. In some embodiments, X42is an amino acid selected from the group consisting of S and A. In some embodiments, X43is an amino acid selected from the group consisting of R and L. In some embodiments, X44is an amino acid selected from the group consisting of V and A. In some embodiments, X45is an amino acid selected from the group consisting of S and L. In some embodiments, X46is an amino acid selected from the group consisting of G and A.

[0143] It is to be understood that a variant of SEQ ID NO: 24 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 XXIV. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 2 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 3 of SEQ ID NO: 24. In some embodiments, the IPTS / 128757636.1 107Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, 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. 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 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. In some embodiments, 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. In some embodiments, 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 25 of SEQ ID NO: 24. In some embodiments, the signal peptide IPTS / 128757636.1 108Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, 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 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. In some embodiments, 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 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. In some embodiments, the signal peptide comprises the amino acid sequence of SEQ ID NO: 24 and a substitution at position 38 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 39 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 40 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 41 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 42 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 43 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 44 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 45 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 46 of SEQ ID NO: 24. The variant may also comprise any number of substitutions as provided by Formula XXIV. Accordingly, in some embodiments, the signal peptide comprises the amino acid sequence IPTS / 128757636.1 109Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46 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 more than one position corresponding to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 15, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 31, 32, 33, 34, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, or 46 of SEQ ID NO: 24.

[0144] In some embodiments, the signal peptide is a novel signal peptide. In the context of the present disclosure, 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. For example, in some embodiments, 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.

[0145] In some embodiments, a novel signal peptide is provided. In some embodiments, 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, or Formula XXIV. In some embodiments, 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. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula X. In some embodiments, the novel signal IPTS / 128757636.1 110Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XVIII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XIX. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XX. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXI. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXIII. In some embodiments, the novel signal peptide comprises an amino acid sequence of Formula XXIV.

[0146] In some embodiments, 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, or 25. 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: 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. 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: 6. In some embodiments, the novel signal peptide comprises an amino acid IPTS / 128757636.1 111Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 7. 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: 8. 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: 9. 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: 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. 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: 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. 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: 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. 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: 25. IPTS / 128757636.1 112Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Recombinant Polypeptides

[0147] In some embodiments, a recombinant polypeptide is provided, the recombinant polypeptide comprising a formula of X1-Z1, wherein X1is a signal peptide as provided for herein and Z1is a payload protein. In some embodiments, the recombinant polypeptide comprises a formula of X1-Z1, wherein X1is a novel signal peptide as provided for herein and Z1is a payload protein.

[0148] In some embodiments, X1comprises 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, or Formula XXIV. In some embodiments, X1comprises an amino acid sequence of Formula I. In some embodiments, X1comprises an amino acid sequence of Formula II. In some embodiments, X1comprises an amino acid sequence of Formula III. In some embodiments, X1comprises an amino acid sequence of Formula IV. In some embodiments, X1comprises an amino acid sequence of Formula V. In some embodiments, X1comprises an amino acid sequence of Formula VI. In some embodiments, X1comprises an amino acid sequence of Formula VII. In some embodiments, X1comprises an amino acid sequence of Formula VIII. In some embodiments, X1comprises an amino acid sequence of Formula IX. In some embodiments, X1comprises an amino acid sequence of Formula X. In some embodiments, X1comprises an amino acid sequence of Formula XI. In some embodiments, X1comprises an amino acid sequence of Formula XII. In some embodiments, X1comprises an amino acid sequence of Formula XIII. In some embodiments, X1comprises an amino acid sequence of Formula XIV. In some embodiments, X1comprises an amino acid sequence of Formula XV. In some embodiments, X1comprises an amino acid sequence of Formula XVI. In some embodiments, X1comprises an amino acid sequence of Formula XVII. In some embodiments, X1comprises an amino acid sequence of Formula XVIII. In some embodiments, X1comprises an amino acid sequence of Formula XIX. In some embodiments, X1comprises an amino acid sequence of Formula XX. In some embodiments, X1comprises an amino acid sequence of Formula XXI. In some embodiments, X1comprises an amino acid sequence of Formula XXII. In some IPTS / 128757636.1 113Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT embodiments, X1comprises an amino acid sequence of Formula XXIII. In some embodiments, X1comprises an amino acid sequence of Formula XXIV.

[0149] In some embodiments, X1comprises 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, or 25. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 1. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 2. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 3. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 4. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 5. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 6. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 7. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 8. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 9. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 10. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 11. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 12. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 13. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 14. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 15. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 16. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid IPTS / 128757636.1 114Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT sequence of SEQ ID NO: 17. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 18. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 19. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 20. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 21. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 22. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 23. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 24. In some embodiments, X1comprises an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 25.

[0150] In some embodiments, the payload protein, Z1, may be any peptide or protein. In some embodiments, the payload protein, Z1, is any peptide or protein that is useful in the treatment of a disease or disorder. In some embodiments, the payload protein, Z1, is any peptide or protein that is useful in the treatment of a disease or disorder associated with the lysosome of a cell.

[0151] In some embodiments, X1is linked directly to Z1. In some embodiments, X1is linked indirectly to Z1through, 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. Accordingly, in some embodiments, the recombinant polypeptide may be represented by the formula X1-(Y1)a-Z1, wherein X1is a signal peptide as provided for herein, Y1is a linker, such as but not limited to a polypeptide linker, Z1is a payload protein as provided for herein, and a is an integer selected from 0 or 1. In some embodiments, X1is a novel signal peptide as provided for herein. Nucleic Acid Molecules

[0152] In some embodiments, a nucleic acid molecule is provided. 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 novel signal peptide as provided for herein. In some embodiments, the nucleic acid molecule is a deoxyribonucleotide sequence (DNA). In some embodiments, the nucleic acid molecule is a ribonucleic acid sequence (RNA). IPTS / 128757636.1 115Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0153] In some embodiments, 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, Formula XV, Formula XVI, Formula XVII, Formula XVIII, Formula XIX, Formula XX, Formula XXI, Formula XXII, Formula XXIII, or 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 I. 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 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. 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 VI. 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 VII. 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 VIII. 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 IX. 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 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. 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 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 IPTS / 128757636.1 116Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. 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 XVIII. 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 XIX. 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 XX. 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 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. 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 XXIV.

[0154] 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% (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, or 25. 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: 1. 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: 2. 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: 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 IPTS / 128757636.1 117Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT novel signal peptide) comprising an amino acid sequence having at least 70% identity to an amino acid sequence of SEQ ID NO: 5. 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: 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. 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: 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. 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: 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. 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: 15. 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: 16. 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: 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 IPTS / 128757636.1 118Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 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. 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: 20. 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: 21. 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: 22. 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: 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.

[0155] In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein. In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide comprising a formula of X1-Z1, wherein X1is a signal peptide as provided for herein and Z1is a payload protein as provided for herein. In some embodiments, the recombinant polypeptide comprises a formula of X1-Z1, wherein X1is a novel signal peptide as provided for herein and Z1is a payload protein as provided for herein. In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide comprising a formula of X1-(Y1)a-Z1, wherein X1is a signal peptide (e.g., a novel signal peptide) as provided for herein, Y1is a linker, such as but not limited to a polypeptide linker, Z1is a payload protein as provided for herein, and a is an integer selected from 0 or 1.

[0156] 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. Further, the skilled artisan will readily recognize that, due to the degenerate nature of codons, multiple nucleic acid molecules are available to encode for the same amino acid sequence. Thus, any nucleic acid sequence capable IPTS / 128757636.1 119Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT of encoding for the amino acid sequences provided for herein are within the scope of the present disclosure.

[0157] In some embodiments, 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. By definition, wild type untranslated regions (UTRs) of a gene are transcribed but not translated. In mRNA, 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 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. In some embodiments, 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. For example, 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. For example, 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. 5’ UTR may comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and / or different genes.

[0158] In some embodiments, the nucleic acid molecules disclosed herein may be assembled inside a cell. In some embodiments, the nucleic acid molecules may be synthesized in vivo. In some embodiments, 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. In some embodiments, the nucleic acid molecules disclosed herein may be incorporated into a suitable viral IPTS / 128757636.1 120Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT vector, expression cassette, expression vector, transposon, extrachromosomal element, integrated into the chromosome, host cell, delivery systems.

[0159] In some embodiments, the nucleic acid molecule is a chemically modified nucleic acid molecule. In some embodiments, the nucleic acid molecule e may comprise one or more modified nucleosides comprising a modified sugar moiety. Such compounds comprising one or more sugar- modified nucleosides may have desirable properties, such as enhanced nuclease stability relative to an oligonucleotide comprising only nucleosides comprising naturally occurring sugar moieties. In some embodiments, modified sugar moieties are substituted sugar moieties. In some embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of substituted sugar moieties. In some embodiments, 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.

[0160] In some embodiments, 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. Examples of sugar substituents suitable for the 2’-position, include, but are not limited to: 2’-F, 2-OCH3(“OMe” or “O-methyl”), and 2’-O(CH2)2OCH3(“MOE”). In certain aspects, sugar substituents at the 2’ position is selected from allyl, amino, azido, thio, O-allyl, O— C1-C10 alkyl, O—C1-C10 substituted alkyl; OCF3, O(CH2)2SCH3, O(CH2)2—O—N(Rm)(Rn), and O—CH2— C(=O)—N(Rm)(Rn), where each Rm and Rn is, independently, H or substituted or unsubstituted C1-C10 alkyl. Examples of sugar substituents at the 5’-position, include, but are not limited to: 5’- methyl (R or S); 5’-vinyl, and 5’-methoxy. In some embodiments, substituted sugars comprise more than one non-bridging sugar substituent, for example, T-F-5’-methyl sugar moieties.

[0161] Nucleosides comprising 2’-substituted sugar moieties are referred to as 2’-substituted nucleosides. In some embodiments, a 2’-substituted nucleoside comprises a 2’-substituent group selected from halo, allyl, amino, azido, SH, CN, OCN, CF3, OCF3, O, S, or N(Rm)-alkyl; O, S, or N(Rm)-alkenyl; O, S or N(Rm)-alkynyl; O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O- aralkyl, O(CH2)2SCH3, O(CH2)2—O—N(Rm)(Rn) or O—CH2—C(=O)—N(Rm)(Rn), where each Rm and Rn is, independently, H, an amino protecting group or substituted or unsubstituted IPTS / 128757636.1 121Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT CI-C10 alkyl. These 2’-substituent groups can be further substituted with one or more substituent groups independently selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO2), thiol, thioalkoxy (S-alkyl), halogen, alkyl, aryl, alkenyl and alkynyl.

[0162] In some embodiments, a 2’-substituted nucleoside comprises a 2’-substituent group selected from F, NH2, N3OCF3, O—CH3, O(CH2)3NH2, CH2—CH=CH2, O—CH2—CH=CH2, OCH2CH2OCH3, O(CH2)2SCH3, O—(CH2)2—O—N(Rm)(Rn), O(CH2)2O(CH2)2N(CH3)2, and N- substituted acetamide (O—CH2—C(=O)—N(Rm)(Rn) where each Rm and R. is, independently, H, an amino protecting group or substituted or unsubstituted C1-C10 alkyl. In some embodiments, a 2’- substituted nucleoside comprises a sugar moiety comprising a 2’-substituent group selected from F, OCF3, O—CH3, O2CH2OCH3, O(CH2)2SCH3, O(CH2)2—O—N(CH3)2, — O(CH2)2O(CH2)2N(CH3)2, and O—CH2—C(=O)—N(H)CH3. In some embodiments, a 2’- substituted nucleoside comprises a sugar moiety comprising a 2’-substituent group selected from F, O—CH3, and OCH2CH2OCH3.

[0163] Certain modified sugar moieties comprise a bridging sugar substituent that forms a second ring resulting in a bicyclic sugar moiety. In some such aspects, the bicyclic sugar moiety comprises a bridge between the 4’ and the 2’ furanose ring atoms. Examples of such 4’ to 2’ 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’-CH2-2’, 4’-(CH2)2-2’, 4’-(CH2)—0-2’ (LNA); 4’-(CH2)— S-2’; 4’-(CH2)2—0-2’ (ENA); 4’-CH(CH3)—0-2’ (cEt) and 4’- CH(CH2OCH3)—0-2’, and analogs thereof (see, e.g., U.S. Pat. No.7,399,845); 4’-C(CH3)(CH3)— 0-2’ and analogs thereof, (see, e.g., WO 2009 / 006478); 4’-CH2—N(OCH3)-2’ and analogs thereof (see, e.g., WO2008 / 150729); 4’- CH2—O—N(CH3)-2’ (see, e.g., US2004 / 0171570, published Sep.2, 2004); 4’-CH2—O—N(R)-2’, and 4-CH2—N(R)—0-2’-, wherein each R is, independently, H, a protecting group, or C1-C12 alkyl; 4-CH2—N(R)—0-2’, wherein R is H, C1-C12 alkyl, or a protecting group (see, U.S. Pat. No. 7,427,672); 4’-CH2—C(H)(CH3)-2’ (see, e.g., Chattopadhyaya et al., J. Org. Chern., 2009, 74, 118-134); and 4-CH2—C(=CH2)-2’ and analogs thereof (see, PCT International Application WO 2008 / 154401).

[0164] In some embodiments, such 4’ to 2’ bridges independently comprise from 1 to 4 linked groups independently selected from —[C(Ra)(Rb)]n—, —C(Ra)=C(Rb)—, —C(Ra)=N—, — C(=NRa)— , —C(=O)—, —C(=S)—, —O—, —Si(Ra)2—S(=O)x—, and —N(Ra)—; wherein: x is 0, 1, or 2; n is 1,2, 3, or 4; each Ra and Rb is, independently, H, a protecting group, hydroxyl, IPTS / 128757636.1 122Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C5-C7 alicyclic radical, substituted C5-C7 alicyclic radical, halogen, OJ1, NJ1J2, SJ1, N3, C00J1, acyl (C(=O)—H), substituted acyl, CN, sulfonyl (S(=0)2-J1), or sulfoxyl (S(=0)-J1); and each J1 and J2 is, independently, H, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C5-C20 aryl, substituted C5-C20 aryl, acyl (C(=O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, 01-012 aminoalkyl, substituted C1- C12 aminoalkyl, or a protecting group.

[0165] Nucleosides comprising bicyclic sugar moieties are referred to as bicyclic nucleosides or BNAs. Bicyclic nucleosides include, but are not limited to, (A) α-L-Methyleneoxy (4-CH2—O- 2’) BNA, (B) β-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, (H) methylene¬amino (4’-CH2—N(R)-2’) BNA, (I) methyl carbocyclic (4’-CH2—CH(CH3)-2’) BNA, (J) propylene carbocyclic (4’-(CH2)3-2’) BNA, and (K) Methoxy(ethyleneoxy) (4’- CH(CH2OMe)-O-2’) BNA (also referred to as constrained MOE or cMOE). Additional bicyclic sugar moieties are known in the art, and any such bicyclic sugar moiety is within the scope of the present disclosure.

[0166] In some embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, a nucleoside comprising a 4’-2’ methylene-oxy bridge, may be in the .alpha.-L configuration or in the .beta.-D configuration. α-L-methyleneoxy (4-CH2—O-2’) bicyclic nucleosides have previously been incorporated into antisense polynucleotides that showed antisense activity.

[0167] In some embodiments, substituted sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent.

[0168] In some embodiments, modified sugar moieties are sugar surrogates. In some embodiments, the oxygen atom of the naturally occurring sugar is substituted, e.g., with a sulfur, carbon or nitrogen atom. In some such aspects, such modified sugar moiety also comprises bridging and / or non-bridging substituents as described above. For example, certain sugar IPTS / 128757636.1 123Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT surrogates comprise a 4’-sulfur atom and a substitution at the 2’-position and / or the 5’ position. By way of additional example, carbocyclic bicyclic nucleosides having a 4-2’ bridge have been described.

[0169] In some embodiments, sugar surrogates comprise rings having other than 5-atoms. For example, In some embodiments, 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).

[0170] Many other bicyclo and tricyclo sugar surrogate ring systems are also known in the art that can be used to modify nucleosides for incorporation into antisense compounds, and any such sugar surrogate ring system is within the scope of the present disclosure.

[0171] Combinations of modifications are also provided without limitation, such as, but not limited to, 2-F-5’- methyl substituted nucleosides and replacement of the ribosyl ring oxygen atom with S and further substitution at the 2’-position or alternatively 5’-substitution of a bicyclic nucleic acid. The synthesis and preparation of carbocyclic bicyclic nucleosides along with their oligomerization and biochemical studies have also been described.

[0172] In some embodiments, the present disclosure provides nucleic acid molecules comprising modified nucleosides. Those modified nucleotides may include modified sugars, modified nucleobases, and / or modified linkages. The specific modifications are selected such that the resulting polynucleotides possess desirable characteristics. In some embodiments, the nucleic acid molecules comprise one or more RNA-like nucleosides. In some embodiments, the nucleic acid molecules comprise one or more DNA- like nucleotides.

[0173] 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.

[0174] In some embodiments, 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- IPTS / 128757636.1 124Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT thiothymine and 2- thiocytosine, 5-halouracil and cytosine, 5-propynyl CH3, uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4- thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8- substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5- substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino- adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine, 3-deazaguanine and 3-deazaadenine, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases as defined herein. Further modified 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). 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.

[0175] In some embodiments, the present disclosure provides nucleic acid molecules comprising linked nucleosides. In some embodiments, 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 phosphorus containing internucleoside linkages include, but are not limited to, phosphodiesters (P=O), phosphotriesters, methylphosphonates, phosphoramidate, and phosphorothioates (P=S). Representative non- phosphorus containing internucleoside linking groups include, but are not limited to, methylenemethylimino (—CH2— N(CH3)—O—CH2—), thiodiester (—O—C(O)—S—). thionocarbamate (—O—C(O)(NH)—S—); siloxane (—O—Si(H)2—O—); and N,N’- dimethylhydrazine (—CH2—N(CH3)—N(CH3)—). Modified linkages, compared to natural phosphodiester linkages, can be used to alter, typically increase, nuclease resistance of the polynucleotide. In some embodiments, 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. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art. IPTS / 128757636.1 125Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0176] The 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.

[0177] Neutral internucleoside linkages include without limitation, phosphotriesters, methylphosphonates, MMI (3-CH2—N(CH3)—O-5’), amide-3 (3-CH2—C(=O)—N(H)-5’), amide- 4 (3’-CH2—N(H)—C(=O)-5’), formacetal (3’-O—CH2—O-5’), and thioformacetal (3’-5- CH2—O-5’). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides. Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH2 component parts.

[0178] Additional modifications may also be made at other positions on the nucleic acid molecule, particularly the 3’ position of the sugar on the 3’ terminal nucleotide and the 5’ position of 5’ terminal nucleotide. For example, one additional modification of the nucleic acid molecules of the present disclosure involves chemically linking to the polynucleotide one or more additional moieties or conjugates which enhance the activity, cellular distribution, or cellular uptake of the polynucleotide. 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.

[0179] In some embodiments, 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. In some embodiments, the nucleic acid molecule encodes for a novel signal peptide as provided for herein. In some embodiments, the nucleic acid molecule encodes for a recombinant polypeptide as provided for herein. IPTS / 128757636.1 126Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Cells

[0180] In some embodiments, a cell is provided. In some embodiments, 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. In some embodiments, the cell is present in vivo. Compositions

[0181] 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.

[0182] 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.

[0183] In some embodiments, 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.

[0184] 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. IPTS / 128757636.1 127Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Methods

[0185] Also contemplated herein are methods of using the novel signal peptides and recombinant polypeptides provided for herein.

[0186] In some embodiments, a method of treating a disease or disorder is provided. In some embodiments, 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. In some embodiments, the payload protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the disease or disorder. In some embodiments, the signal peptide directs the payload protein to be expressed at a particular cellular localization useful for the treatment of the disease or disorder. In some embodiments, 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. In some embodiments, the disease or disorder is any disease or disorder that would benefit from the targeting of a payload protein to a desired location via a novel signal peptide as provided for herein. 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, immunology, cell and immune cell engineering / reprogramming (including, but not limited to, ex vivo engineered macrophage therapy, in situ engineered macrophage therapy, ex vivo engineered NK cell therapy, in situ engineered NK cell therapy, ex vivo engineered NKT cell therapy, in situ engineered NKT cell therapy, ex vivo engineered T cell therapy, in situ engineered T cell therapy, ex vivo engineered islet cell therapy, in situ engineered islet cell therapy, ex vivo engineered B cell therapy, in situ engineered B cell therapy, ex vivo engineered HSPC cell therapy, in situ engineered HSPC cell therapy, ex vivo engineered stem and progenitor cell therapy, in situ engineered stem and progenitor cell therapy, cell surface functionalization with receptor targeting ligands, and the like), CAR-T cell engineering, cell targeting, cell signaling, cell surface antigen presentation, cell surface receptor presentation, cell membrane antigen presentation, cell membrane antigen integration, cell membrane receptor presentation, cell membrane receptor integration, inflammatory diseases or disorders, autoimmune disease or disorders, mitochondria associated diseases or disorders, genetic diseases or disorders, metabolic disorders, cell storage disorders, IPTS / 128757636.1 128Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT protein trafficking disorders, protein recycling disorders, immunotherapeutics, enzyme replacement therapeutics, protein replacement therapeutics, biologics manufacturing, diabetes, blood disorders (e.g., hemophilia), hormone replacement therapies, peptide-based drugs (e.g., GLP-1 for obesity), gene therapy, or the like. These examples are illustrative only and are not meant to be limiting in any way. The skilled artisan will recognize the applicability of the embodiments provided for herein to other diseases and disorders or other applications not recited. Such additional diseases or disorders or additional applications are within the scope of the present disclosure. In some embodiments, the disease or disorder is a lysosomal disease or disorder, such as, but not limited to, lysosomal storage diseases (including lipidoses, mucopolysaccharidoses, and sphingolipidoses) and neurodegenerative diseases.

[0187] In some embodiments, a method of treating a lysosomal disease or disorder is provided, the method 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 lysosomal disease or disorder. In some embodiments, the payload protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the lysosomal disease or disorder. In some embodiments, the signal peptide directs the payload protein to be expressed in the lysosome, thereby treating the lysosomal disease or disorder. In some embodiments, 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.

[0188] In some embodiments, a method of treating a disease or disorder is provided. In some embodiments, the method 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. In some embodiments, the payload protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the disease or disorder. In some embodiments, the signal peptide directs the payload protein to be expressed at a particular cellular localization useful for the treatment of the disease or disorder. In some embodiments, 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. In some embodiments, the disease or disorder is any disease or IPTS / 128757636.1 129Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT disorder that would benefit from the targeting of a payload protein to a desired location via a novel signal peptide as provided for herein. 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, immunology, cell and immune cell engineering / reprogramming (including, but not limited to, ex vivo engineered macrophage therapy, in situ engineered macrophage therapy, ex vivo engineered NK cell therapy, in situ engineered NK cell therapy, ex vivo engineered NKT cell therapy, in situ engineered NKT cell therapy, ex vivo engineered T cell therapy, in situ engineered T cell therapy, ex vivo engineered islet cell therapy, in situ engineered islet cell therapy, ex vivo engineered B cell therapy, in situ engineered B cell therapy, ex vivo engineered HSPC cell therapy, in situ engineered HSPC cell therapy, ex vivo engineered stem and progenitor cell therapy, in situ engineered stem and progenitor cell therapy, cell surface functionalization with receptor targeting ligands, and the like), CAR-T cell engineering, cell targeting, cell signaling, cell surface antigen presentation, cell surface receptor presentation, cell membrane antigen presentation, cell membrane antigen integration, cell membrane receptor presentation, cell membrane receptor integration, inflammatory diseases or disorders, autoimmune disease or disorders, mitochondria associated diseases or disorders, genetic diseases or disorders, metabolic disorders, cell storage disorders, protein trafficking disorders, protein recycling disorders, immunotherapeutics, enzyme replacement therapeutics, protein replacement therapeutics, biologics manufacturing, diabetes, blood disorders (e.g., hemophilia), hormone replacement therapies, peptide-based drugs (e.g., GLP-1 for obesity), gene therapy, or the like. These examples are illustrative only and are not meant to be limiting in any way. The skilled artisan will recognize the applicability of the embodiments provided for herein to other diseases and disorders or other applications not recited. Such additional diseases or disorders or additional applications are within the scope of the present disclosure. In some embodiments, the disease or disorder is a lysosomal disease or disorder, such as, but not limited to, lysosomal storage diseases (including lipidoses, mucopolysaccharidoses, and sphingolipidoses) and neurodegenerative diseases.

[0189] In some embodiments, a method of treating a lysosomal disease or disorder is provided, the method 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 lysosomal disease or disorder. In some embodiments, the payload IPTS / 128757636.1 130Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT protein of the recombinant polypeptide is a peptide or protein useful for the treatment of the lysosomal disease or disorder. In some embodiments, the signal peptide directs the payload protein to be expressed in the lysosomes, thereby treating the lysosomal disease or disorder. In some embodiments, 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.

[0190] In some embodiments, a method of producing a payload protein is provided, the method 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. In some embodiments, 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. In some embodiments, 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.

[0191] In some embodiments, a method of manufacturing a payload protein is provided, the method 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. In some embodiments, 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. In some embodiments, 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.

[0192] Without being bound to any particular theory, the novel signal peptides of the present disclosure are useful in the treatment of a lysosomal disease through inclusion of the signal peptide in a recombinant polypeptide comprising a payload protein used in the treatment of a lysosomal disease. Correct or, in some instances, enhanced targeting of the payload protein to the lysosome is beneficial in the treatment of the lysosomal disease. Furthermore, by utilizing the cells that are afflicted with the lysosomal disease to produce the payload protein, the present methods avoid the need of timely and inefficient recombinant protein infusions and instead allow the patient’s own cells to produce the therapeutic molecule. IPTS / 128757636.1 131Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT

[0193] 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. Without being bound to any particular theory, the novel signal peptides as provided for herein direct the payload protein to a particular cellular location, such as, but not limited to, the nucleus, the endoplasmic reticulum, the mitochondria, the cytoplasm, the cell membrane, cell junctions, cell projections, synapses, or lysosomes, or excreted into the extracellular space. Use of the novel signal peptides to direct a payload protein to a particular cellular location can enhance the expression and or production of the payload protein. EXAMPLES

[0194] The following examples illustrative of the compounds, compositions, particles, polypeptides, and methods described herein and should not be construed to be limiting in any way. Methods SP-mCherry plasmid (pDNA) construction

[0195] Plasmids were constructed in a similar manner as described in Cheng, Qiang et al. Proceedings of the National Academy of Sciences of the United States of America vol. 120,52 (2023) and International Patent Publication Serial No. WO2024064874A2, each of which is hereby incorporated by reference in their entirety. Briefly, SP-mCherry coding region were obtained directly by PCR with well-designed primers. The SPs of the following examples are as provided in Table 2 below: Table 2 Sequence Reference Sequence SEQ ID NO: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. IPTS / 128757636.1 132Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT In vitro SP screening by pDNA transfection

[0196] To perform SPs screening, pDNA transfection was executed in cells. pDNAs were encapsulated in Lipfectamine2000 and administered to HeLa cells at 100 ng / well in 6 well plates and allowed to incubate for 24 hours. Following incubation, LysoTracker Green DND-26 was used to stain lysosomes of live cells via manufacturer protocols. The cells were then imaged using confocal microscopy for LysoTracker Green DND-26 (lysosome) signal (FITC) with mCherry signal. Fiji software was utilized to assess co-localization of lysosome signal with mCherry signal and quantified. Example 1: Use of novel signal peptides to deliver mCherry to lysosomes.

[0197] The ability of the endogenous signal peptides provided for herein to deliver payload protein to the lysosomes was tested by constructing signal peptide modified mCherry pDNA plasmids containing an encoded lysosome targeting signal peptide directly upstream of the mCherry sequence. As a control, unmodified mCherry plasmids containing no signal peptide were also used. The general plasmid construction as well as the general method is as provided above and in FIG.1A.

[0198] As shown in FIG. 1B-1F, all five novel signal peptides tested were able to significantly drive mCherry protein to the lysosomes, whereas mCherry protein without the signal peptides did not localize to the endoplasmic reticulum. Results for each of Nov-EMI 21-1 (SEQ ID NO: 6), Nov-EMI 23-1 (SEQ ID NO: 8), Nov-EMI 27-1 (SEQ ID NO: 12), Nov-EMI 29-1 (SEQ ID NO: 25), and Nov-EMI 32-1 (SEQ ID NO: 17) exhibited a statistically significant increase in lysosome localized mCherry as compared to the NO SP control.

[0199] The data for this example demonstrates that lysosome targeting signal peptide sequences encoded directly upstream from the mCherry sequence drives localization of the mCherry protein to the lysosome. Example 2: Use of novel signal peptides to deliver an antibody to lysosomes.

[0200] 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 lysosomal signal peptides are also used. In lieu of mCherry assessment, proper antibody targeting is IPTS / 128757636.1 133Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT determined via staining for the payload antibody with an appropriate secondary antibody and assessment via confocal microscopy. Example 3: mRNA synthesis and mRNA-Nanoparticle formulation

[0201] mRNA are produced by in vitro transcription 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, linear pDNA with optimized 5’(3’)-untranslated regions (UTR) and poly A sequences were obtained first by enzyme digestion, then IVT reactions were prepared with standard protocols with N1-methylpseudouridine-5’-triphosphate modification. Finally, mRNA was capped (Cap-1) by Vaccinia Capping Enzyme and 2’-O-methyltransferase (NEB).

[0202] 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. Then the two solutions were rapidly mixed at an aqueous to ethanol ratio of 3:1 by volume (3:1, aq.:ethanol, vol:vol) to satisfy a final weight ratio of 40:1 (total lipids:mRNA). After incubation for 10 min at room temperature, the mRNA LNPs formulations were added immediately into cells or dialyzed against PBS for 2 h for in vivo experiments. Example 4: Signal peptide targeted mCherry is properly secreted from cells transfected with pDNA or treated with mRNA loaded LNPs.

[0203] The SPs of the present example are as provided in Table 3 below: Table 3 Sequence Reference Sequence SEQ ID NO:IPTS / 128757636.1 134Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT Sequence Reference Sequence SEQ ID NO: hFVII MVSQALRLLCLLLGLQGCLA SEQ ID NO: 29ide were generated and tested as detailed in Cheng, Qiang et al. Proceedings of the National Academy of Sciences of the United States of America vol. 120,52 (2023); and International Patent Publication Serial No. WO2024064874A2, each of which is hereby incorporated by reference in their entirety. Briefly, 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. Additionally, 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). The set of SPs was then expanded to include a negative control (scramble sequence), hAlb, hApoB, and hFVII, in addition to gLuc. HeLa cells were again transfected with the pDNA constructs using Lipofectamine2000. Images taken 72h post transfection via fluorescence microscopy and IVIS demonstrated that the SPs hApoB, gLuc, and hFVII all generated high levels of mCherry protein secretion, while the NC and hAlb constructs effectively mediated intracellular mCherry expression but did not promote significant extracellular secretion (FIG.2B). The same set of SPs were evaluate in the liver cancer cell line Huh7 wherein the observed trends of mCherry secretion in HeLa cells persisted (FIG.2C).

[0205] Based on the above, it was investigated whether mRNA containing an integrated SP sequence would yield similar observations to what was exhibited with pDNA. hFVII-mCherry mRNA from the FVII-mCherry-pCS2-MT plasmid was generated via in vitro transcription (IVT). A mDLNP lipid nanoparticle was tested for use as an initial carrier for the RNA. Transfection of multiple different cell lines with mDLNPs containing FVII-mCherry mRNA demonstrated that protein export into medium positively correlates with time post-transfection as well as dose, with greater fluorescence signal intensity being observed at longer time intervals and higher dosages across cell lines (FIGs 3A and 3B). The data for this example demonstrates that pDNA can be transcribed into mRNA via IVT, and that transfection of cells with pDNA via lipofectamine or transfection of cells with mRNA IPTS / 128757636.1 135Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT generated from the same pDNA via LNPs results in comparable experimental outcomes. Thus, the data in this example supports the conclusion that the constructs tested in Example 1 in pDNA format would be expected to result in similar outcomes in embodiments where the pDNA is first transcribed into mRNA via IVT. IPTS / 128757636.1 136

Claims

Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT CLAIMS What is claimed is:

1. A signal peptide comprising 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, XX, XXI, XXII, XXIII, and XXIV; wherein Formula I is represented as: A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16(Formula I) and the identities of A1-A16are as provided in Table 2; wherein Formula II is represented as: B1-B2-B3-B4-B5-B6-B7-B8-B9-B10-B11-B12-B13-B14-B15-B16-B17(Formula II) and the identities of B1-B17are as provided in Table 3; wherein Formula III is represented as: C1-C2-C3-C4-C5-C6-C7-C8-C9-C10-C11-C12-C13-C14-C15-C16-C17-C18(Formula III) and the identities of C1-C18are as provided in Table 4; wherein Formula IV is represented as: D1-D2-D3-D4-D5-D6-D7-D8-D9-D10-D11-D12-D13-D14-D15-D16-D17-D18-D19(Formula IV) and the identities of D1-D19are as provided in Table 5; wherein Formula V is represented as: E1-E2-E3-E4-E5-E6-E7-E8-E9-E10-E11-E12-E13-E14-E15-E16-E17-E18-E19-E20(Formula V) and the identities of E1-E20are as provided in Table 6; wherein Formula VI is represented as: F1-F2-F3-F4-F5-F6-F7-F8-F9-F10-F11-F12-F13-F14-F15-F16-F17-F18-F19-F20-F21(Formula VI) and the identities of F1-F21are as provided in Table 7; wherein Formula VII is represented as: G1-G2-G3-G4-G5-G6-G7-G8-G9-G10-G11-G12-G13-G14-G15-G16-G17-G18-G19-G20-G21-G22(Formula VII) and the identities of G1-G22are as provided in Table 8; wherein Formula VIII is represented as: H1-H2-H3-H4-H5-H6-H7-H8-H9-H10-H11-H12-H13-H14-H15-H16-H17-H18-H19-H20-H21-H22-H23(Formula VIII) IPTS / 128757636.1 137Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT and the identities of H1-H23are as provided in Table 9; wherein Formula IX is represented as: I1-I2-I3-I4-I5-I6-I7-I8-I9-I10-I11-I12-I13-I14-I15-I16-I17-I18-I19-I20-I21-I22-I23-I24(Formula IX) and the identities of I1-I24are as provided in Table 10; wherein Formula X is represented as: J1-J2-J3-J4-J5-J6-J7-J8-J9-J10-J11-J12-J13-J14-J15-J16-J17-J18-J19-J20-J21-J22-J23-J24-J25(Formula X) and the identities of J1-J25are as provided in Table 11; wherein Formula XI is represented as: K1-K2-K3-K4-K5-K6-K7-K8-K9-K10-K11-K12-K13-K14-K15-K16-K17-K18-K19-K20-K21-K22-K23-K24- K25-K26(Formula XI) and the identities of K1-K26are as provided in Table 12; wherein Formula XII is represented as: L1-L2-L3-L4-L5-L6-L7-L8-L9-L10-L11-L12-L13-L14-L15-L16-L17-L18-L19-L20-L21-L22-L23-L24-L25-L26- L27(Formula XII) and the identities of L1-L27are as provided in Table 13; wherein Formula XIII is represented as: M1-M2-M3-M4-M5-M6-M7-M8-M9-M10-M11-M12-M13-M14-M15-M16-M17-M18-M19-M20-M21-M22- M23-M24-M25-M26-M27-M28(Formula XIII) and the identities of M1-M28are as provided in Table 14; wherein Formula XIV is represented as: N1-N2-N3-N4-N5-N6-N7-N8-N9-N10-N11-N12-N13-N14-N15-N16-N17-N18-N19-N20-N21-N22-N23-N24- N25-N26-N27-N28-N29(Formula XIV) and the identities of N1-N29are as provided in Table 15; wherein Formula XV is represented as: O1-O2-O3-O4-O5-O6-O7-O8-O9-O10-O11-O12-O13-O14-O15-O16-O17-O18-O19-O20-O21-O22-O23-O24- O25-O26-O27-O28-O29-O30(Formula XV) and the identities of O1-O30are as provided in Table 16; wherein Formula XVI is represented as: P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-P15-P16-P17-P18-P19-P20-P21-P22-P23-P24-P25-P26- P27-P28-P29-P30-P31(Formula XVI) and the identities of P1-P31are as provided in Table 17; IPTS / 128757636.1 138Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT wherein Formula XVII is represented as: Q1-Q2-Q3-Q4-Q5-Q6-Q7-Q8-Q9-Q10-Q11-Q12-Q13-Q14-Q15-Q16-Q17-Q18-Q19-Q20-Q21-Q22-Q23-Q24- Q25-Q26-Q27-Q28-Q29-Q30-Q31-Q32(Formula XVII) and the identities of Q1-Q32are as provided in Table 18; wherein Formula XVIII is represented as: R1-R2-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22-R23-R24-R25- R26-R27-R28-R29-R30-R31-R32-R33(Formula XVIII) and the identities of R1-R33are as provided in Table 19; wherein Formula XIX is represented as: S1-S2-S3-S4-S5-S6-S7-S8-S9-S10-S11-S12-S13-S14-S15-S16-S17-S18-S19-S20-S21-S22-S23-S24-S25-S26- S27-S28-S29-S30-S31-S32-S33-S34-S35(Formula XIX) and the identities of S1-S35are as provided in Table 20; wherein Formula XX is represented as: T1-T2-T3-T4-T5-T6-T7-T8-T9-T10-T11-T12-T13-T14-T15-T16-T17-T18-T19-T20-T21-T22-T23-T24-T25-T26- T27-T28-T29-T30-T31-T32-T33-T34-T35-T36(Formula XX) and the identities of T1-T36are as provided in Table 21; wherein Formula XXI is represented as: U1-U2-U3-U4-U5-U6-U7-U8-U9-U10-U11-U12-U13-U14-U15-U16-U17-U18-U19-U20-U21-U22-U23-U24- U25-U26-U27-U28-U29-U30-U31-U32-U33-U34-U35-U36-U37(Formula XXI) and the identities of U1-U37are as provided in Table 22; wherein Formula XXII is represented as: V1-V2-V3-V4-V5-V6-V7-V8-V9-V10-V11-V12-V13-V14-V15-V16-V17-V18-V19-V20-V21-V22-V23-V24- V25-V26-V27-V28-V29-V30-V31-V32-V33-V34-V35-V36-V37-V38(Formula XXII) and the identities of V1-V38are as provided in Table 23; wherein Formula XXIII is represented as: W1-W2-W3-W4-W5-W6-W7-W8-W9-W10-W11-W12-W13-W14-W15-W16-W17-W18-W19-W20-W21- W22-W23-W24-W25-W26-W27-W28-W29-W30-W31-W32-W33-W34-W35-W36-W37-W38-W39-W40-W41- W42(Formula XXIII) and the identities of W1-W42are as provided in Table 24; and wherein Formula XXIV is represented as: IPTS / 128757636.1 139Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24- X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-X43-X44-X45-X46(Formula XXIV) and the identities of X1-X46are as provided in Table 25.

2. The signal peptide of claim 1, 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, or 25.

3. 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, or 25.

4. The signal peptide of any one of claims 1-3, wherein the signal peptide is a novel signal peptide.

5. A recombinant polypeptide comprising a formula of X1-(Y1)a-Z1, wherein: X1is a signal peptide, Y1is a peptide linker, and Z1is a payload protein, wherein a is an integer selected from 0 and 1.

6. The recombinant polypeptide of claim 5, wherein X1comprises 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, XX, XXI, XXII, XXIII, and XXIV; wherein Formula I is represented as: A1-A2-A3-A4-A5-A6-A7-A8-A9-A10-A11-A12-A13-A14-A15-A16(Formula I) and the identities of A1-A16are as provided in Table 2; wherein Formula II is represented as: IPTS / 128757636.1 140Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT B1-B2-B3-B4-B5-B6-B7-B8-B9-B10-B11-B12-B13-B14-B15-B16-B17(Formula II) and the identities of B1-B17are as provided in Table 3; wherein Formula III is represented as: C1-C2-C3-C4-C5-C6-C7-C8-C9-C10-C11-C12-C13-C14-C15-C16-C17-C18(Formula III) and the identities of C1-C18are as provided in Table 4; wherein Formula IV is represented as: D1-D2-D3-D4-D5-D6-D7-D8-D9-D10-D11-D12-D13-D14-D15-D16-D17-D18-D19(Formula IV) and the identities of D1-D19are as provided in Table 5; wherein Formula V is represented as: E1-E2-E3-E4-E5-E6-E7-E8-E9-E10-E11-E12-E13-E14-E15-E16-E17-E18-E19-E20(Formula V) and the identities of E1-E20are as provided in Table 6; wherein Formula VI is represented as: F1-F2-F3-F4-F5-F6-F7-F8-F9-F10-F11-F12-F13-F14-F15-F16-F17-F18-F19-F20-F21(Formula VI) and the identities of F1-F21are as provided in Table 7; wherein Formula VII is represented as: G1-G2-G3-G4-G5-G6-G7-G8-G9-G10-G11-G12-G13-G14-G15-G16-G17-G18-G19-G20-G21-G22(Formula VII) and the identities of G1-G22are as provided in Table 8; wherein Formula VIII is represented as: H1-H2-H3-H4-H5-H6-H7-H8-H9-H10-H11-H12-H13-H14-H15-H16-H17-H18-H19-H20-H21-H22-H23(Formula VIII) and the identities of H1-H23are as provided in Table 9; wherein Formula IX is represented as: I1-I2-I3-I4-I5-I6-I7-I8-I9-I10-I11-I12-I13-I14-I15-I16-I17-I18-I19-I20-I21-I22-I23-I24(Formula IX) and the identities of I1-I24are as provided in Table 10; wherein Formula X is represented as: J1-J2-J3-J4-J5-J6-J7-J8-J9-J10-J11-J12-J13-J14-J15-J16-J17-J18-J19-J20-J21-J22-J23-J24-J25(Formula X) and the identities of J1-J25are as provided in Table 11; wherein Formula XI is represented as: K1-K2-K3-K4-K5-K6-K7-K8-K9-K10-K11-K12-K13-K14-K15-K16-K17-K18-K19-K20-K21-K22-K23-K24- K25-K26(Formula XI) IPTS / 128757636.1 141Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT and the identities of K1-K26are as provided in Table 12; wherein Formula XII is represented as: L1-L2-L3-L4-L5-L6-L7-L8-L9-L10-L11-L12-L13-L14-L15-L16-L17-L18-L19-L20-L21-L22-L23-L24-L25-L26- L27(Formula XII) and the identities of L1-L27are as provided in Table 13; wherein Formula XIII is represented as: M1-M2-M3-M4-M5-M6-M7-M8-M9-M10-M11-M12-M13-M14-M15-M16-M17-M18-M19-M20-M21-M22- M23-M24-M25-M26-M27-M28(Formula XIII) and the identities of M1-M28are as provided in Table 14; wherein Formula XIV is represented as: N1-N2-N3-N4-N5-N6-N7-N8-N9-N10-N11-N12-N13-N14-N15-N16-N17-N18-N19-N20-N21-N22-N23-N24- N25-N26-N27-N28-N29(Formula XIV) and the identities of N1-N29are as provided in Table 15; wherein Formula XV is represented as: O1-O2-O3-O4-O5-O6-O7-O8-O9-O10-O11-O12-O13-O14-O15-O16-O17-O18-O19-O20-O21-O22-O23-O24- O25-O26-O27-O28-O29-O30(Formula XV) and the identities of O1-O30are as provided in Table 16; wherein Formula XVI is represented as: P1-P2-P3-P4-P5-P6-P7-P8-P9-P10-P11-P12-P13-P14-P15-P16-P17-P18-P19-P20-P21-P22-P23-P24-P25-P26- P27-P28-P29-P30-P31(Formula XVI) and the identities of P1-P31are as provided in Table 17; wherein Formula XVII is represented as: Q1-Q2-Q3-Q4-Q5-Q6-Q7-Q8-Q9-Q10-Q11-Q12-Q13-Q14-Q15-Q16-Q17-Q18-Q19-Q20-Q21-Q22-Q23-Q24- Q25-Q26-Q27-Q28-Q29-Q30-Q31-Q32(Formula XVII) and the identities of Q1-Q32are as provided in Table 18; wherein Formula XVIII is represented as: R1-R2-R3-R4-R5-R6-R7-R8-R9-R10-R11-R12-R13-R14-R15-R16-R17-R18-R19-R20-R21-R22-R23-R24-R25- R26-R27-R28-R29-R30-R31-R32-R33(Formula XVIII) and the identities of R1-R33are as provided in Table 19; wherein Formula XIX is represented as: IPTS / 128757636.1 142Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT S1-S2-S3-S4-S5-S6-S7-S8-S9-S10-S11-S12-S13-S14-S15-S16-S17-S18-S19-S20-S21-S22-S23-S24-S25-S26- S27-S28-S29-S30-S31-S32-S33-S34-S35(Formula XIX) and the identities of S1-S35are as provided in Table 20; wherein Formula XX is represented as: T1-T2-T3-T4-T5-T6-T7-T8-T9-T10-T11-T12-T13-T14-T15-T16-T17-T18-T19-T20-T21-T22-T23-T24-T25-T26- T27-T28-T29-T30-T31-T32-T33-T34-T35-T36(Formula XX) and the identities of T1-T36are as provided in Table 21; wherein Formula XXI is represented as: U1-U2-U3-U4-U5-U6-U7-U8-U9-U10-U11-U12-U13-U14-U15-U16-U17-U18-U19-U20-U21-U22-U23-U24- U25-U26-U27-U28-U29-U30-U31-U32-U33-U34-U35-U36-U37(Formula XXI) and the identities of U1-U37are as provided in Table 22; wherein Formula XXII is represented as: V1-V2-V3-V4-V5-V6-V7-V8-V9-V10-V11-V12-V13-V14-V15-V16-V17-V18-V19-V20-V21-V22-V23-V24- V25-V26-V27-V28-V29-V30-V31-V32-V33-V34-V35-V36-V37-V38(Formula XXII) and the identities of V1-V38are as provided in Table 23; wherein Formula XXIII is represented as: W1-W2-W3-W4-W5-W6-W7-W8-W9-W10-W11-W12-W13-W14-W15-W16-W17-W18-W19-W20-W21- W22-W23-W24-W25-W26-W27-W28-W29-W30-W31-W32-W33-W34-W35-W36-W37-W38-W39-W40-W41- W42(Formula XXIII) and the identities of W1-W42are as provided in Table 24; and wherein Formula XXIV is represented as: X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24- X25-X26-X27-X28-X29-X30-X31-X32-X33-X34-X35-X36-X37-X38-X39-X40-X41-X42-X43-X44-X45-X46(Formula XXIV) and the identities of X1-X46are as provided in Table 25.

7. The recombinant polypeptide of claim 5 or claim 6, wherein X1comprises 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, or 25. IPTS / 128757636.1 143Attorney Docket No. UTSD 4345 (106546-827226) (SIGY-013WO) PATENT 8. The recombinant polypeptide of any one of claims 5-7, wherein the payload protein is a therapeutic peptide or protein.

9. A nucleic acid molecule encoding for the signal peptide of any one of claims 1-4.

10. A nucleic acid molecule encoding for the recombinant polypeptide of any one of claims 5- 8.

11. A vector comprising the nucleic acid molecule of claim 9 or claim 10.

12. A cell comprising the nucleic acid molecule of claim 9 or claim 10 or the vector of claim 11.

13. A composition comprising the nucleic acid molecule of claim 9 or claim 10 or the vector of claim 11.

14. A method for treating a disease or disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of the nucleic acid molecule of claim 10 to the subject, thereby treating the disease or disorder.

15. The method of claim 14, wherein the disease or disorder is cancer.

16. A method for treating a cancer in a subject in need thereof, the method comprising administering to the subject a vector comprising a nucleic acid molecule encoding for a signal peptide fused or linked to a payload protein, wherein the signal peptide is the signal peptide of any one of claims 1-4 and wherein the payload protein is a therapeutic peptide or protein useful for the treatment of the cancer. IPTS / 128757636.1 144

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