Sortilin binding conjugate compounds, compositions thereof, and uses thereof for treating cancer

Abstract

The present disclosure relates to compositions comprising a solubilizing agent and a peptide compound and / or a conjugated compound, processes, methods, and uses thereof for treating cancer or aggressive cancer. For example, the conjugated compound can comprise the formula A-(B)n, wherein A is a peptide compound; and B is at least one therapeutic agent, and A is a peptide compound of formula (X): GVRAKAGVRN(Nle)FKSESY (X) (SEQ ID NO: 10), wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide compound at the N-terminus and / or C-terminus.

Description

[0001] Cross Reference to Related Applications

[0002] This application claims priority to U.S. Provisional Application No. 62 / 945,111, filed December 6, 2019. This document is hereby incorporated by reference in its entirety. TECHNICAL FIELD

[0003] The present disclosure relates to peptide compounds, peptide conjugates, peptide compositions, and methods and uses related thereto. BACKGROUND

[0004] According to a recent report by the World Health Organization, 8.2 million patients died from cancer in 2012 (1). Thus, cancer is a growing health problem in both developing and developed countries. It is estimated that the number of cancer cases per year will increase in the next two decades (1). The common general treatment methods for cancer are surgery, endocrine therapy, chemotherapy, and radiation therapy (2). However, recently, there is hope for the emergence of “targeted therapy” that targets specific molecular defects in cancer cells, which is expected to be a more effective and less toxic therapy than imprecise chemotherapeutic agents (3).

[0005] Currently, when anticancer drugs are administered through classic formulations, it is estimated that about 95% of the therapeutic agents are absorbed by cells within healthy tissues, while only about 2-5% of the therapeutic agents effectively reach tumors (4). Therefore, the challenge of any future successful personalized treatment method is to partially increase the selectivity of targeted therapy by actively transporting anticancer drugs into cancer cell compartments (5-6).

[0006] Sortilin can be considered as one of the cell’s own shuttling systems in view of its role in ligand internalization and cellular trafficking (11). Recent studies have shown that Sortilin has a dual role in both endocytosis and receptor trafficking, allowing the sorting of ligands from the cell surface to specific subcellular compartments and trafficking neurotrophic factor precursors such as neuropeptide neurotensin (NT), proNGF, and proBDNF (8, 11-16). Sortilin expression is elevated in several human cancers, including breast cancer, prostate cancer, colon cancer, pancreatic cancer, skin cancer, and pituitary cancer (17-20). Sortilin is reported to be overexpressed in ovarian cancer compared to healthy ovarian tissue (21, 22). SUMMARY

[0007] Accordingly, a first aspect is a composition comprising a solubilizing agent and a peptide compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the peptide compound having at least 60% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), and a compound of Formula (XII):

[0008] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I) (SEQ ID NO: 1)

[0009] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II) (SEQ ID NO: 2)

[0010] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III) (SEQ ID NO: 3)

[0011] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV) (SEQ ID NO: 4)

[0012] IKLSGGVQAKAGVINMDKSESM (V) (SEQ ID NO: 5)

[0013] IKLSGGVQAKAGVINMFKSESY (VI) (SEQ ID NO: 6)

[0014] IKLSGGVQAKAGVINMFKSESYK (VII) (SEQ ID NO: 7)

[0015] GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8)

[0016] GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9)

[0017] GVRAKAGVRN(Nle)FKSESY (X)(SEQ ID NO: 10)

[0018] YKSLRRKAPRWDAPLRDPALRQLL (XI)(SEQ ID NO: 11)

[0019] YKSLRRKAPRWDAYLRDPALRQLL (XII)(SEQ ID NO: 12)

[0020] YKSLRRKAPRWDAYLRDPALRPLL (XIII)(SEQ ID NO: 13)

[0021] wherein

[0022] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently selected from any amino acid;

[0023] X 16 , X 17 , X 20 and X 21 are independently selected from Q, P, Y, I and L;

[0024] n is 0, 1, 2, 3, 4 or 5;

[0025] when X9is present more than once, each said X9is independently selected from any amino acid;

[0026] when X 19 is present more than once, each said X9is independently selected from any amino acid,

[0027] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to said peptide at the N-terminus and / or C-terminus,

[0028] optionally, said peptide compound is cyclic.

[0029] Another aspect is a composition comprising a solubilizing agent and a peptide compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the peptide compound having at least 80% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), and a compound of Formula (XII):

[0030] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I)(SEQ ID NO:1)

[0031] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II)(SEQ ID NO:2)

[0032] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III)(SEQ ID NO:3)

[0033] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV)(SEQ ID NO:4)

[0034] IKLSGGVQAKAGVINMDKSESM (V)(SEQ ID NO:5)

[0035] IKLSGGVQAKAGVINMFKSESY (VI)(SEQ ID NO:6)

[0036] IKLSGGVQAKAGVINMFKSESYK (VII)(SEQ ID NO:7)

[0037] GVQAKAGVINMFKSESY (VIII)(SEQ ID NO:8)

[0038] GVRAKAGVRNMFKSESY (IX)(SEQ ID NO:9)

[0039] GVRAKAGVRN(Nle)FKSESY (X)(SEQ ID NO: 10)

[0040] YKSLRRKAPRWDAPLRDPALRQLL (XI)(SEQ ID NO: 11)

[0041] YKSLRRKAPRWDAYLRDPALRQLL (XII)(SEQ ID NO: 12)

[0042] YKSLRRKAPRWDAYLRDPALRPLL (XIII)(SEQ ID NO: 13)

[0043] wherein

[0044] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently selected from any amino acid;

[0045] X 16 , X 17 , X 20 and X 21 are independently selected from Q, P, Y, I and L;

[0046] n is 0, 1, 2, 3, 4 or 5;

[0047] when X9is present more than once, each said X9is independently selected from any amino acid;

[0048] when X 19 is present more than once, each said X9is independently selected from any amino acid,

[0049] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to said peptide at the N-terminus and / or C-terminus,

[0050] optionally, said peptide compound is cyclic.

[0051] In one aspect, a composition comprising a solubilizing agent and a peptide compound or derivative thereof for targeting Sortilin receptor is provided.

[0052] In one aspect, a composition comprising a solubilizing agent and a peptide compound or derivative thereof for targeting Sortilin receptor is provided.

[0053] In another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the conjugate compound having the formula A-(B) n ,

[0054] wherein

[0055] n is 1, 2, 3, or 4;

[0056] A is a peptide compound as defined by the disclosure, wherein the peptide is optionally protected by a protecting group; and

[0057] B is at least one therapeutic agent, wherein B is linked to A.

[0058] In another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the conjugate compound having the formula A-(B) n ,

[0059] wherein

[0060] n is 1, 2, 3, or 4;

[0061] A is a peptide compound as defined by the disclosure, wherein the peptide compound is optionally protected by a protecting group; and

[0062] B is at least one therapeutic agent, wherein B is linked to A, optionally at a free amine of the peptide compound, at an N-terminal position of the peptide compound, at a free -SH of the peptide compound, or at a free carboxyl of the peptide compound.

[0063] In another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the conjugate compound having the formula A-(B) n ,

[0064] wherein

[0065] n is 1, 2, 3, or 4;

[0066] A is a peptide compound as defined by the disclosure, wherein the peptide is optionally protected by a protecting group; and

[0067] B is at least one therapeutic agent, wherein B is linked to A, optionally through a linker, at a free amine of a lysine residue of the peptide compound, or, optionally through a linker, at an N-terminal position of the peptide compound.

[0068] In another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the conjugate compound represented by formula (XXIII):

[0069] Acetyl-GVRAK (docetaxel) AGVRN(Nle)FK (docetaxel) SESY - Formula (XXIII)

[0070] comprising the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a docetaxel molecule attached thereto.

[0071] Another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the conjugate compound being represented by Formula (XXVIII):

[0072] Acetyl-GVRAK (doxorubicin) AGVRN(Nle)FK (doxorubicin) SESY - Formula (XXVIII)

[0073] comprising the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a doxorubicin molecule attached thereto.

[0074] Another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the conjugate compound being represented by Formula (LII):

[0075] Acetyl-GVRAK AGVRN(Nle)FK SESYC (adriamycin) - Formula (LII)

[0076] comprising the peptide compound having SEQ ID NO: 24, wherein the cysteine residue has an adriamycin molecule attached thereto, or

[0077] comprising the peptide compound having SEQ ID NO: 15, wherein a cysteine residue is added to the C-terminus of the peptide compound, and wherein the cysteine residue has an adriamycin molecule attached thereto.

[0078] Another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the conjugate compound being selected from the group consisting of a compound of Formula (XVI) and a compound of Formula (XVII):

[0079] Acetyl-GVRAK (docetaxel) AGVRN(Nle)FK (docetaxel) SESY - Formula (XXIII)

[0080] comprising the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a docetaxel molecule attached thereto.

[0081] Acetyl-YK (curcumin) SLRRK (curcumin) APRWDAPLRDPALRQLL - Formula (XVII)

[0082] comprises a peptide compound having SEQ ID NO: 16, wherein each lysine residue has a curcumin molecule attached thereto.

[0083] In another aspect, a method of increasing the half-life and / or stability of i) a peptide compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the peptide having at least 60% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII), or ii) a conjugate compound having Formula A-(B) n

[0084] wherein

[0085] n is 1, 2, 3, or 4;

[0086] A is the peptide compound; and

[0087] B is at least one therapeutic agent, wherein B is attached to A at a free amine of a lysine residue of the peptide compound, optionally through a linker, or at an N-terminal position of the peptide compound, optionally through a linker,

[0088] the method comprises mixing the peptide compound or the conjugate compound with a solubilizing agent to increase the half-life by at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, or at least 6-fold.

[0089] In another aspect, a method of increasing the half-life and / or stability of a peptide, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, the peptide having at least 60% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII), the method comprising conjugating the peptide compound to at least one molecule.

[0090] ​In another aspect, there is provided a method of treating cancer or aggressive cancer comprising administering to a subject in need thereof a therapeutically effective amount of at least one composition as defined herein.

[0091] In one aspect, there is provided use of a composition as defined herein for the treatment of cancer.

[0092] In one aspect, there is provided use of a composition as defined herein for targeting Sortilin receptors.

[0093] In one aspect, there is provided use of a composition as defined herein for the treatment of cancer or aggressive cancer.

[0094] In one aspect, there is provided use of a composition as defined herein for the treatment of cancer or aggressive cancer in cancerous tissue or cells expressing Sortilin.

[0095] In one aspect, there is provided use of a composition as defined herein in the manufacture of a medicament for the treatment of cancer.

[0096] In one aspect, there is provided use of a composition as defined herein in the manufacture of a medicament for targeting Sortilin receptors.

[0097] In one aspect, there is provided use of a composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer.

[0098] In one aspect, there is provided use of a composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer in cancerous tissue or cells expressing Sortilin.

[0099] In another aspect, there is provided use of a composition as defined herein in the manufacture of a medicament for targeting Sortilin receptors.

[0100] In another aspect, there is provided a liposome, graphene, nanotube or nanoparticle comprising a composition as defined herein.

[0101] In another aspect, there is provided a liposome, graphene, nanotube or nanoparticle comprising a composition as defined herein for targeting Sortilin receptors. BRIEF DESCRIPTION OF DRAWINGS

[0102] Further features and advantages of the present disclosure will become more apparent from the following description of specific embodiments, as exemplified by the examples set forth in the schemes and drawings, wherein:

[0103] Figure 1 is a tissue immunohistochemistry microarray showing high expression of sortilin in human breast cancer (invasive ductal carcinoma and lymph node metastatic carcinoma).

[0104] Figure 2 FIG. 33 is a bar graph showing sortilin expression levels in infiltrating ductal carcinoma, lymph node metastatic carcinoma, TNBC, and normal tissue.

[0105] Figure 3 FIG. 37 is a graph showing survival rates in TNBC patients with high and low sortilin expression.

[0106] Figure 4 FIG. 39 is a graph showing survival rates in lymph node metastatic TNBC with high and low sortilin expression.

[0107] Figure 5 FIG. 41 is a Western blot image showing high expression of Sortilin in different human TNBC cancer cell lines.

[0108] Figure 6 FIG. 43 is a bar graph showing inhibition of peptide TH19P01 uptake with the use of sortilin siRNA.

[0109] Figure 7 FIG. 45 is a bar graph showing apoptosis of MDA-MB-231 cells in cells treated with docetaxel and TH1902 as a function of concentration and time.

[0110] Figure 8 FIG. 47 is a bar graph showing reversal of apoptosis of TH1902-treated MDA-MB-231 cells by sortilin ligands TH19P01, neurotensin, and progranulin.

[0111] Figure 9 FIG. 49 is a series of images showing a-tubulin immunostaining of MDA-MB-231 cells treated with docetaxel or TH1902 versus control.

[0112] Figure 10 FIG. 51 is a graph showing that TH1902 inhibits cell migration in a sortilin-dependent manner.

[0113] Figure 11 FIG. 53 is a bar graph showing neutrophil counts as a function of the number of treatments with docetaxel or TH1902.

[0114] Figure 12 FIG. 55 is a graph showing TH1902 and released docetaxel concentrations in the plasma of mice injected intravenously with TH1902 as a function of time.

[0115] Figure 13 FIG. 57 is a graph showing tumor volume as a function of time in mice treated with vehicle, high-dose docetaxel, or TH1902 (at equivalent docetaxel doses).

[0116] Figure 14 is a plot showing tumor volume over time in mice treated with vehicle, low dose of docetaxel, or TH1902 (at equivalent docetaxel dose).

[0117] Figure 15 is a plot showing stability of DoceKA (i.e., TH1902 conjugate) when formulated versus when dissolved in DMSO.

[0118] Figure 16 is a plot showing MDA-MB-231 tumor volume over time in mice treated with vehicle, docetaxel, or various TH1902 formulations.

[0119] Figure 17 is a plot showing tumor volume over time in mice treated with vehicle, docetaxel, or TH1902 (Formulation 2).

[0120] Figure 18 is a plot showing body weight over time in mice treated with vehicle, docetaxel, or TH1902 (Formulation 2).

[0121] Figure 19 is a plot showing MDA-MB231 tumor volume over time in mice treated with vehicle or various TH1902 formulations.

[0122] Figure 20 is a bar graph showing tumor progression in mice treated with vehicle or various TH1902 formulations (at 17.5 mg / kg / week).

[0123] Figure 21 is a plot showing heating profile during dissolution of TH1902 API for R&D stability lab batch (Example 5A).

[0124] Figure 22 is a plot showing heating profile during dissolution of TH1902 API using in-house procedure (Example 5B).

[0125] Figure 23 is a representative UPLC analysis of 10 mg / ml TH1902 stock solution after dissolution using in-house procedure (Example 5B).

[0126] Figure 24 Results from endometrial cancer xenograft model (AN3-CA) in mice treated with vehicle, low and high dose docetaxel, or low and high dose TH1902 are shown: A) is a plot showing tumor volume over time, B) is a bar graph showing tumor progression at study endpoint, and C) is a plot showing body weight over time in mice.

[0127] Figure 25Results of a mouse xenograft model of colorectal cancer (HT-29) treated with the mediator, docetaxel, or TH1902 are shown: A) is a graph showing tumor volume over time at low doses, B) is a graph showing tumor volume over time at high doses, C) is a graph showing mouse body weight over time at low doses, D) is a graph showing mouse body weight over time at high doses, E) is a bar graph showing tumor progression at the study endpoint at low doses, and F) is a bar graph showing tumor progression at the study endpoint at high doses.

[0128] Figure 26 Results of a mouse model of pancreatic cancer xenograft (PANC-1) treated with a medium, low and high doses of docetaxel, or low and high doses of TH1902 are shown: A) and B) are graphs showing changes in tumor volume over time, and C) is a bar graph showing tumor progression at the study endpoint.

[0129] Figure 27 Results of a mouse melanoma xenograft model (SK-Mel-28) treated with a medium, low and high doses of docetaxel, or low and high doses of TH1902 are shown: A) is a graph showing tumor volume changes over time, B) is a bar graph showing tumor progression at the study endpoint, and C) is a graph showing mouse body weight changes over time.

[0130] Figure 28 Results of a mouse syngeneic melanoma tumor model (B16F10) treated with a medium, high-dose docetaxel, or high-dose TH1902 are shown: A) is a graph showing tumor volume over time, B) is a bar graph showing tumor progression at the study endpoint, C) is a graph showing mouse body weight over time, and D) is an image of the ex vivo tumor at the study endpoint.

[0131] Figure 29 The dose-response results of mice treated with the mediator, docetaxel, or TH1902 at three equivalent escalating doses in an syngeneic melanoma tumor model (B16F10) are shown: A) is a graph showing tumor volume over time, B) is a bar graph showing tumor progression at the study endpoint, and C) is a graph showing mouse body weight over time. Detailed Implementation

[0132] As used herein, the term“peptide compound” refers to a peptide derived, for example, from a bacterial protein or from a receptor ligand targeting a receptor expressed on cancer cells including multi-drug resistant cancer cells. For example, the peptide compound can be derived from a bacterial protein involved in cell penetration or from a sortilin ligand such as progranulin and neuromedin. For example, the peptide compound can be cyclic. In certain embodiments, the peptide compound is linked (e.g., by a covalent bond, atom, or linker) to at least one therapeutic agent such as an anti-cancer agent or a phytochemical, thereby forming a conjugated compound that can be used, for example, to treat cancer or an aggressive cancer. In certain other embodiments, the peptide compound can be used on the surface of a liposome. For example, the peptide compound can be used to coat a liposome, a graphene, a nanotube, or a nanoparticle, which can be loaded with at least one therapeutic agent such as an anti-cancer agent or a phytochemical, or a gene or siRNA.

[0133] The term“KBP Family 1 peptide compound” refers to a peptide compound derived from a bacterial cell penetration protein. For example, the KBP Family 1 peptide compound can be derived from a protein having the amino acid sequence of IKLSGGVQAKAGVINMDKSESM (SEQ ID NO: 5). Non-limiting examples of KBP Family 1 peptide compounds are shown below:

[0134] Amino acid sequence

[0135] KBP-101 IKLSGGVQAKAGVINMDKSESM - Formula (V) (represented by SEQ ID NO: 5)

[0136] KBP-102 Succinyl-IKLSGGVQAKAGVINMFKSESY - Formula (XXXVI) (comprising SEQ ID NO: 6, wherein succinyl is attached at the N-terminus)

[0137] KBP-103 IKLSGGVQAKAGVINMFKSESYK (Biotin) - Formula (XXXVII) (comprising SEQ ID NO: 7, wherein a biotin molecule is attached to it at the C-terminus)

[0138] KBP-104 GVQAKAGVINMFKSESY - Formula (VIII) (represented by SEQ ID NO: 8)

[0139] KBP-105 Acetyl-GVRAKAGVRNMFKSESY - Formula (XXXVIII) (represented by SEQ ID NO: 14)

[0140] KBP-106 Acetyl-GVRAKAGVRN(Nle)FKSESY - Formula (XXXIX) (represented by SEQ ID NO: 15)

[0141] As used herein, the peptide compound KBP-101 is represented by the amino acid sequence of IKLSGGVQAKAGVINMDKSESM (SEQ ID NO: 5).

[0142] As used herein, the peptide compound KBP-102 is represented by the amino acid sequence of succinyl-IKLSGGVQAKAGVINMFKSESY, which comprises the peptide sequence of SEQ ID NO: 6, with a succinyl group attached to the N-terminus thereof.

[0143] As used herein, the peptide compound KBP-103 is represented by the amino acid sequence of IKLSGGVQAKAGVINMFKSESYK (biotin), which comprises the peptide sequence of SEQ ID NO: 7, with a biotin molecule attached to the C-terminus thereof.

[0144] As used herein, the peptide compound KBP-104 is represented by the amino acid sequence of GVQAKAGVINMFKSESY (SEQ ID NO: 8).

[0145] As used herein, the peptide compound KBP-105 is represented by the amino acid sequence of acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14).

[0146] As used herein, the peptide compound KBP-106 is represented by the amino acid sequence of acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15).

[0147] As used herein, “TH19P01” or “TH19P01 peptide” is synonymous with the peptide compound KBP-106, which is represented by the sequence of SEQ ID NO: 15.

[0148] The term "KBP Family 2 Peptide Compound" refers to a peptide derived from sortilin ligand, progranulin, and neurotensin. For example, the peptide can be derived from human, rat, or mouse progranulin. For example, the KBP Family 2 Peptide Compound can be derived from, for example, human progranulin having the amino acid sequence KCLRREAPRWDAPLRDPALRQLL (SEQ ID NO: 19), from, for example, rat progranulin having the amino acid sequence KCLRKKTPRWDILLRDPAPRPLL (SEQ ID NO: 20), from, for example, mouse progranulin having the amino acid sequence KCLRKKIPRWDMFLRDPVPRPLL (SEQ ID NO: 21), or from, for example, neurotensin having the amino acid sequence XLYENKPRRPYIL (SEQ ID NO: 22). Non-limiting examples of KBP Family 2 Peptide Compounds are shown below:

[0149] Amino acid sequence

[0150] KBP-201 Acetyl-YKSLRRKAPRWDAPLRDPALRQLL - Formula (XXXX) (represented by SEQ ID NO: 16)

[0151] KBP-202 Acetyl-YKSLRRKAPRWDAYLRDPALRQLL - Formula (XXXXI) (represented by SEQ ID NO: 17)

[0152] KBP-203 Acetyl-YKSLRRKAPRWDAYLRDPALRPLL - Formula (XXXXII) (represented by SEQ ID NO: 18)

[0153] As used herein, the Peptide Compound KBP-201 is represented by the amino acid sequence of Acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16).

[0154] As used herein, the Peptide Compound KBP-202 is represented by the amino acid sequence of Acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17).

[0155] As used herein, the Peptide Compound KBP-203 is represented by the amino acid sequence of Acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 18).

[0156] As used herein, the term "Sortilin" or "Sortilin receptor" refers to a neuronal type 1 membrane glycoprotein encoded by the SORT1 gene, belonging to the vacuolar protein sorting 10 (VpslO) family of receptors. Sortilin (also known as Neuromedin receptor 3; Accession No. NP_002950, incorporated herein by reference) is abundantly expressed in the central and peripheral nervous system and also in other types of tissues. For example, expression of sortilin is upregulated in many cancers, including, for example, ovarian cancer, breast cancer, colon cancer, and prostate cancer. The encoded preproprotein is proteolytically processed by furin, generating a mature receptor with a molecular weight of 100-110 kDa. A truncated and soluble form of Sortilin (95 kDa) corresponding to its large lumenal domain (i.e., extracellular domain or ectodomain) has also been described, previously detected in the supernatant media of sortilin overexpressing cells (48). Amino acid residue references to sortilin herein correspond to the position of the full-length form (i.e., Accession No. NP_002950). The extracellular domain of Sortilin is located at amino acid residues 78-755 of the full-length form. The peptide compounds and conjugate compounds described herein can have high binding affinity for sortilin and thus can specifically target cancer cells that express or overexpress sortilin.

[0157] The term "compound" as used in this document refers to a compound of Formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XIX), (XXIII), (XXVI), (XXVIII), (LI), (LII), or a pharmaceutically acceptable salt, solvate, hydrate, and / or prodrug of these compounds, an isomer of these latter compounds, or a racemic mixture of these latter compounds, and / or a composition made with such compounds, as previously indicated in this disclosure. The expression "compound" also refers to a mixture of the various compounds disclosed herein.

[0158] The compounds of the present disclosure include prodrugs. In general, such prodrugs will be functional derivatives of these compounds, which are readily convertible in vivo into their theoretically derived compounds. The prodrugs of the compounds of the present disclosure can be formed using readily available reagents, such as the hydroxyl or amino groups, to form the usual esters. For example, available OH or nitrogen in the compounds of the present disclosure can be acylated using an activated acid in the presence of a base, and optionally in an inert solvent, such as an acyl chloride in pyridine. Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C8-C 24) esters, acyloxymethyl esters, carbamates, and amino acid esters. In certain instances, prodrugs of the compounds of the disclosure are those in which one or more hydroxyl groups of the compounds are masked with groups which can be cleaved in vivo to release the hydroxyl group. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs" by H. Bundgaard, Elsevier 1985.

[0159] The compounds of the disclosure include radiolabeled forms, for example, by incorporation of a radioactive isotope within a structure 2 H, 3 H, 14 C, 15 N or a radioactive halogen such as 125 I. Radiolabeled compounds of the compounds of the disclosure can be prepared using standard methods known in the art.

[0160] As used herein, the term "analog" includes a moiety, extension, substitution, variant, modification, or chemical equivalent and derivative of an amino acid of the disclosure that performs essentially the same function in essentially the same way as a peptide or antigen of the disclosure. For example, analogs of the peptides and antigens of the disclosure include, but are not limited to, conservative amino acid substitutions. Analogues of the peptides and antigens of the disclosure also include additions and deletions to the peptides and antigens of the disclosure.

[0161] As used herein, a "conservative amino acid substitution" is one in which one amino acid residue is replaced with another amino acid residue that does not eliminate the desired properties of the peptide or antigen.

[0162] As used herein, the expression "derivatives thereof" when referring to a compound means derivatives of the compound that have similar reactivity and can be used as a substitute for the compound to achieve the same desired result.

[0163] As used herein, the term "cancer" refers to a primary or secondary cancer and includes non-metastatic cancer and / or metastatic cancer. Reference to a cancer includes reference to cancerous tissue or cells. For example, a cancer is an ovarian cancer, a brain cancer, a breast cancer (e.g., triple negative breast cancer), a melanoma, a colorectal cancer, a glioblastoma, a liver cancer, a lung cancer, a prostate cancer, a cervical cancer, a head cancer, a stomach cancer, a kidney cancer, an endometrial cancer, a testicular cancer, a urothelial cancer, acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, Hodgkin's lymphoma, neuroblastoma, non-Hodgkin's lymphoma, soft tissue cancer, osteosarcoma, thyroid cancer, transitional cell bladder cancer, Wilms' tumor, glioma, pancreatic cancer, or spleen cancer. As used herein, the term "cancer" also encompasses any cancer involving Sortilin expression.

[0164] As used herein, the term “aggressive cancer” refers to a cancer having cancer cells that divide and grow rapidly. An aggressive cancer can be invasive or metastatic, or more likely to be invasive or metastatic and spread to lymph nodes and / or other body organs. Reference to an aggressive cancer includes reference to aggressive cancer tissue or cells. An aggressive cancer can be any of the cancer types described herein.

[0165] As used herein, the expression “therapeutic agent” refers to an agent that is capable of producing a therapeutic effect by inhibiting, suppressing, or reducing a cancer in a subject, cancer tissue, or cells (e.g., as determined by clinical symptoms or amount of cancer cells) as compared to a control. Examples of therapeutic agents include, for example, anti-cancer agents and phytochemicals.

[0166] As used herein, the term “anti-cancer agent” refers to an agent that is capable of causing toxicity in cancer cells. For example, taxanes derived from the bark of the Pacific yew tree Taxus brevifolia can be used as anti-cancer agents. Taxanes include, for example, docetaxel, paclitaxel, and cabazitaxel. Other anti-cancer agents include, for example, anthracyclines that act by intercalating DNA. For example, anthracyclines include doxorubicin and adozelesin.

[0167] As used herein, the term “docetaxel” or “doce” refers to an anti-cancer agent having the following structure:

[0168]

[0169] or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and mixtures thereof. For example, docetaxel can be conjugated to a peptide compound of the present disclosure through an oxygen atom connected to a carbon atom at position 2 of a side chain of docetaxel. Docetaxel can be connected to a peptide compound directly or through a linker.

[0170] As used herein, the term “doxorubicin,” “dox,” or “doxo” refers to an anti-cancer agent having the following structure:

[0171]

[0172] or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and mixtures thereof. For example, doxorubicin can be conjugated to a peptide compound of the present disclosure through an oxygen atom connected to a carbon atom at position 14. Doxorubicin can be connected to a peptide compound directly or through a linker.

[0173] As used herein, the term “cabazitaxel” or “cab” refers to an anti-cancer agent having the following structure:

[0174]

[0175] or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and mixtures thereof. For example, cabazitaxel can be conjugated to a peptide compound of the present disclosure through the oxygen atom of cabazitaxel’s side chain at position 2 that is attached to a carbon atom. Cabazitaxel can be attached to a peptide compound directly or through a linker.

[0176] As used herein, the term “doxorubicin” or “aldo” refers to an anticancer agent having the following structure:

[0177]

[0178] or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and mixtures thereof. For example, doxorubicin can be conjugated to a peptide compound of the present disclosure through the (6-maleimidocaproyl) hydrazone of doxorubicin’s side chain at position 13 that is attached to a carbon. Doxorubicin can be attached to a peptide compound directly or through a linker thereof.

[0179] As used herein, the term “phytochemical” refers to a compound that naturally occurs in a plant and can be used to treat cancer. Examples of phytochemicals include, for example, curcumin. Curcumin (diferuloylmethane) is a yellow pigment found in the spice turmeric (Curcuma longa) that is associated with anti-inflammatory properties. Other phytochemicals with anti-inflammatory properties include, for example, omega-3, white willow bark, green tea, catechins, pygeum, boswellia resin, resveratrol, uncaria tomentosa, capsaicin, anthocyanins / anthocyanidins, flavonoids, olive oil compounds, chlorogenic acid, and sulforaphane.

[0180] As used herein, the term “curcumin” or “cur” refers to a phytochemical having the following structure:

[0181]

[0182] or pharmaceutically acceptable salts, solvates, or prodrugs thereof, and mixtures thereof. For example, curcumin can be conjugated to a peptide compound of the present disclosure through the oxygen atom of its phenolic group. Curcumin can be attached to a peptide compound directly or through a linker.

[0183] As used herein, the expression “conjugated compound,” “peptide-drug conjugate,” or “peptide conjugate” refers to a compound comprising a peptide compound disclosed herein linked to at least one therapeutic agent, optionally through a linker. A conjugated compound can comprise, for example, 1, 2, 3, or 4 molecules of a therapeutic agent linked thereto. The 1-4 molecules of therapeutic agent can be the same or different, i.e., up to four different therapeutic agents can be linked to a peptide compound. The therapeutic agent is linked to the peptide compound by at least one covalent bond, at least one atom, or at least one linker. Conjugated compounds are useful for treating cancer. Examples of conjugated compounds include, but are not limited to, the conjugated compounds shown below:

[0184]

[0185]

[0186] As used herein, the term "conjugation" refers to the preparation of a conjugate, e.g., as defined above. Such an action includes linking together a peptide compound with at least one therapeutic agent, optionally through a linker.

[0187] For example, the following are general chemical formulas for some of the peptide-conjugate compounds disclosed herein.

[0188] Curcumin-peptide conjugate compounds:

[0189]

[0190] For example, the following are chemical structures for some of the conjugate compounds disclosed herein.

[0191] Docetaxel-peptide conjugate (DoceKA) (TH1902):

[0192]

[0193] Doxorubicin-peptide conjugate (DoxKA):

[0194]

[0195] KBC-106:

[0196]

[0197] Curcumin-peptide conjugate:

[0198] KBC-201:

[0199]

[0200] KBP-106-Cys-Adriamycin:

[0201]

[0202] As used herein, the term "linker" refers to a chemical structure that links a peptide compound disclosed herein to at least one therapeutic agent. The linker can link to the peptide compound at different functional groups on the peptide compound. For example, the linker can link to the peptide compound at a primary amine (amine (-NH2)): this group is present at the N-terminus of each polypeptide chain (termed the a-amine) and the side chain of lysine (Lys, K) residues (termed the e-amine). For example, the linker can link to the peptide compound at a carboxyl group (-COOH): this group is present at the C-terminus of each polypeptide chain as well as the side chains of aspartic acid (Asp, D) and glutamic acid (Glu, E). For example, the linker can link to the peptide compound at a thiol group (-SH): this group is present at the side chain of cysteine (Cys, C). Typically, as part of the secondary or tertiary structure of a protein, cysteines are linked together at their side chains by disulfide bonds (-S-S-). These must be reduced to thiol groups for them to be available for cross-linking to most types of reactive groups. For example, the linker can link to the peptide compound at a carbonyl group (-CHO): ketone or aldehyde groups can be generated in glycoproteins by post-translational modification (glycosylation) with oxidation of the polysaccharide by sodium metaperiodate. For example, the linker can be a cleavable linker. For example, the linker can be a non-cleavable linker.

[0203] The following table summarizes the reaction classes and chemical groups of some of the main linkers for standard chemical conjugation:

[0204]

[0205] For example, homo- and hetero-bifunctional cross-linking reagents can be used. For example, disuccinimidyl suberate (DSS) is a homo-bifunctional cross-linking reagent with the same amine-reactive NHS-ester group at either end of a short spacer arm. For example, 4-(N-maleimidomethyl) cyclohexane-1-carboxylate sulfosuccinimidyl ester (sulfo-SMCC) is a hetero-bifunctional cross-linking reagent with an amine-reactive sulfo-NHS-ester group at one end of a cyclohexane spacer arm and a thiol-reactive maleimide group at the opposite end. This allows a sequential two-step conjugation procedure. Commercially available homo-bifunctional cross-linking reagents include: BSOCOES (Bis(2-[succimidoxycarbonyloxy]ethyl) sulfone); DPDPB (1,4-di-(3'-[2 pyridyldisulfanyl]-propionamido)butane); DSS (disuccinimidyl suberate); DST (ditartrate succinimidyl ester); sulfo-DST (sulfotartrate succinimidyl ester); DSP (dithiobis(succinimidyl propionate)); DTSSP (3,3'-dithiobis(sulfosuccinimidyl propionate)); EGS (ethyleneglycol bis(succinimidyl succinate)); and BASED (iodinatable bis(beta-[4-azidosalicylamido]-ethyl) disulfide).

[0206] Peptide compounds can be conjugated through a variety of linkers, for example, thiol, amino (amine), or any suitable reactive group. The linker can be a covalent bond. The linker group can comprise a flexible arm, for example, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms.

[0207] Exemplary linkers include, but are not limited to, pyridyl disulfide, thiosulfonate, vinyl sulfonate, isocyanate, imidoester, diazine, hydrazine, thiol, carboxylic acid, polypeptide linker, and ethyne. Alternatively, other linkers that can be used include BS 3 [bis(sulfosuccinimidyl)suberate] (which is a homobifunctional N-hydroxysuccinimide ester that targets accessible primary amines), NHS / EDC (N-hydroxysuccinimide and l-ethyl-3-(3- dimethylaminopropyl)carbodiimide) (NHS / EDC allows conjugation of primary amine groups to carboxyl groups), sulfo-EMCS ([N-e-maleimidocaproyl]hydrazide (sulfo-EMCS is a heterobifunctional reactive group that is reactive toward both sulfhydryl and amino groups), hydrazide (most proteins contain exposed carbohydrates, and hydrazide is a useful reagent for linking carboxyl and primary amines).

[0208] To form a covalent bond, a variety of active carboxyl groups (e.g., esters) can be used as the chemical reactive group, where the hydroxyl moiety is physiologically acceptable at the level required to modify the peptide compound. Specific agents include, for example, N-hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (sulfo-NHS), maleimide-benzoyl-succinimide (MBS), gamma-maleimidobutyryloxy-succinimide ester (GMBS), maleimidopropanoic acid (MPA), maleimidocapronic acid (MHA), and maleimidoundecanoic acid (MUA).

[0209] Primary amines are the main target of NHS esters; NHS esters react with primary amines to form a covalent amide bond. Accessible a-amine groups present at the N-terminus of proteins and the e-amine of lysine react with NHS esters. Thus, the conjugated compounds disclosed herein can include linkers having an NHS ester conjugated to the N-terminal amino group or the e-amine of lysine of a peptide compound. When the NHS ester reacts with the primary amine, N-hydroxysuccinimide is released, forming an amide bond. The reactive group containing succinimide can be more simply referred to as a succinimidyl group. In some embodiments, the functional group on the peptide compound will be a thiol group and the chemical reactive group will be a maleimide-containing group, such as gamma-maleimido-butyramide (GMBA or MPA). Such maleimide-containing groups can be referred to herein as maleimidyl groups.

[0210] Amine-amine linkers include NHS esters, imidoesters, and the like, which are exemplified as listed below.

[0211]

[0212] Linkers can also be thiol-thiol linkers, such as the maleimide and pyridyl dithiol listed below.

[0213]

[0214] Linkers can be amine-thiol linkers, which include NHS ester / maleimide compounds. Examples of these compounds are provided below.

[0215]

[0216]

[0217] Linkers can react with amino and non-selective entities. Such linkers include NHS ester / aryl azide and NHS ester / diazirine linkers, examples of which are listed below.

[0218]

[0219]

[0220] Exemplary amine-carboxyl linkers include carbodiimide compounds (e.g., DCC (N,N- dicyclohexylcarbodiimide) and EDC (1-ethyl-3-[3-dimethylaminopropyl]-carbodiimide)). Exemplary thiol-non-selective linkers include pyridyl dithiol / aryl azide compounds (e.g., APDP (N-[4-(p-azidosalicylamido)butyl]-3'-(2'-pyridyldithio)propionamide)). Exemplary thiol-carbohydrate linkers include maleimide / hydrazide compounds (e.g., BMPH (N-[beta-maleimidopropionic acid]hydrazide), EMCH ([N-epsilon-maleimidocaproic acid]hydrazide), MPBH (4-(4-N-maleimidophenyl)butyric acid hydrazide), and KMUH (N-[kappa-maleimidoundecanoic acid]hydrazide)) and pyridyl dithiol / hydrazide compounds (e.g., PDPH (3-(2-pyridyldithio)propionhydrazide)). Exemplary carbohydrate-non-selective linkers include hydrazide / aryl azide compounds (e.g., ABH (p-azidobenzhydrazide)). Exemplary hydroxyl-thiol linkers include isocyanate / maleimide compounds (e.g., (N-[p-maleimidophenyl] isocyanate)). Exemplary amine-DNA linkers include NHS ester / psoralen compounds (e.g., SPB (succinimidyl-[4-(psoralen-8-yloxy)]-butyrate)).

[0221] To create branching points of different complexity in the conjugate peptide compound, the linker can be able to link 3-7 entities.

[0222]

[0223] TMEA and TSAT reach thiols through their maleimide groups. The hydroxyl and carboxyl groups of THPP can react with primary or secondary amines. Other useful linkers conform to the formula Y=C=N-Q-A-C(O)-Z, where Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 bridge group, Y is O or S; and Z is CI, Br, I, N3, N-succinimidyl oxy, imidazolyl, 1- benzotriazolyl oxy, OAr, where Ar is an electron-deficient activated aryl group, or OC(O)R, where R is -A-Q-N=C=Y or a C4-20 tertiary alkyl group (see U.S. Patent No. 4,680,338).

[0224] Other useful linkers have the formula where R1is H, C 1-6 alkyl, C 2-6 alkenyl, C 6-12 aryl or aralkyl or these with divalent organic -O-, -S or coupling, where R' is C 1-6 alkyl, a linking moiety; R2is H, C 1-12 alkyl, C 6-12 aryl or C 6-12 aralkyl, R3is or other chemical structure capable of delocalizing the lone pair of electrons of the adjacent nitrogen and R4is a side chain reactive group capable of linking R3to a peptide compound or agent (see, e.g., U.S. Patent No. 5,306,809).

[0225] The linker can include at least one amino acid residue and can be a peptide having at least or about 2, 3, 4, 5, 6, 7, 10, 15, 20, 25, 30, 40, or 50 amino acid residues. Where the linker is a single amino acid residue, it can be any naturally or non-naturally occurring amino acid (e.g., Gly or Cys). Where the linker is a short peptide, it can be a glycine-rich peptide (tending to be flexible), such as a peptide having the sequence [Gly-Gly-Gly-Gly-Ser]n, where n is an integer from 1 to 6, inclusive (see U.S. Patent No. 7,271,149) or a serine-rich peptide linker (see U.S. Patent No. 5,525,491). Serine-rich peptide linkers include the formula [X-X-X-X-Gly] ythose in which at most two X are Thr and the rest are Ser, and y is an integer from 1 to 5, inclusive (e.g., Ser-Ser-Ser-Ser-Gly, where y is greater than 1). Other linkers include rigid linkers (e.g., PAPAP and (PT) n P, where n is 2, 3, 4, 5, 6, or 7) and alpha-helical linkers (e.g., A(EAAAK) n A, where n is 1, 2, 3, 4, or 5).

[0226] The linker can be an aliphatic linker (e.g., having an amide bond to the polypeptide and an ester bond to the therapeutic agent). In cases where an aliphatic linker is used, its length (e.g., C1-C 20 ) and the chemical moieties (e.g., amino or carbamate) it comprises can vary.

[0227] Examples of suitable amino acid linkers are succinic acid, Lys, Glu, and Asp, or dipeptides such as Gly-Lys. When the linker is succinic acid, one of its carboxyl groups can form an amide bond with the amino group of an amino acid residue, and its other carboxyl group can form an amide bond, for example, with the amino group of a peptide or substituent. When the linker is Lys, Glu, or Asp, its carboxyl group can form an amide bond with the amino group of an amino acid residue, and its amino group can form an amide bond, for example, with the carboxyl group of a substituent. When Lys is used as a linker, an additional linker can be inserted between the epsilon-amino group of the Lys and the substituent. The additional linker can be succinic acid, which can form amide bonds with the epsilon-amino group of the Lys and an amino group present in the substituent. In one embodiment, the additional linker is Glu or Asp (e.g., which forms an amide bond with the epsilon-amino group of the Lys and another amide bond with a carboxyl group present in the substituent), i.e., the substituent is N ε -acylated lysine residue.

[0228] The linker can also be a branched polypeptide. Exemplary branched peptide linkers are described in U.S. Patent No. 6,759,509, which is incorporated herein by reference.

[0229] Linkers can provide cleavable bonds (e.g., thioester bonds) or non-cleavable bonds (e.g., maleimide bonds). For example, a cytotoxic protein can be conjugated to a linker that reacts with free amines present on lysine residues within a polypeptide and at the amino terminus of a polypeptide. Thus, linkers useful in the conjugate compounds described herein can comprise a group that is reactive with a primary amine on a polypeptide or modified polypeptide conjugated to a therapeutic agent moiety. More specifically, the linker can be selected from the group consisting of monofluorocyclooctyne (MFCO), bicyclononyne (BCN), N-succinimidyl-S-acetylthioacetate (SATA), N-succinimidyl-S-acetylthiopropionate (SATP), maleimide, and dibenzocyclooctyne ester (DBCO ester). Cyclooctynes useful in a given linker include OCT, ALO, MOFO, DIFO, DIBO, BARAC, DIBAC, and DIMAC.

[0230] Linkers can comprise a flexible arm, such as, for example, a short arm (<2 carbon chains), a medium size arm (2-5 carbon chains), or a long arm (3-6 carbon chains).

[0231] Click chemistry can also be used for conjugation on peptides (DBCO, TCO, tetrazine, azide, and alkyne linkers). These linker families can be reactive towards amines, carboxyls, and thiols. In addition, these linkers can also be biotinylated, pegylated, modified with fluorescent imaging dyes, or phosphoramidites for incorporation on oligonucleotide sequences.

[0232] As used herein, the term "intermediate" refers to an intermediate or activated form of a therapeutic agent that has been reacted with a linker to form the therapeutic agent. The intermediate can be reacted with a peptide compound disclosed herein to form a conjugate compound disclosed herein that is useful for treating cancer or an aggressive cancer.

[0233] The expression "amino acid" refers to the common natural (genetically encoded) or synthetic amino acids and their common derivatives known to those skilled in the art. "Standard" or "proteogenic" when applied to amino acids refers to the 20 natural configuration amino acids that are genetically encoded. Similarly, "non-standard," "non-natural," or "unusual" when applied to amino acids refers to a broad selection of non-natural, exotic, or synthetic amino acids such as those described by Hunt, S. in Chemistry and Biochemistry of the Amino Acids, Barrett, G. C., ed., Chapman and Hall: New York 1985. Some examples of non-standard amino acids include non-alpha amino acids, D-amino acids.

[0234] The abbreviations used for amino acids and the nomenclature of peptides follow the rules of the IUPAC-IUB Biochemical Nomenclature Commission, J. Biol. Chem. 1972, 247, 977-983. This document has been updated: Biochem. J. 1984, 219, 345-373; Eur. J. Biochem. 1984, 138, 9-37; 1985, 152, 1; Int. J. Pept. Prot. Res. 1984, 24, after p. 84; J. Biol. Chem. 1985, 260, 14-42; Pure Appl. Chem. 1984, 56, 595-624; Amino Acids and Peptides 1985, 16, 387-410; and Biochemical Nomenclature and Related Documents, 2nd Ed., Portland Press, 1992, pp 39-67. Extensions of the rules are published in JCBN / NC-IUB Newsletter 1985, 1986, 1989; see Biochemical Nomenclature and Related Documents, 2nd Ed., Portland Press, 1992, pp 68-69.

[0235] The term "antagonist" refers to a compound that reduces at least some of the effects of an endogenous ligand of a protein, receptor, enzyme, interaction, etc.

[0236] The term "inhibitor" refers to a compound that reduces the normal activity of a protein, receptor, enzyme, interaction, etc.

[0237] The term "library" refers to a collection of compounds that can be used, for example, for drug discovery purposes. For example, the library compounds can be the peptide compounds or peptide conjugates disclosed herein.

[0238] As used herein, the term “mixture” refers to a composition comprising two or more peptide compounds. In one embodiment, the mixture is a mixture of two or more different peptide compounds. In a further embodiment, when a peptide compound is referred to as a “mixture,” it means that it can comprise two or more “forms” of the peptide compound, such as a salt, solvate, prodrug, or, where applicable, stereoisomers of the peptide compound in any proportion. One of skill in the art will appreciate that the peptide compounds in the mixture can also exist in a mixed form. For example, the peptide compound can exist in the form of a hydrate of a salt of the peptide compound or a hydrate of a salt of a prodrug of the peptide compound. All forms of the peptide compound herein are within the scope of the present application.

[0239] The term “modulator” refers to a peptide compound that has an effect on a biological or chemical process or mechanism. For example, a modulator can increase, promote, upregulate, activate, inhibit, decrease, block, prevent, delay, desensitize, inactivate, downregulate, etc. a biological or chemical process or mechanism. Thus, a modulator can be an “agonist” or an “antagonist.” Exemplary biological processes or mechanisms affected by a modulator include, but are not limited to, enzyme binding, receptor binding, and hormone release or secretion. Exemplary chemical processes or mechanisms affected by a modulator include, but are not limited to, catalysis and hydrolysis.

[0240] The term “peptide” refers to a compound comprising at least two amino acids covalently bonded together using amide linkages.

[0241] As used herein, the term “prodrug” refers to a derivative of an active form of a known compound or composition that, upon administration to a subject, gradually converts to the active form to produce a better therapeutic response and / or a reduced level of toxicity. In general, a prodrug will be a functional derivative of a compound disclosed herein that can be readily converted into its theoretically derived compound in vivo. Prodrugs include, but are not limited to, acyl esters, carbonates, phosphates, and carbamates. These groups are exemplary and not exhaustive, and one of skill in the art can make other prodrugs of known kinds. For example, a prodrug can be formed with available hydroxyl, thiol, amino, or carboxyl groups. For example, available OH and / or NH2 in a compound of the present disclosure can be acylated using an activated acid in the presence of a base, and optionally in an inert solvent (e.g., acyl chloride in pyridine). Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbamates, and amino acid esters. In certain instances, prodrugs of the compounds of the present disclosure are those in which a hydroxyl and / or amino group in a compound is masked with a group which can be readily converted in vivo into a hydroxyl and / or amino group. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in “Design of Prodrugs,” edited by H. Bundgaard, Elsevier 1985.

[0242] The expression "protecting group" refers to any compound that can be used to prevent a potentially reactive functional group on a molecule, such as an amine, hydroxyl, or carboxyl, from undergoing a chemical reaction while a chemical change occurs elsewhere in the molecule. Many such protecting groups are known to those skilled in the art, and examples can be found in T. W. Greene and P. G. Wuts, editors, Protective Groups in Organic Synthesis, 4th edition, John Wiley & Sons, New York, 2006, 1082 pp, ISBN 9780471697541. Examples of amino protecting groups include, but are not limited to, phthalimido, trichloroacetyl, benzyloxycarbonyl, tert-butyloxycarbonyl, and adamantyl-oxycarbonyl. In some embodiments, the amino protecting group is a carbamate amino protecting group, which is defined as an amino protecting group that forms a carbamate when bound to an amino group. In other embodiments, the amino carbamate protecting group is allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), tert-butyloxycarbonyl (Boc), and a, a dimethyl-3,5 dimethoxybenzyloxycarbonyl (Ddz). For a recent discussion of newer nitrogen protecting groups see: Tetrahedron 2000, 56, 2339-2358. Examples of hydroxyl protecting groups include, but are not limited to, acetyl, tert-butyldimethylsilyl (TBDMS), trityl (Trt), tert-butyl, and tetrahydropyranyl (THP). Examples of carboxyl protecting groups include, but are not limited to, methyl ester, tert-butyl ester, benzyl ester, trimethylsilyl ethyl ester, and 2,2,2-trichloroethyl ester.

[0243] As used herein, the expression "sequence identity" refers to the percentage of sequence identity between two polypeptide sequences or between two nucleic acid sequences. To determine the percent identity of two amino acid sequences or of two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in the sequence of a first amino acid or nucleic acid sequence for optimal alignment with a second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = # of identical overlapping positions / total # of positions x 100%). In one embodiment, the two sequences are the same length. Determining the percent identity between two sequences can also be accomplished using a mathematical algorithm. One preferred, non-limiting example of a mathematical algorithm utilized for the comparison of two sequences is the algorithm of Karlin and Altschul 1990, modified to calculate percent identity as set forth in Karlin and Altschul 1993. Such an algorithm is incorporated in the NBLAST and XBLAST programs of Altschul et al. 1990. BLAST nucleotide searches are performed with the NBLAST nucleotide program parameters set (e.g., score = 100, word length = 12). BLAST protein searches are performed with the XBLAST program parameters set (e.g., score 50, word length = 3). To obtain gapped alignments for comparison purposes, one can utilize a gapped BLAST (Altschul et al. 1997). Alternatively, PSI BLAST can be used to perform an iterative search that detects distant relationships between molecules (Id.). When utilizing BLAST, gapped BLAST and PSI BLAST programs, the default parameters of the respective programs (see, e.g., NCBI website) can be used. Another preferred, non-limiting example of a mathematical algorithm utilized for the comparison of sequences is the algorithm of Myers and Miller 1988, CABIOS 4: 11-17. Such an algorithm is incorporated in the ALIGN program (version 2.0), which is part of the GCG sequence alignment software package. When utilizing the ALIGN program to compare amino acid sequences, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between two sequences is determined using techniques similar to those described above, with or without gapping. In calculating percent identity, only exact matches are typically counted.

[0244] As used herein, the expression "consisting essentially of is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps and those that do not materially affect the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps.

[0245] The expression "solid phase chemistry" refers to the conduct of chemical reactions in which one component of the reaction is covalently bound to a polymeric material (a solid support as defined below). Methods for conducting chemistry on a solid phase have become more widely known and established outside the traditional field of peptide and oligonucleotide chemistry (F. Albericio, ed. Solid-Phase Synthesis: A Practical Guide, CRC Press, 2000, 848 pp, ISBN: 978-0824703592; Organic Synthesis on Solid Phase, 2ndEdition, Florencio Zaragoza-Sucre, ed. Wiley-VCH, 2002, 530 pp, ISBN: 3-527-30603-X; P. H. Toy, Y. Lam, eds. Solid-Phase Organic Synthesis: Concepts, Strategies, and Applications, Wiley, 2012, 568 pp, ISBN: 978-0470599143).

[0246] The term "solid support", "solid phase" or "resin" refers to a mechanically and chemically stable polymeric matrix used for the conduct of solid phase chemistry. This is indicated by "resin", "P-" or the following symbol:

[0247] Examples of suitable polymeric materials include, but are not limited to, polystyrene, polyethylene, polyethylene glycol (PEG, including but not limited to (Matrix Innovation, Quebec, Quebec, Canada; J. Comb. Chem. 2006, 8, 213-220)), polyethylene glycol grafted or covalently bound to polystyrene (also known as PEG-polystyrene, TentaGel TM ​Rapp, W.; Zhang, L.; Bayer, E. Innovations and Perspectives in Solid Phase Synthesis, in Peptides, Polypeptides and Oligonucleotides; Epton, R., Ed.; SPCC Ltd.: Birmingham, UK; p 205), polyacrylates (CLEAR TM ), polyacrylamides, polyurethanes, PEGA [polyethylene glycol poly(N,N dimethyl- acrylamide) copolymer (Tetrahedron Lett. 1992, 33, 3077-3080)], cellulose, and the like. These materials can optionally contain additional chemical agents to form crosslinks to mechanically stabilize the structure, for example, polystyrene crosslinked with divinylbenzene (DVB, typically 0.1-5%, preferably 0.5-2%). Such solid supports can include aminomethyl polystyrene, hydroxymethyl polystyrene, benzhydrylamine polystyrene (BHA), methylbenzhydrylamine (MBHA) polystyrene, and other polymeric backbones containing free chemical functional groups, most typically NH2or -OH, as non-limiting examples for further derivatization or reaction. The term also implies the inclusion of “super resins” with a high proportion (“loading”) of these functional groups, such as those prepared from polyethyleneimine and crosslinking molecules (J. Comb. Chem. 2004, 6, 340-349). At the end of synthesis, the resin is typically discarded, although they have been shown to be recyclable (Tetrahedron Lett. 1975, 16, 3055).

[0248] In general, the materials used as resins are insoluble polymers, but certain polymers have different solubilities depending on the solvent, and can also be used in solid phase chemistry. For example, polyethylene glycol can be used in this way, as it is soluble in many organic solvents in which chemistry can be performed, but it is insoluble in other solvents, such as diethyl ether. Thus, the reaction can be carried out uniformly in solution, and then the product on the polymer is precipitated as a solid by the addition of diethyl ether and handled as a solid. This is known as “liquid phase” chemistry.

[0249] The expression “pharmaceutically acceptable” means compatible with the treatment of a subject, such as an animal or human.

[0250] The expression “pharmaceutically acceptable salt” means an acid addition or base addition salt which is suitable for or compatible with the treatment of a subject, such as an animal or human.

[0251] As used herein, the expression "pharmaceutically acceptable acid addition salt" refers to any non-toxic, inorganic or organic acid addition salt of a compound of the present disclosure or any intermediate thereof. Illustrative inorganic acids whose salts are suitable for use include hydrochloric, hydrobromic, sulfuric and phosphoric acids, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids whose salts are suitable for use include mono-, di-, and tricarboxylic acids such as glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, formic, acetic, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids, as well as sulfonic acids such as p-toluenesulfonic and methanesulfonic acids. Mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, acid addition salts of the compounds of the present disclosure are more soluble in water and various hydrophilic organic solvents than their free base forms, and they generally exhibit higher melting points. The selection of suitable salts can be made by one of ordinary skill in the art. Other non-pharmaceutically acceptable salts, for example, oxalates, can be used, for example, in the isolation or purification of a compound of the present disclosure for laboratory use, or in the preparation of pharmaceutically acceptable acid addition salts.

[0252] As used herein, the expression "pharmaceutically acceptable base addition salt" refers to any non-toxic, inorganic or organic base addition salt of an acid compound of the present disclosure or any intermediate thereof. Acidic compounds of the present disclosure which can form base addition salts include, for example, wherein CO2H is the functional group. Illustrative inorganic bases which form suitable salts include hydroxides of lithium, sodium, potassium, calcium, magnesium, or barium. Illustrative organic bases which form suitable salts include aliphatic, cycloaliphatic or aromatic organic amines such as methylamine, trimethylamine and methylpyridinium or ammonia. The selection of suitable salts is known to those of ordinary skill in the art. Other non-pharmaceutically acceptable base addition salts can be used, for example, in the isolation or purification of a compound of the present disclosure or conjugated compound for laboratory use, or in the preparation of pharmaceutically acceptable acid addition salts.

[0253] Formation of the salt of the desired compound is accomplished using standard techniques. For example, a neutral compound is treated with an acid or base in a suitable solvent, and the salt formed is isolated by filtration, extraction, or any other suitable method.

[0254] As used herein, the term "solvate" refers to a compound of the present disclosure or a pharmaceutically acceptable salt thereof, wherein the molecules of a suitable solvent are incorporated in the crystal lattice. Suitable solvents are physiologically tolerable at the administered dose. An example of a suitable solvent is ethanol, water, and the like. When water is the solvent, the molecules are referred to as "hydrates." The formation of solvates depends on the compound and the solvate. Typically, solvates are formed by dissolving the compound in an appropriate solvent and isolating the solvate by cooling or using an antisolvent. Solvates are typically dried or co-evaporated under ambient conditions.

[0255] As used herein, the term "subject" includes all members of the animal kingdom, including mammals such as mice, rats, dogs, and humans.

[0256] The terms "suitable" and "appropriate" mean that the selection of a particular group or condition will depend on the particular synthetic operation to be performed and the identity of the molecule, but the selection is well within the skill of a person trained in the art. All process steps described herein will be carried out under conditions suitable to provide the indicated products. It will be understood by those skilled in the art that all reaction conditions, including for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratios, and whether the reaction should be carried out under water-free or inert atmosphere, can be varied in order to optimize the yield of the desired product and are within the skill of the artisan.

[0257] The expression "therapeutically effective amount", "effective amount" or "sufficient amount" of a compound or composition of the present disclosure is an amount sufficient to, when administered to a subject, including a mammal, such as a human, to elicit a beneficial or desired result including a clinical result, and as such, a "therapeutically effective amount" or "effective amount" depends on the context in which it is being applied. For example, in the context of treating a cancer, it is an amount of a compound, peptide compound-conjugate, or composition that is sufficient to effect such treatment of the cancer as compared to the response obtained without administration of the compound, peptide compound-conjugate, or composition. The amount of a given compound, peptide compound-conjugate, or composition of the present disclosure that corresponds to an effective amount will vary depending on factors such as the given drug, peptide compound-conjugate, pharmaceutical formulation, route of administration, type of disease or disorder, identity of the subject or host being treated, and the like, but can nevertheless be routinely determined by one of skill in the art. Furthermore, as used herein, a "therapeutically effective amount" or "effective amount" of a compound, peptide compound-conjugate, or composition of the present disclosure is an amount that inhibits, suppresses, or reduces a subject's cancer (e.g., as determined by clinical symptoms or number of cancer cells) as compared to a control.

[0258] As used herein and as well understood in the art, "treatment" or "treating" is an approach for obtaining beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, decreasing tumor progression, decreasing tumor size, decreasing tumor growth rate, decreasing tumor invasiveness and metastatic potential, alleviation or amelioration of one or more symptoms or conditions, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, prevention of disease spread, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment" or "treating" can also mean prolonging survival as compared to expected survival if not receiving treatment.

[0259] As used herein, the term "tolerance" or "tolerated" refers to the degree to which a therapeutic agent can be tolerated or accepted by a subject being treated with the therapeutic agent. For example, tolerance can be assessed by measuring different parameters such as (i) maintenance or absence of weight loss, (ii) duration of treatment endured, and (iii) reduction or absence of side effects such as, for example, neutropenia. For example, a therapeutic agent has been well established to be tolerated by a subject when no weight loss is observed during treatment with such therapeutic agent. For example, the conjugates of the present disclosure (comprising at least one therapeutic agent) can increase the tolerance of a given therapeutic agent as the conjugates are more selective to the recipient than the therapeutic agent used alone. Unconjugated toxins can be too toxic to be administered or used alone in a subject. Thus, potent toxins can be used in a drug conjugate to increase tolerance. In some embodiments, the therapeutic agent is a toxin selected from the group consisting of maytansinoids, auristatins, calicheamicins, boticins, and amatoxins.

[0260] As used herein, the term "administered" or "administering" refers to the administration of a therapeutically effective amount of a compound, a peptide compound-conjugate, or a composition of the present application to a cell in vitro (e.g., cell culture) or in vivo (e.g., a subject).

[0261] In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be open-ended terms that specify the presence of the stated features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to like terms, such as the terms "comprising," also "including," "containing," "having," and their derivatives, and their hybrids. Finally, as used herein, the terms "substantially," "about," and "approximately" mean an acceptable quantity of deviation away from the stated meaning when used in conjunction with any term and / or adjective that is directly and unequivocally modified thereto. These terms are to be construed as including a reasonable amount of deviation of the modifying term or adjective, such that the end result is not significantly altered. These terms are to be interpreted as including at least ±5% of the modifying term or adjective.

[0262] As used in the specification and the appended claims, the singular forms "a," "an" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, a composition containing "a compound" includes mixtures of two or more compounds. It should also be noted that the term "or" as used in the specification and / or claims is generally used in its sense of "and / or" unless the content clearly dictates otherwise.

[0263] In compositions comprising an "additional" or "second" component, the second component as used herein is chemically distinct from the other components or first component. The "third" component is distinct from the other, first and second components, and further recited or "additional" components are similarly distinct.

[0264] As will be appreciated by those skilled in the art, definitions and embodiments described in particular sections are intended to apply to other embodiments described herein for which they are suitable.

[0265] Numerical ranges as endpoints herein recited by endpoints include all numbers and fractions subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2, 2.75, 3, 3.90, 4, and 5). It is also to be understood that all numbers are presumed to be modified by the term "about."

[0266] A platform was previously developed that allows for the transport of therapeutic agents into cancer cells for novel therapies against primary and secondary tumors. The method utilizes a peptide compound derived from a bacterial protein or receptor ligand expressed in cancer cells (e.g., sortilin / polymeric glycosan).

[0267] Disclosed herein are compositions comprising a solubilizing agent and a peptide compound for treating cancer and compositions comprising a solubilizing agent and a conjugated compound comprising at least one therapeutic agent linked to a peptide compound.

[0268] Accordingly, a first aspect is a peptide compound having at least 60% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII):

[0269] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I) (SEQ ID NO: 1)

[0270] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II) (SEQ ID NO: 2)

[0271] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17L (III) (SEQ ID NO: 3)

[0272] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV) (SEQ ID NO: 4)

[0273] IKLSGGVQAKAGVINMDKSESM (V) (SEQ ID NO: 5)

[0274] IKLSGGVQAKAGVINMFKSESY (VI) (SEQ ID NO: 6)

[0275] IKLSGGVQAKAGVINMFKSESYK (VII) (SEQ ID NO: 7)

[0276] GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8)

[0277] GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9)

[0278] GVRAKAGVRN(Nle)FKSESY (X) (SEQ ID NO: 10)

[0279] YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11)

[0280] YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 12)

[0281] YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 13)

[0282] wherein

[0283] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently selected from any amino acid;

[0284] X 16 , X17 , X 20 and X 21 are independently selected from Q, P, Y, I and L;

[0285] n is 0, 1, 2, 3, 4 or 5;

[0286] when X9is present more than once, each said X9is independently selected from any amino acid;

[0287] when X 19 is present more than once, each said X9is independently selected from any amino acid,

[0288] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to said peptide at the N-terminus and / or C-terminus.

[0289] Another aspect is a composition comprising a solubilizing agent and a peptide compound having at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII):

[0290] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I)(SEQ ID NO:1)

[0291] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II)(SEQ ID NO:2)

[0292] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III)(SEQ ID NO:3)

[0293] YKX 18 LRR(X 19 ) nPLRDPALRX 20 X 21 L (IV)(SEQ ID NO:4)

[0294] IKLSGGVQAKAGVINMDKSESM (V)(SEQ ID NO:5)

[0295] IKLSGGVQAKAGVINMFKSESY (VI)(SEQ ID NO:6)

[0296] IKLSGGVQAKAGVINMFKSESYK (VII)(SEQ ID NO:7)

[0297] GVQAKAGVINMFKSESY (VIII)(SEQ ID NO:8)

[0298] GVRAKAGVRNMFKSESY (IX)(SEQ ID NO:9)

[0299] GVRAKAGVRN(Nle)FKSESY (X)(SEQ ID NO:10)

[0300] YKSLRRKAPRWDAPLRDPALRQLL (XI)(SEQ ID NO:11)

[0301] YKSLRRKAPRWDAYLRDPALRQLL (XII)(SEQ ID NO:12)

[0302] YKSLRRKAPRWDAYLRDPALRPLL (XIII)(SEQ ID NO:13)

[0303] wherein

[0304] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently selected from any amino acid;

[0305] X 16 , X 17 , X 20 and X 21 are independently selected from Q, P, Y, I and L;

[0306] n is 0, 1, 2, 3, 4, or 5;

[0307] each said X9, when present more than once, is independently selected from any amino acid;

[0308] each said X9, when present more than once, is independently selected from any amino acid, 19 each said X9, when present more than once, is independently selected from any amino acid,

[0309] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to said peptide at the N-terminus and / or C-terminus.

[0310] Yet another aspect is a composition comprising a solubilizing agent and a peptide compound having at least 80% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII):

[0311] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I)(SEQ ID NO:1)

[0312] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II)(SEQ ID NO:2)

[0313] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III)(SEQ ID NO:3)

[0314] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV)(SEQ ID NO:4)

[0315] IKLSGGVQAKAGVINMDKSESM (V)(SEQ ID NO:5)

[0316] IKLSGGVQAKAGVINMFKSESY (VI)(SEQ ID NO:6)

[0317] IKLSGGVQAKAGVINMFKSESYK (VII) (SEQ ID NO: 7)

[0318] GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8)

[0319] GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9)

[0320] GVRAKAGVRN(Nle)FKSESY (X) (SEQ ID NO: 10)

[0321] YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11)

[0322] YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 12)

[0323] YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 13)

[0324] wherein

[0325] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently selected from any amino acid;

[0326] X 16 , X 17 , X 20 and X 21 are independently selected from Q, P, Y, I and L;

[0327] n is 0, 1, 2, 3, 4 or 5;

[0328] when X9is present more than once, each said X9is independently selected from any amino acid;

[0329] when X 19 is present more than once, each said X9is independently selected from any amino acid,

[0330] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide at the N-terminus and / or C-terminus.

[0331] In some embodiments, the peptide compound targets a Sortilin receptor. In some embodiments, the peptide compound is used to target a Sortilin receptor.

[0332] For example, the peptide compound is a peptide compound comprising:

[0333] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I) (SEQ ID NO: 1)

[0334] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II) (SEQ ID NO: 2)

[0335] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III) (SEQ ID NO: 3)

[0336] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV) (SEQ ID NO: 4)

[0337] IKLSGGVQAKAGVINMDKSESM (V) (SEQ ID NO: 5)

[0338] IKLSGGVQAKAGVINMFKSESY (VI) (SEQ ID NO: 6)

[0339] IKLSGGVQAKAGVINMFKSESYK (VII) (SEQ ID NO: 7)

[0340] GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8)

[0341] GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9)

[0342] GVRAKAGVRN(Nle)FKSESY (X)(SEQ ID NO: 10)

[0343] YKSLRRKAPRWDAPLRDPALRQLL (XI)(SEQ ID NO: 11)

[0344] YKSLRRKAPRWDAYLRDPALRQLL (XII)(SEQ ID NO: 12) or

[0345] YKSLRRKAPRWDAYLRDPALRPLL (XIII)(SEQ ID NO: 13).

[0346] For example, the peptide compound is a peptide compound consisting essentially of:

[0347] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I)(SEQ ID NO: 1)

[0348] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II)(SEQ ID NO: 2)

[0349] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III)(SEQ ID NO: 3)

[0350] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV)(SEQ ID NO: 4)

[0351] IKLSGGVQAKAGVINMDKSESM (V)(SEQ ID NO: 5)

[0352] IKLSGGVQAKAGVINMFKSESY (VI)(SEQ ID NO: 6)

[0353] IKLSGGVQAKAGVINMFKSESYK (VII)(SEQ ID NO: 7)

[0354] GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8)

[0355] GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9)

[0356] GVRAKAGVRN(Nle)FKSESY (X) (SEQ ID NO: 10)

[0357] YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11)

[0358] YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 12) or

[0359] YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 13).

[0360] For example, the peptide compound is a peptide compound consisting of:

[0361] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I) (SEQ ID NO: 1)

[0362] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II) (SEQ ID NO: 2)

[0363] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (III) (SEQ ID NO: 3)

[0364] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV) (SEQ ID NO: 4)

[0365] IKLSGGVQAKAGVINMDKSESM (V) (SEQ ID NO: 5)

[0366] IKLSGGVQAKAGVINMFKSESY (VI) (SEQ ID NO: 6)

[0367] IKLSGGVQAKAGVINMFKSESYK (VII) (SEQ ID NO: 7)

[0368] GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8)

[0369] GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9)

[0370] GVRAKAGVRN(Nle)FKSESY (X) (SEQ ID NO: 10)

[0371] YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11)

[0372] YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 12) or

[0373] YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 13).

[0374] For example, the peptide compound comprises a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII):

[0375] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (I) (SEQ ID NO: 1)

[0376] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (II) (SEQ ID NO: 2)

[0377] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17L (III) (SEQ ID NO: 3)

[0378] YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L (IV) (SEQ ID NO: 4)

[0379] IKLSGGVQAKAGVINMDKSESM (V) (SEQ ID NO: 5)

[0380] IKLSGGVQAKAGVINMFKSESY (VI) (SEQ ID NO: 6)

[0381] IKLSGGVQAKAGVINMFKSESYK (VII) (SEQ ID NO: 7)

[0382] GVQAKAGVINMFKSESY (VIII) (SEQ ID NO: 8)

[0383] GVRAKAGVRNMFKSESY (IX) (SEQ ID NO: 9)

[0384] GVRAKAGVRN(Nle)FKSESY (X) (SEQ ID NO: 10)

[0385] YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11)

[0386] YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 12)

[0387] YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 13)

[0388] wherein

[0389] X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 18 and X 19 are independently selected from any amino acid;

[0390] X 16 , X17 , X 20 and X 21 are independently selected from Q, P, Y, I and L;

[0391] n is 0, 1, 2, 3, 4 or 5;

[0392] when X9is present more than once, each said X9is independently selected from any amino acid;

[0393] when X 19 is present more than once, each said X9is independently selected from any amino acid,

[0394] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to said peptide at the N-terminus and / or C-terminus.

[0395] For example, a peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound selected from the group consisting of a peptide compound of Formula (I), a peptide compound of Formula (II), a peptide compound of Formula (III), a peptide compound of Formula (IV), a peptide compound of Formula (V), a peptide compound of Formula (VI), a peptide compound of Formula (VII), a peptide compound of Formula (VIII), a peptide compound of Formula (IX), a peptide compound of Formula (X), a peptide compound of Formula (XI), a peptide compound of Formula (XII), and a peptide compound of Formula (XIII).

[0396] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (I) or SEQ ID NO: 1.

[0397] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (II) or SEQ ID NO: 2.

[0398] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (III) or SEQ ID NO: 3.

[0399] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (IV) or SEQ ID NO: 4.

[0400] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (V) or SEQ ID NO: 5.

[0401] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (VI) or SEQ ID NO: 6.

[0402] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (VII) or SEQ ID NO: 7.

[0403] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (VIII) or SEQ ID NO: 8.

[0404] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (IX) or SEQ ID NO: 9.

[0405] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (X) or SEQ ID NO: 10.

[0406] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (XI) or SEQ ID NO: 11.

[0407] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (XII) or SEQ ID NO: 12.

[0408] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (XIII) or SEQ ID NO: 13.

[0409] For example, the peptide compound has at least 60%, at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, 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% sequence identity to a peptide compound represented by Formula (LI) or SEQ ID NO: 23.

[0410] In one embodiment, n is 0. In one embodiment, n is 1. In one embodiment, n is 2. In one embodiment, n is 3. In one embodiment, n is 4. In one embodiment, n is 5.

[0411] In one embodiment, the peptide compound is represented by Formula (I) or Formula (II). In one embodiment, the peptide compound is represented by Formula (I) or SEQ ID NO: 1. In one embodiment, the peptide compound is represented by Formula (II) or SEQ ID NO: 2. In one embodiment, the peptide compound is represented by Formula (III) or Formula (IV). In one embodiment, the peptide compound is represented by Formula (III). In one embodiment, the peptide compound is represented by Formula (IV). In one embodiment, the peptide compound is represented by Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), or Formula (X). In one embodiment, the peptide compound is represented by Formula (V). In one embodiment, the peptide compound is represented by Formula (VI). In one embodiment, the peptide compound is represented by Formula (VII). In one embodiment, the peptide compound is represented by Formula (VIII). In one embodiment, the peptide compound is represented by Formula (IX). In one embodiment, the peptide compound is represented by Formula (X). In one embodiment, the peptide compound is represented by Formula (XI), Formula (XII), or Formula (XIII). In one embodiment, the peptide compound is represented by Formula (XI). In one embodiment, the peptide compound is represented by Formula (XII). In one embodiment, the peptide compound is represented by Formula (XIII). In one embodiment, the peptide compound is represented by Formula (LI).

[0412] In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 1. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 2. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 3. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 4. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 5. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 6. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 7. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 8. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 9. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 10. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 11. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 12. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 13. In one embodiment, the peptide compound is represented by the amino acid sequence of SEQ ID NO: 23.

[0413] In one embodiment, at least one protecting group is attached to the peptide at the N-terminus and / or the C-terminus.

[0414] In one embodiment, an acetyl group is attached to the peptide compound. For example, the peptide compound has the sequence acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14). For example, the peptide compound has the sequence acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15). For example, the peptide compound has the sequence acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16). For example, the peptide compound has the sequence acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17). For example, the peptide compound has the sequence acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 18).

[0415] In one embodiment, an acetyl group is attached to the peptide compound. For example, the peptide compound has the sequence acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14). For example, the peptide compound has the sequence acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15). For example, the peptide compound has the sequence acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16). For example, the peptide compound has the sequence acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17). For example, the peptide compound has the sequence acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 18).

[0416] In one embodiment, at least one protecting group is attached to the peptide at the N-terminus and / or the C-terminus.

[0417] The skilled person will appreciate that common labelling agents can be used. For example, the labelling agent is a vitamin. For example, the labelling agent is biotin. For example, the labelling agent is used as a fluorescent probe and / or an imaging agent.

[0418] In one embodiment, the peptide compound is biotinylated. For example, the peptide compound has the sequence IKLSGGVQAKAGVINMFKSESYK (biotin) which corresponds to SEQ ID NO: 7 and has a biotin molecule attached to it at the C-terminus.

[0419] For example, the peptide compound is represented by formula (XXXVI):

[0420] succinyl-IKLSGGVQAKAGVINMFKSESY (XXXVI)

[0421] which comprises a peptide compound having SEQ ID NO: 6, wherein a succinyl group is attached at the N-terminus.

[0422] In one embodiment, X 16 is independently selected from Q, P, Y, I and L.

[0423] For example, X 16is Q. For example, X 16 is P. For example, X 16 is Y. For example, X 16 is I.

[0424] In one embodiment, X 17 is independently selected from Q, P, Y, I, and L.

[0425] For example, X 17 is Q. For example, X 17 is P. For example, X 17 is Y. For example, X 17 is I.

[0426] In one embodiment, X 20 is independently selected from Q, P, Y, I, and L.

[0427] For example, X 20 is Q. For example, X 20 is P. For example, X 20 is Y. For example, X 20 is I.

[0428] In one embodiment, X 21 is independently selected from Q, P, Y, I, and L.

[0429] For example, X 21 is Q. For example, X 21 is P. For example, X 21 is Y. For example, X 21 is I.

[0430] In one embodiment, the peptide compound is selected from:

[0431] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY (SEQ ID NO: 1);

[0432] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (SEQ ID NO: 2);

[0433] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L (SEQ ID NO: 3);

[0434] YKX 18 LRR(X 19 ) nPLRDPALRX 20 X 21 L (SEQ ID NO:4);

[0435] IKLSGGVQAKAGVINMDKSESM (SEQ ID NO:5);

[0436] succinyl-IKLSGGVQAKAGVINMFKSESY (which comprises SEQ ID NO: 6, with a succinyl group attached at the N-terminus thereto);

[0437] IKLSGGVQAKAGVINMFKSESYK (biotin) (which comprises SEQ ID NO: 7, with a biotin molecule attached at the C-terminus thereto);

[0438] GVQAKAGVINMFKSESY (SEQ ID NO:8);

[0439] acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14);

[0440] acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15);

[0441] acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16);

[0442] acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17);

[0443] acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 18);

[0444] GVRAKAGVRN(Nle)FKSESYC (SEQ ID NO: 23); and

[0445] acetyl-GVRAKAGVRN(Nle)FKSESYC (SEQ ID NO: 24).

[0446] In one embodiment, the peptide compound can be modified at the C-terminus and / or N-terminus by the addition of one or more amino acid residues to obtain or increase the preferential binding site at the peptide terminus. For example, the amino acid can be cysteine. For example, the amino acid can be lysine. For example, the amino acid can be a cysteine added at the C-terminus of the peptide. In one embodiment, the peptide compound is modified by the addition of a cysteine at the C-terminus. In one particular embodiment, the peptide compound has the sequence acetyl-GVRAKAGVRN(Nle)FKSESY, which corresponds to SEQ ID NO: 15, modified by the addition of a cysteine at the C-terminus.

[0447] The peptide compounds described herein can be associated, linked, mixed or conjugated with a small molecule, a peptide, a protein, an oligonucleotide, a diagnostic agent, an imaging agent or a radionuclide agent, a macromolecule such as a monoclonal antibody, a therapeutic agent such as a phytochemical or with a drug delivery system including nanoparticles, liposomes, nanotubes, graphene particles loaded with therapeutic agents, imaging agents, genes, siRNA. The resulting conjugate can be used as a monotherapy or a combination therapy, for example, for the treatment of cancer.

[0448] Thus, another aspect disclosed herein is a conjugate compound having the formula A-(B) n ,

[0449] wherein

[0450] n is 1, 2, 3 or 4;

[0451] A is a peptide compound as defined herein, wherein the peptide is optionally protected with a protecting group; and

[0452] B is at least one therapeutic agent, wherein B is linked to A,

[0453] Optionally, the peptide compound is cyclic.

[0454] Yet another aspect disclosed herein is a conjugate compound having the formula A-(B) n ,

[0455] wherein

[0456] n is 1, 2, 3 or 4;

[0457] A is a peptide compound as defined herein, wherein the peptide is optionally protected with a protecting group; and

[0458] B is at least one therapeutic agent, wherein B is linked to A, optionally at a free amine of the peptide compound, at an N-terminal position of the peptide compound, at a free -SH of the peptide compound or at a free carboxyl of the peptide compound,

[0459] Optionally, the peptide compound is cyclic.

[0460] In some embodiments, the conjugate peptides described herein target Sortilin receptors. In some embodiments, the conjugate peptides described herein are used to target Sortilin receptors.

[0461] Yet another aspect disclosed herein is a conjugate compound having the formula A-(B) n

[0462] wherein

[0463] n is 1, 2, 3, or 4;

[0464] A is a peptide compound as defined herein; and

[0465] B is at least one therapeutic agent, wherein B is linked to A at a free amine of a lysine residue of the peptide compound, optionally through a linker, or at an N-terminal position of the peptide compound, optionally through a linker,

[0466] Optionally, the peptide compound is cyclic,

[0467] for treating cancer or an aggressive cancer.

[0468] In one embodiment, B is linked to A through a linker, which is optionally a cleavable linker.

[0469] For example, the at least one therapeutic agent is a phytochemical selected from the group consisting of curcumin, omega-3, white willow bark, green tea, catechin, pyrodioxane, boswellia serrata resin, resveratrol, Uncaria tomentosa, capsaicin, anthocyanin, flavonoid, olive oil compounds, chlorogenic acid, and sulforaphane.

[0470] In one embodiment, the therapeutic agent is a phytochemical or an anti-cancer agent.

[0471] In one embodiment, the phytochemical is curcumin.

[0472] In one embodiment, the conjugate compound is selected from the group consisting of:

[0473] GVRAK (curcumin) AGVRN (Nle) FK (curcumin) SESY - Formula (XIV)

[0474] comprising a peptide compound having SEQ ID NO: 10, wherein each lysine residue has a curcumin molecule linked thereto; and

[0475] YK (curcumin) SLRRK (curcumin) APRWDAPLRDPALRQLL - Formula (XV)

[0476] ​comprises a peptide compound having SEQ ID NO: 11, wherein each lysine residue has a curcumin molecule attached thereto.

[0477] For example, the conjugated compound is represented by formula (XIV).

[0478] For example, the conjugated compound is represented by formula (XV).

[0479] In one embodiment, the conjugated compound is selected from:

[0480] Acetyl-GVRAK(curcumin)AGVRN(Nle)FK(curcumin)SESY - Formula (XVI)

[0481] comprises a peptide compound having SEQ ID NO: 15, wherein each lysine residue has a curcumin molecule attached thereto, and

[0482] Acetyl-YK(curcumin)SLRRK(curcumin)APRWDAPLRDPALRQLL - Formula (XVII)

[0483] comprises a peptide compound having SEQ ID NO: 16, wherein each lysine residue has a curcumin molecule attached thereto.

[0484] For example, the conjugated compound is represented by formula (XVI).

[0485] For example, the conjugated compound is represented by formula (XVII).

[0486] In one embodiment, the therapeutic agent is an anti-cancer agent.

[0487] In one embodiment, the anti-cancer agent is docetaxel.

[0488] In one embodiment, the conjugated compound is represented by formula (XIX):

[0489] GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY - Formula (XIX)

[0490] comprises a peptide compound having SEQ ID NO: 10, wherein each lysine residue has a docetaxel molecule attached thereto.

[0491] In another embodiment, the conjugated compound is represented by formula (XXIII):

[0492] Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY - Formula (XXIII)

[0493] comprises a peptide compound having SEQ ID NO: 15, wherein each lysine residue has a docetaxel molecule attached thereto.

[0494] In one embodiment, the anti-cancer agent is doxorubicin.

[0495] In one embodiment, the conjugated compound is represented by formula (XXVI):

[0496] Acetyl-GVRAKAGVRN(Nle)FKSESYC(doxorubicin) - Formula (XXVI)

[0497] comprises a peptide compound having SEQ ID NO: 15, wherein each lysine residue has a doxorubicin molecule attached thereto.

[0498] In another embodiment, the conjugated compound is represented by formula (XXVIII):

[0499] Acetyl-GVRAKAGVRN(Nle)FKSESYC(doxorubicin) - Formula (XXVI)

[0500] comprises a peptide compound having SEQ ID NO: 15, wherein each lysine residue has a doxorubicin molecule attached thereto.

[0501] In one embodiment, the anti-cancer agent is cabazitaxel.

[0502] In one embodiment, the anti-cancer agent is doxorubicin.

[0503] In one embodiment, the conjugated compound is represented by formula (LI):

[0504] GVRAKAGVRN(Nle)FKSESYC(doxorubicin) - Formula (LI)

[0505] comprises a peptide compound having SEQ ID NO: 23, wherein the cysteine residue has a doxorubicin molecule attached thereto, or

[0506] comprises a peptide compound having SEQ ID NO: 10, wherein a cysteine residue is added to the C-terminus of the peptide compound, and wherein the cysteine residue has a doxorubicin molecule attached thereto.

[0507] In one embodiment, the conjugated compound is represented by formula (LII):

[0508] Acetyl-GVRAKAGVRN(Nle)FKSESYC(doxorubicin) - Formula (XXVI)

[0509] comprises a peptide compound having SEQ ID NO: 24, wherein the cysteine residue has a doxorubicin molecule attached thereto, or

[0510] comprises a peptide compound having SEQ ID NO: 15, wherein a cysteine residue is added to the C-terminal end of the peptide compound, and wherein the cysteine residue has a doxorubicin molecule attached thereto.

[0511] In one embodiment, at least one therapeutic agent B is linked to peptide compound A at the free amine of the lysine residue of the peptide compound via a linker.

[0512] In one embodiment, at least one therapeutic agent B is linked to peptide compound A at the N-terminal position of the peptide compound via a linker.

[0513] In one embodiment, the linker is selected from the group consisting of a succinic acid and a dimethyl glutaric acid linker.

[0514] For example, the linker is a cleavable linker. For example, the linker is a non-cleavable linker.

[0515] For example, the conjugated compound can comprise a cleavable linker linking the at least one therapeutic agent to the peptide compound. For example, the at least one therapeutic agent can be released from the peptide compound by action of an esterase on an ester bond.

[0516] For example, the therapeutic agent can be conjugated to the peptide compound at a free amine available at the lysine or amino terminus by formation of a bond such as a peptide bond.

[0517] In one embodiment, wherein B is linked to A’ via a linker, the linker is optionally a cleavable linker or a non-cleavable linker. In one embodiment, the at least one therapeutic agent is an anti-cancer agent. In one embodiment, the anti-cancer agent is docetaxel, doxorubicin, cabazitaxel, adozelesin, maytansinoid, auristatin, calicheamicin, amatoxin, and oligopeptide mimetic (e.g. tubulysin). In one embodiment, the at least one therapeutic agent is a phytochemical, optionally curcumin. In one embodiment, the anti-cancer agent is docetaxel. In one embodiment, the anti-cancer agent is doxorubicin. In one embodiment, the anti-cancer agent is cabazitaxel. In one embodiment, the anti-cancer agent is adozelesin.

[0518] In one embodiment, the conjugated compound comprises 1 molecule of therapeutic agent linked to the peptide compound. In one embodiment, the conjugated compound comprises at least 1 molecule of therapeutic agent linked to the peptide compound. In one embodiment, the conjugated compound comprises at most 8 molecules of therapeutic agent linked to the peptide compound.

[0519] In one embodiment, the conjugated compound comprises 2 therapeutic agent molecules linked to the peptide compound. In one embodiment, the conjugated compound comprises 3 therapeutic agent molecules linked to the peptide compound. In one embodiment, the conjugated compound comprises 4 therapeutic agent molecules linked to the peptide compound. In one embodiment, the conjugated compound comprises 1-8 therapeutic agent molecules linked to the peptide compound.

[0520] In one aspect, the compounds described herein target Sortilin receptors. In one aspect, the compounds described herein are used to target Sortilin receptors.

[0521] In one aspect, the compounds described herein are used to treat cancer or an aggressive cancer.

[0522] For example, the Sortilin-expressing cell is an immune cell, optionally a macrophage, CD4+, CD8+, B220+, myeloid-derived cell basophil, eosinophil, and cytotoxic T lymphocyte, natural killer (NK) cell, T helper type 1 (Th1) cell.

[0523] For example, the Sortilin-expressing cell is a cancer cell, optionally an ovarian cancer cell, endometrial cancer cell, breast cancer cell (e.g., triple negative breast cancer cell, optionally HCC1599, HCC1937, HCC1143, MDA-MB468, HCC38, HCC70, HCC1806, HCC1187, DU4475, BT-549, Hs578T, MDA-MB231, MDA-MB436, MDA-MB157, MDA-MB453, BT-20, or HCC1395 cell), prostate cancer cell, colorectal cancer cell, lung cancer cell, pancreatic cancer cell, skin cancer cell, brain (glioma) cancer cell, urothelial cancer cell, carcinoid cancer cell, kidney cancer cell, testicular cancer cell, pituitary cancer cell, and blood cancer cell such as myeloid cancer cell, diffuse large B-cell lymphoma cancer cell, myeloma cancer cell, or chronic B-cell leukemia cancer cell.

[0524] For example, the Sortilin-expressing cell is a cancer cell, optionally an ovarian cancer cell, endometrial cancer cell, breast cancer cell (e.g., triple negative breast cancer cell), prostate cancer cell, colorectal cancer cell, lung cancer cell, pancreatic cancer cell, skin cancer cell, brain (glioma) cancer cell, urothelial cancer cell, carcinoid cancer cell, kidney cancer cell, testicular cancer cell, pituitary cancer cell, and blood cancer cell such as myeloid cancer cell, diffuse large B-cell lymphoma cancer cell, myeloma cancer cell, or chronic B-cell leukemia cancer cell.

[0525] For example, the triple negative breast cancer cells are HCC1599, HCC1937, HCC1143, MDA-MB468, HCC38, HCC70, HCC1806, HCC1187, DU4475, BT-549, Hs578T, MDA-MB231, MDA-MB436, MDA-MB157, MDA-MB453, BT-20, or HCC1395 cells.

[0526] The conjugate compounds disclosed herein can also be used to transport a therapeutic agent into a cell as they are not a substrate for efflux pumps, such as the P-glycoprotein membrane transport pump, which pumps out other therapeutic agents from multidrug resistant cells.

[0527] In one aspect, there is provided a method for obtaining a peptide compound, comprising i) providing a library of binding peptides; and ii) selecting a sortilin binding peptide from the library using a target by affinity selection;

[0528] wherein the target is immobilized on a solid support;

[0529] wherein the target consists of an amino acid sequence as set forth in any one of SEQ ID NOs: 25-50, an analogue thereof, or a fragment thereof; and

[0530] wherein the target interacts with the sortilin binding peptide.

[0531] In another aspect, there is provided a process for preparing a conjugate compound conjugate disclosed herein, the process comprising:

[0532] reacting a linker with the therapeutic agent to obtain an intermediate;

[0533] optionally purifying the intermediate;

[0534] reacting the intermediate with a peptide compound to obtain the conjugate; and

[0535] optionally purifying the conjugate compound conjugate,

[0536] wherein the therapeutic agent is linked to the peptide compound at a free amine of a lysine residue or at the N-terminus; and wherein the peptide compound comprises 1, 2, 3, or 4 therapeutic agent molecules linked thereto.

[0537] For example, the peptide compound comprises 1 therapeutic agent molecule linked thereto. For example, the peptide compound comprises 2 therapeutic agent molecules linked thereto. For example, the peptide compound comprises 3 therapeutic agent molecules linked thereto. For example, the peptide compound comprises 4 therapeutic agent molecules linked thereto.

[0538] For example, the linker is succinic acid. For example, the linker is a dimethyl glutaric acid linker.

[0539] In one embodiment, the peptide compound is protected at the N-terminus prior to reaction with the intermediate.

[0540] For example, a protecting group such as FMOC can be added as a protecting group to a free amine on the therapeutic agent prior to conjugation to the linker. Following its synthesis, the conjugated compound can undergo deprotection of the protecting group. For example, a conjugated compound comprising the protecting agent FMOC can be deprotected using piperidine. Those of skill in the art will readily appreciate that other known chemical reagents can be used for deprotection of the conjugated compound.

[0541] For example, the peptide compound can be capped by acetylation of the N-terminus of the therapeutic agent, thereby providing an irreversible protecting group at the N-terminus.

[0542] In one embodiment, the intermediate is activated prior to reaction with the peptide compound.

[0543] For example, the intermediate is activated prior to reaction of the compound with a coupling agent, which is optionally selected from N,N,N',N'-tetramethyl-O-(benzotriazol-1-yl)uronium tetrafluoroborate (TBTU), (2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (HBTU), and (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate) (HATU).

[0544] For example, the intermediate comprising the therapeutic agent linked to the linker can be activated with the peptide coupling agent TBTU prior to conjugation to the peptide compound.

[0545] In one embodiment, the conjugated compound is purified following its synthesis.

[0546] The peptide compounds disclosed herein can be used in the context of fusion proteins. For example, a fusion protein can be engineered by fusing a peptide compound disclosed herein (e.g., a peptide compound) to one or more proteins or portions thereof, such as functional domains. The fusion protein can be engineered, for example, by recombinant DNA technology, and expressed using a protein expression system, such as a bacterial or mammalian protein expression system. In some embodiments, a peptide linker is added between the proteins. In other embodiments, the fusion protein does not comprise a linker connecting the proteins.

[0547] Commonly used protein expression systems include those derived from bacteria, yeast, baculovirus / insect, plant, and mammalian cells, and more recently filamentous fungi such as Myceliopthora thermophila.

[0548] One aspect disclosed herein is a composition comprising a solubilizing agent and a liposome, graphene, nanotube or nanoparticle comprising at least one peptide compound disclosed herein for use in the treatment of cancer.

[0549] One aspect disclosed herein is a composition comprising a solubilizing agent and a liposome, graphene, nanotube or nanoparticle comprising at least one peptide compound disclosed herein for use in targeting Sortilin receptors.

[0550] One aspect disclosed herein is a composition comprising a solubilizing agent and a liposome, graphene, nanotube or nanoparticle comprising at least one peptide compound disclosed herein for use in targeting Sortilin receptors.

[0551] Another aspect is a composition for use in the treatment of cancer comprising a solubilizing agent and a liposome, graphene, nanotube or nanoparticle coated with at least one compound disclosed herein.

[0552] Another aspect is a composition for use in targeting Sortilin receptors comprising a solubilizing agent and a liposome, graphene, nanotube or nanoparticle coated with at least one compound disclosed herein.

[0553] Another aspect is a composition for use in targeting Sortilin receptors comprising a solubilizing agent and a liposome, graphene, nanotube or nanoparticle coated with at least one compound disclosed herein.

[0554] Another aspect is a composition for use in the treatment of cancer comprising a solubilizing agent and a liposome, graphene, nanotube or nanoparticle loaded with at least one therapeutic agent, gene or siRNA; and the liposome or nanoparticle is coated with at least one compound as defined herein.

[0555] Different embodiments of liposomes, nanotubes, graphene, or nanoparticles can be envisioned by one of skill in the art. For example, a liposome or nanoparticle can comprise at least one compound disclosed herein coated on the surface of the liposome or nanoparticle and a therapeutic agent, e.g., an anticancer agent, within the liposome or nanoparticle. For example, a liposome or nanoparticle can comprise at least one peptide compound disclosed herein coated on the surface of the liposome or nanoparticle and a therapeutic agent, e.g., an anticancer agent, within the liposome or nanoparticle. For example, a liposome or nanoparticle can comprise at least one conjugated compound disclosed herein coated on the surface of the liposome or nanoparticle and a therapeutic agent, e.g., an anticancer agent, within the liposome or nanoparticle. For example, a liposome or nanoparticle can comprise at least one compound disclosed herein coated on the surface of the liposome or nanoparticle and a therapeutic agent, e.g., an anticancer agent, within the liposome or nanoparticle. Furthermore, in some embodiments, the compounds described herein can be associated, linked, or related to one or more other compounds to form multimers, such as dimers, trimers, or tetramers, as well as branched peptides, optionally the peptide compound is cyclic. Such compounds can be linked together, e.g., by a covalent bond, atom, or linker. For example, a multimer comprises more than one compound. Methods for making peptide compounds in the form of multimers, e.g., dimers, trimers, are described in U.S. Patent No. 9,161,988, which is incorporated by reference herein in its entirety.

[0556] Other aspects of the present disclosure generally include methods of treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of at least one disclosed composition or compound and / or contacting a Sortilin-expressing cell with at least one composition or compound disclosed herein. Other aspects include the use of the compositions, peptide compounds, conjugated compounds described herein for treating cancer and in the manufacture of a medicament for treating cancer.

[0557] In some aspects, the solubilizing agent is present in an amount of about 5% to about 15% by weight, per total volume of the composition. In other aspects, the solubilizing agent is present in an amount of about 8% to about 12% by weight, per total volume of the composition. In other aspects, the solubilizing agent is present in an amount of about 9% to about 11% by weight, per total volume of the composition. In other aspects, the solubilizing agent is present in an amount of about 10% by weight, per total volume of the composition.

[0558] In some aspects, the conjugated compound is present in an amount of about 0.1 w / w% to about 5 w / w% based on the total weight of the composition. In some aspects, the conjugated compound is present in an amount of about 0.5 w / w% to about 2.5 w / w% based on the total weight of the composition. In some aspects, the conjugated compound is present in an amount of about 0.5 w / w% to about 1.5 w / w% based on the total weight of the composition. In some aspects, the conjugated compound is present in an amount of about 0.8 w / w% to about 1.2 w / w% based on the total weight of the composition. In some aspects, the conjugated compound is present in an amount of about 0.9 w / w% to about 1.1 w / w% based on the total weight of the composition.

[0559] In some aspects, the composition further comprises a solution suitable for injection present in an amount of about 1% by weight to about 10% by weight based on the total volume of the composition. In some aspects, the composition further comprises a solution suitable for injection present in an amount of about 2% by weight to about 8% by weight based on the total volume of the composition. In some aspects, the composition further comprises a solution suitable for injection present in an amount of about 3% by weight to about 7% by weight based on the total volume of the composition. In some aspects, the composition further comprises a solution suitable for injection present in an amount of about 4% by weight to about 6% by weight based on the total volume of the composition. In some aspects, the composition further comprises a solution suitable for injection present in an amount of about 5% by weight based on the total volume of the composition.

[0560] In some aspects, the solubilizing agent is selected from the group consisting of polysorbate (Tween TM ), polyethylene glycol (15)-hydroxystearate (Solutol TM ), dimethyl sulfoxide (DMSO), water soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide and dimethyl sulfoxide), non-ionic surfactants (Cremophor TM EL, Cremophor TM RH 40, Cremophor TM RH 60, d-a-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol TM HS 15, sorbitan monooleate, poloxamer 407, Labrafil TM M-1944CS, Labrafil TM M-2125CS, Labrasol TM , Gellucire TM 44 / 14, Softigen TM767, and mono- and di-fatty acid esters of PEG 300, 400, or 1750), water-insoluble lipids (castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and medium-chain triglycerides of coconut oil and palm seed oil), organic liquids / semi-solids (beeswax, d-a-tocopherol, oleic acid, medium-chain mono- and diglycerides), cyclodextrins (a-cyclodextrin, b-cyclodextrin, hydroxypropyl-b-cyclodextrin, and sulfobutyl ether-b-cyclodextrin), phospholipids (hydrogenated soy lecithin, distearoyl phosphatidylglycerol, L-a-dimyristoyl phosphatidylcholine, L-a-dimyristoyl phosphatidylglycerol).

[0561] In some aspects, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0562] In some aspects, the composition of the present application further comprises a buffer selected from the group consisting of acetate buffer, borate buffer, citrate buffer, glycine buffer, HEPES buffer, phosphate buffer, Tris buffer, AES, ammonia, AMP, AMPD, AMPSO, BES, bicarbonate Bicine, BIS-Tris BIS-Tris-propane borate, cacodylate, CAPS, CAPSO carbonate, CHES, citrate, DIPSO, formate, glycine bicine HEPES, HEPPS, EPPS HEPPSO imidazole malate, maleate, MES, MOPS, MOPSO phosphate, PIPES, POPSO, phosphate, pyridine succinate, TAPS, TAPSO, taurine, TEA, TES, Tricine, Tris, and mixtures thereof.

[0563] In some aspects, the composition of the present application further comprises a glucose solution (e.g., D5W), a sodium lactate solution (lactated Ringer’s solution), saline, water, ethanol, acetic acid, formic acid, sodium hydroxide, and mixtures thereof.

[0564] In some aspects, the composition is an aqueous solution having a pH of about 3 to about 5. In some aspects, the composition is an aqueous solution having a pH of about 3.5 to about 4.5. In some aspects, the composition is an aqueous solution having a pH of about 3.75 to about 4.25. In some aspects, the composition is an aqueous solution having a pH of about 3.8 to about 4.1.

[0565] In some aspects, the composition comprises a polysorbate, a glucose solution, formic acid, sodium hydroxide, and optionally water.

[0566] In some aspects, the polysorbate is present in an amount of about 5% to about 15% by weight, per total volume of the composition. In other aspects, the polysorbate is present in an amount of about 8% to about 12% by weight, per total volume of the composition. In other aspects, the polysorbate is present in an amount of about 9% to about 11% by weight, per total volume of the composition. In other aspects, the polysorbate is present in an amount of about 10% by weight, per total volume of the composition.

[0567] In some aspects, the glucose solution has a concentration of about 2% to about 8% and is present in an amount of about 2% to about 8% by weight, per total volume of the composition. In other aspects, the glucose solution has a concentration of about 4% to about 6% and is present in an amount of about 4% to about 6% by weight, per total volume of the composition. In some aspects, the glucose solution has a concentration of about 5% and is present in an amount of about 5% by weight, per total volume of the composition.

[0568] In some aspects, the formic acid is present in an amount of about 0.02% to about 0.06% by volume, per total volume of the composition. In some aspects, the formic acid is present in an amount of about 0.03% to about 0.05% by volume, per total volume of the composition. In some aspects, the formic acid is present in an amount of about 0.04% by volume, per total volume of the composition.

[0569] In some aspects, the sodium hydroxide is in a solution having a concentration of about 0.05N to about 1.5N and is present in an amount such that the composition has a pH of about 4 to about 4.6. In some aspects, the sodium hydroxide is in a solution having a concentration of about 0.1N to about 1N. In some aspects, the sodium hydroxide is in a solution having a concentration of about 0.1N. In some aspects, the sodium hydroxide is in a solution having a concentration of about 1N. In some aspects, the sodium hydroxide solution is present in an amount such that the composition has a pH of about 4.1 to about 4.5. In some aspects, the sodium hydroxide solution is present in an amount such that the composition has a pH of about 4.3.

[0570] In some aspects, the composition comprises polysorbate 80 present in an amount of about 10% by weight, per total volume of the composition, a glucose solution having a concentration of about 5% and present in an amount of about 5% by weight, per total volume of the composition, formic acid present in an amount of about 0.04% by volume, per total volume of the composition, sodium hydroxide in a solution having a concentration of about 0.1N to about 1N and present in an amount such that the composition has a pH of about 4.1 to about 4.5, and optionally water or diluent.

[0571] In one aspect, there is provided a method of treating a cancer or an aggressive cancer, comprising administering to a subject in need thereof a therapeutically effective amount of at least one composition or compound as defined herein.

[0572] In another aspect, there is provided a method of treating a cancer or an aggressive cancer in a subject having a Sortilin-expressing cancer tissue or cell, comprising contacting the cancer tissue or cell with at least one composition or compound as defined herein.

[0573] In another aspect, there is provided a method of treating a cancer or an aggressive cancer in a subject having a Sortilin-expressing cancer tissue or cell, comprising contacting the cancer tissue or cell with at least one composition or compound as defined herein.

[0574] In another aspect, there is provided a method of treating a cancer or an aggressive cancer in a subject having a Sortilin-expressing cancer tissue or cell, comprising contacting the cancer tissue or cell with at least one composition or compound as defined herein.

[0575] In another aspect, there is provided a method of minimizing, reducing or decreasing tumor regrowth, comprising administering to a subject in need thereof a therapeutically effective amount of a composition as defined herein.

[0576] In some aspects, the composition is administered at a dose of about 1 mg / kg / week to about 100 mg / kg / week. In some aspects, the composition is administered at a dose of about 2 mg / kg / week to about 40 mg / kg / week. In other aspects, the composition is administered at a dose of about 5 mg / kg / week to about 10 mg / kg / week. In other aspects, the composition is administered at a dose of about 5 mg / kg / week to about 25 mg / kg / week. In other aspects, the composition is administered at a dose of about 10 mg / kg / week to about 20 mg / kg / week. In other aspects, the composition is administered at a dose of about 10 mg / kg / week to about 75 mg / kg / week. In other aspects, the composition is administered at a dose of about 35 mg / kg / week to about 50 mg / kg / week.

[0577] In other aspects, the composition is administered at a dose of about 3 mg / kg / three weeks to about 300 mg / kg / three weeks. In other aspects, the composition is administered at a dose of about 6 mg / kg / three weeks to about 240 mg / kg / three weeks. In other aspects, the composition is administered at a dose of about 15 mg / kg / three weeks to about 30 mg / kg / three weeks. In other aspects, the composition is administered at a dose of about 15 mg / kg / three weeks to about 75 mg / kg / three weeks. In other aspects, the composition is administered at a dose of about 30 mg / kg / three weeks to about 60 mg / kg / three weeks. In other aspects, the composition is administered at a dose of about 30 mg / kg / three weeks to about 225 mg / kg / three weeks. In other aspects, the composition is administered at a dose of about 105 mg / kg / three weeks to about 150 mg / kg / three weeks.

[0578] In some aspects, the dose is defined in terms of the active ingredient in the composition. For example, for an exemplary formulation of a conjugated compound comprising docetaxel (TH1902), about 44% of the total weight of the conjugated compound corresponds to one docetaxel molecule. In other words, 1 equivalent of docetaxel weighs about 2.33 times the weight of the conjugate TH1902, i.e., 1 g of docetaxel = about 2.33 g of TH1902.

[0579] In some aspects, the composition is administered at a dose of about 3 mg / mm 2 / week to about 300 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 5 mg / mm 2 / week to about 210 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 75 mg / mm 2 / week to about 150 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 10 mg / mm 2 / week to about 300 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 30 mg / mm 2 / week to about 150 mg / mm 2 / week.

[0580] In some aspects, the composition is administered at a dose of about 10 mg / mm 2 / week to about 1000 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 15 mg / mm 2 / week to about 500 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 10 mg / mm 2 / week to about 250 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 10 mg / mm 2 / week to about 500 mg / mm 2 / week. In other aspects, the composition is administered at a dose of about 50 mg / mm 2 / week to about 450 mg / mm 2 / week.

[0581] In some aspects, the composition prevents tumor growth or progression for a period of at least 10 days after treatment. In some aspects, the composition prevents tumor growth or progression for a period of at least 20 days after treatment. In other aspects, the composition prevents tumor growth or progression for a period of at least 30 days after treatment. In other aspects, the composition prevents tumor growth or progression for a period of at least 40 days after treatment.

[0582] In some aspects, the composition prevents tumor growth or progression for a period of about 10 to about 50 days after treatment. In other aspects, the composition prevents tumor growth or progression for a period of about 10 to about 25 days after treatment. In other aspects, the composition prevents tumor growth or progression for a period of about 10 to about 20 days after treatment. In other aspects, the composition prevents tumor growth or progression for a period of about 10 to about 15 days after treatment.

[0583] In some aspects, the composition effectively reduces tumor size for a period of at least 10 days after treatment. In other aspects, the composition effectively reduces tumor size for a period of at least 20 days after treatment. In other aspects, the composition effectively reduces tumor size for a period of at least 30 days after treatment. In other aspects, the composition effectively reduces tumor size for a period of at least 40 days after treatment.

[0584] In some aspects, the composition effectively reduces tumor size for a period of about 10 to about 50 days after treatment. In other aspects, the composition effectively reduces tumor size for a period of about 10 to about 25 days after treatment. In other aspects, the composition effectively reduces tumor size for a period of about 10 to about 20 days after treatment. In other aspects, the composition effectively reduces tumor size for a period of about 10 to about 15 days after treatment.

[0585] In some aspects, the subject is a mammal. In some aspects, the subject is an animal. In some aspects, the subject is a human.

[0586] In another aspect, a method of increasing the stability and / or bioavailability of a therapeutic agent is provided, comprising:

[0587] obtaining a composition or conjugated compound disclosed herein, wherein the composition or conjugated compound comprises the therapeutic agent, and

[0588] administering to a subject in need thereof a therapeutically effective amount of the composition or conjugated compound.

[0589] In another aspect, a method of increasing the stability and / or bioavailability of a therapeutic agent is provided, comprising:

[0590] conjugating the therapeutic agent to a peptide compound as defined herein to obtain a conjugated compound, and

[0591] administering to a subject in need thereof a therapeutically effective amount of the conjugate compound.

[0592] In another aspect, a method for increasing the half-life and / or stability of i) a peptide compound having at least 60% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII), or ii) a conjugate compound having the formula A-(B) n

[0593] wherein

[0594] n is 1, 2, 3, or 4;

[0595] A is the peptide compound; and

[0596] B is at least one therapeutic agent, wherein B is linked to A at a free amine of a lysine residue of the peptide compound, optionally through a linker, or at an N-terminal position of the peptide compound, optionally through a linker,

[0597] the method comprises mixing the peptide compound or the conjugate compound with a solubilizing agent to increase the half-life by at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, or at least 6-fold.

[0598] In another aspect, a method for increasing the half-life and / or stability of a peptide having at least 60% sequence identity to a compound selected from the group consisting of a compound of Formula (I), a compound of Formula (II), a compound of Formula (III), a compound of Formula (IV), a compound of Formula (V), a compound of Formula (VI), a compound of Formula (VII), a compound of Formula (VIII), a compound of Formula (IX), a compound of Formula (X), a compound of Formula (XI), a compound of Formula (XII), and a compound of Formula (XIII), the method comprises conjugating a peptide compound to at least one molecule.

[0599] For example, the at least one molecule is at least one therapeutic agent. For example, the at least one therapeutic agent is an anti-cancer agent. For example, the anti-cancer agent is docetaxel.

[0600] ​For example, the at least one molecule is selected from a small molecule, a peptide, a protein, an oligonucleotide, a diagnostic agent, an imaging agent or a radionuclide agent, a macromolecule such as a monoclonal antibody, a drug delivery system including a nanoparticle, a liposome, a nanotube, a graphene loaded with a therapeutic agent, an imaging agent, a gene, an siRNA.

[0601] For example, the half-life of the conjugated peptide is increased at least 1.5-fold, at least 2-fold, at least 2.5-fold, at least 3-fold, at least 3.5-fold, at least 4-fold, at least 4.5-fold, at least 5-fold, at least 5.5-fold, at least 6-fold, at least 8-fold, at least 10-fold, at least 12-fold, at least 15-fold, or at least 20-fold compared to the same peptide that is not conjugated.

[0602] The conjugate compounds disclosed herein can also provide greater tolerability compared to unconjugated therapeutic agents. For example, in International Application published as WO 2017 / 088058 and entitled PEPTIDE COMPOUNDS AND CONJUGATE COMPOUNDS FOR THE TREATMENT OF CANCER THROUGH RECEPTOR-MEDIATED CHEMOTHERAPY, filed November 24, 2016 (incorporated by reference in its entirety), it has been shown that peptide-drug conjugates have better tolerability than unconjugated therapeutic agents of equivalent dosage due to specific receptor targeting. In particular, in vivo studies showed that treatment with the conjugate compounds had little effect on the body weight of the subject mice, thus demonstrating the tolerability of the conjugate compounds.

[0603] For example, provided herein is a method of increasing tolerability of a therapeutic agent, comprising:

[0604] conjugating a therapeutic agent to a peptide compound disclosed herein to obtain a conjugate compound, or, and

[0605] administering to a subject in need thereof a therapeutically effective amount of the conjugate compound.

[0606] For example, provided herein is a method of increasing tolerability of a therapeutic agent, comprising:

[0607] obtaining a conjugate compound disclosed herein, wherein the conjugate compound comprises a therapeutic agent, and

[0608] administering to a subject in need thereof a therapeutically effective amount of the conjugate compound.

[0609] For example, provided is the use of a compound or composition disclosed herein for increasing tolerability of a therapeutic agent.

[0610] In another aspect, there is provided use of a compound or composition as defined herein for the treatment of cancer.

[0611] In another aspect, there is provided use of a compound or composition as defined herein for targeting Sortilin receptors.

[0612] In another aspect, there is provided use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer.

[0613] In another aspect, there is provided use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer involving Sortilin expression.

[0614] In another aspect, there is provided use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer in a cancer tissue or cell expressing Sortilin.

[0615] In another aspect, there is provided use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer in a CD133 positive cell.

[0616] In another aspect, there is provided use of a compound or composition as defined herein for increasing the stability and / or bioavailability of at least one therapeutic agent.

[0617] In another aspect, there is provided use of a compound or composition as defined herein for increasing the stability and / or bioavailability of at least one peptide compound.

[0618] In another aspect, there is provided use of a compound or composition as defined herein for minimizing, reducing or decreasing tumor regrowth.

[0619] In another aspect, there is provided use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer.

[0620] In another aspect, there is provided use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer.

[0621] In another aspect, there is provided use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer involving Sortilin expression.

[0622] In another aspect, there is provided use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer in a cancer tissue or cell expressing Sortilin.

[0623] In another aspect, there is provided use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer in a CD133 positive cell.

[0624] In another aspect, there is provided use of a compound or composition as defined herein in the manufacture of a medicament for minimizing, reducing or decreasing tumor regrowth.

[0625] For example, the at least one therapeutic compound comprised in the conjugated compound and / or used in the manufacture of a medicament for treating cancer is an anticancer agent. For example, the anticancer agent is selected from the group consisting of docetaxel, cabazitaxel, doxorubicin, maytansinoid, auristatin, calicheamicin, amatoxin, and a doxorubicin.

[0626] For example, the at least one therapeutic compound comprised in the conjugated compound and / or used in the manufacture of a medicament for treating cancer is a phytochemical. For example, the phytochemical is curcumin.

[0627] For example, the phytochemical is selected from the group consisting of curcumin, omega-3, white willow bark, green tea, catechin, pygeum, boswellia serrata resin, resveratrol, Uncaria tomentosa, capsaicin, anthocyanin, flavonoid, olive oil compounds, chlorogenic acid, and sulforaphane.

[0628] In another aspect, there is provided use of a compound or composition disclosed herein in combination with a therapeutic agent such as a cytotoxic agent, a toxin and an anticancer peptide; an immunomodulatory agent such as anti-PD1 and anti-PDL1; an anticancer delivery system, an anti-angiogenic agent; and / or radiotherapy for treating cancer.

[0629] In another aspect, there is provided use of a compound or composition disclosed herein in combination with a therapeutic agent such as a cytotoxic agent, a toxin and an anticancer peptide; an immunomodulatory agent such as anti-PD1 and anti-PDL1; an anticancer delivery system, an anti-angiogenic agent; and / or radiotherapy for targeting Sortilin receptor.

[0630] Further provided is a method of making a composition of the application, the method comprising: preparing a diluent solution comprising a solubilizing agent; adding a conjugated compound to the diluent solution in an amount sufficient to obtain a desired concentration; heating the solution to dissolve the conjugated compound; cooling the solution; adjusting the pH of the solution to a pH of about 4 to about 4.6; and optionally adding a diluent to the final volume of the composition.

[0631] Further embodiments of the disclosure will now be described with reference to the following examples. It is to be understood that these examples are for illustration only and do not limit the scope of the disclosure.

[0632] Examples

[0633] Example 1: Receptor-mediated therapy using docetaxel-peptide conjugate for sortilin-positive triple-negative breast cancer

[0634] Introduction

[0635] Taxanes are a class of widely used chemotherapeutic molecules that prevent microtubule depolymerization, thereby inhibiting cell division. Examples of taxanes include paclitaxel and docetaxel. These taxanes are used to treat a variety of cancers, including breast cancer.

[0636] Sortilin is a molecule found in cell surface and intracellular membrane locations in a variety of tissues. It acts as a receptor for several peptide molecules and plays a little-understood role in intracellular transport of targeted membrane vesicles. Sortilin is overexpressed in multiple forms of cancer, including breast, ovarian, endometrial, lung, melanoma, colorectal, and pancreatic cancer. Sortilin was found to be overexpressed in 79% of invasive ductal breast cancer and 59% of triple negative breast cancer (TNBC). TNBC accounts for 15-20% of breast cancer worldwide and remains the most deadly breast cancer subset. BC is considered more aggressive and more difficult to treat than other breast cancers. Of women treated for TNBC, 42% will relapse rapidly, peaking at 3 years from diagnosis. Currently, no targeted therapy has been approved for the treatment of TNBC; therefore, surgery, anthracycline-based, taxane-based chemotherapy, and radiation therapy are the main treatment options for TNBC patients.

[0637] A TH19P01 peptide has been developed and specifically binds to the extracellular surface of sortilin and is internalized by the protein, enabling it to bring the cell portion bound to the peptide with it. One molecule that has been studied is TH1902, which contains two docetaxel ester molecules attached to the peptide, and it has shown considerable promise as a chemotherapeutic agent when tested in cell cultures and human xenografts in nude mice.

[0638] High Sortilin Expression in Human Breast Cancer

[0639] As shown in Figure 1 and Figure 2 , immunohistochemical staining was used to show high expression of sortilin in human breast cancer (invasive ductal carcinoma, lymph node metastatic carcinoma, and triple negative breast cancer). The highest level of expression was detected in lymph node metastasis. As shown in Figure 3 , Kaplan-Meier curves showed that high sortilin gene expression was associated with poor prognosis in 3 or 4 late-stage TNBC patients (n=161 cases). As shown in Figure 4 , Kaplan-Meier analysis of TNBC patients with lymph node metastasis (n=72 cases) showed an extreme effect of high sortilin gene expression on patient survival. Figure 5 is a western blot showing high expression of Sortilin in different human TNBC cancer cell lines.

[0640] Sortilin-mediated Chemotherapy Internalization, Proliferation, Migration, and Apoptosis

[0641] In vitro assays were performed on the TH19P01 peptide and the TH1902 conjugate. (For example...) Figure 6 As shown, the uptake of peptide TH19P01 was inhibited when sortilinsiRNA was used. TH19P02 showed potent antiproliferative activity in MDA-MB-231 breast cancer cells, with an IC50 value of [missing information]. 50 The value was 0.19 ± 0.09 nM, compared to 0.56 ± 0.19 nM for docetaxel. Furthermore, TH1902-induced apoptosis in MDA-MB-231 cells was found to be stronger than that induced by docetaxel. Figure 7 ), and it was found that it was reversed by sortilin ligand TH19P01, neurotensin, and granulin precursor ( Figure 8 ) It was also found that TH1902 altered MDA-MB-231 microtubule polymerization, as shown by immunostaining of α-tubulin (). Figure 9 ) It was also found that TH1902 inhibited cell migration in a sortilin-dependent manner. Figure 10 ).

[0642] In vivo validation of safety: Assessment of TH1902 treatment of neutropenia in mice

[0643] One of the more common oncological emergencies associated with the use of taxanes in chemotherapy is febrile neutropenia (defined as a cell count below 5 x 10^6 cells / mL). 8 / L and is expected to worsen).

[0644] Fifteen young adult female homozygous athymic mice (Crl:CD1-Foxn1) nu (4-6 weeks old) received 6 consecutive doses of docetaxel or TH1902 (equivalent dose of docetaxel (15 mg / kg / week)). Figure 11 As shown, docetaxel administration caused a sharp decrease in neutrophil levels just four days after the first administration. This level continued to decrease with continued docetaxel administration. Although the decrease in neutrophil count after administration of the docetaxel test sample was statistically significant following the first and third injections, there was no significant change in neutrophil count in mice administered the TH1902 test sample at any measurement time (up to 6 cycles; total dose 195 mg / kg), nor was there a significant change in animals receiving the single agent (data not shown). These results suggest that TH1902 may be useful for the prevention or reduction of neutropenia, a common side effect of docetaxel treatment. Furthermore, no weight loss was observed in mice treated with TH1902 (data not shown).

[0645] Furthermore, plasma levels of TH1902 and docetaxel were evaluated in TH1902-treated mice. Figure 12 As shown, high plasma concentrations of TH1902 were measured after an IV bolus (50 mg / kg). Very low concentrations of docetaxel released from TH1902 were measured in mouse plasma, while approximately 15-20% docetaxel concentrations could be measured when administered as the free drug.

[0646] In vivo validation of efficacy: Strong inhibition of TNBC tumor growth in MDA-MB-231 subcutaneous xenografts

[0647] The first group of mice implanted with MDA-MB-231 subcutaneous xenografts received high doses of docetaxel (15 mg / kg), TH1902 (an equivalent dose of docetaxel), or a mediator (see [link to relevant medication]). Figure 13 The second group of mice, which also received MDA-MB-231 subcutaneous xenografts, received low-dose docetaxel (3.75 mg / kg, 1 / 4 MTD), TH1902 (an equivalent dose of docetaxel), or a mediator (see [link to relevant documentation]). Figure 14 In the first group (high dose), TH1902 was found to provide better and more sustained efficacy in inhibiting tumor growth. In the second group (low dose), significantly improved efficacy of TH1902 was observed when administered at lower doses compared to docetaxel. Furthermore, a higher cumulative injection dose of TH1902 (up to 2 times higher) was observed compared to docetaxel alone.

[0648] Conclusion

[0649] Compared to docetaxel alone (equivalent dose), TH1902 demonstrated improved tolerability (lower toxicity) and improved efficacy (stronger inhibition of TNBC tumor growth). Other breast cancer types expressing sortilin may benefit from TH1902.

[0650] Example 2: Increased the in vitro stability of TH1902 prepared in mouse plasma.

[0651] Additional tests were conducted to investigate the stability of the formulated TH1902 in mouse plasma. TH1902 was either dissolved in DMO or formulated with a solubilizer (formulation: DMSO / Solutol). TM HS15 / Tween TM-80 / EtOH / Sol. Ac. Ac. / D5W / water, V / V ratio as follows: 5 / 6 / 2.5 / 0.75 / 0.005 / 69 / 16.75). TH1902 was incubated in mouse plasma at 37°C for the indicated times. Plasma proteins were precipitated by adding 4 volumes of ACN (87%) containing formic acid (0.125%), followed by centrifugation (10,000 rpm x 5 min). The supernatant was injected into UPLC / MS. Peak areas corresponding to TH1902 were calculated and compared to time 0. Results are expressed as period stability (%) as a function of time as shown in Figure 15 It can be seen that the half-life of TH1902 dissolved in DMSO is 5 hours, while the half-life of TH1902 formulated with a solubilizer is 30 hours.

[0652] Example 3: Improved TH1902 formulation

[0653] Example 3A: Formulation comprising 8.75 mg / kg / week TH1902

[0654] Introduction

[0655] An important factor in the development of any drug is the formulation of the product to be administered. This refers to the collection of chemical substances present with the test article that can affect solubility, stability, pH, or other characteristics that can affect the bioavailability and activity of the drug.

[0656] Objectives:

[0657] The objective was to compare the tumor growth inhibition against subcutaneous human tumor model MDA-MB-231 / Luc (triple negative breast cancer constitutively expressing luciferase) xenografts growing in nude mice when TH1902 (8.75 mg / kg / week) was infused in different formulations to determine the best formulation.

[0658] Methods

[0659] Compound characterization

[0660] TH1902 and docetaxel (provided by Wonda Science Inc.) were used. Docetaxel (molecular weight of 808 g / mol) was formulated in EtOH / Tween TM -80 / D5W (1 : 1 :78). Specifically, 2.5 mg of docetaxel was dissolved in 40 μΐ of ethanol, followed by the addition of 40 μΐ of Tween TM-80, followed by the addition of 3120 μΐ D5W. TH1902 (molecular weight of 3704 g / mol) was formulated as further described below. Both treatments were administered intravenously every week for 6 weeks. The treatment dose of TH1902 was 8.75 mg / kg (at a concentration of 1.35 mg / mL) and the treatment dose of docetaxel was 3.75 mg / kg (at a concentration of 0.625 mg / mL).

[0661] Eight different formulations containing TH1902 were tested. For Formulations 7 and 8 (described below), TH1902 was loaded onto an HPLC column, then rinsed with 0.25 M ammonium acetate, rinsed with 2% acetic acid and eluted with 50% acetonitrile, 2% acetic acid. The eluate (TH1902 with acetate counterions) was freeze-dried until use for Formulations 7 and 8. The various TH1902 formulations are detailed in Tables 1 and 2 below.

[0662] Table 1: TH1902 Formulation Components

[0663]

[0664] Table 2: Representative Examples of Formulations

[0665]

[0666]

[0667]

[0668] Tumor Cell Preparation

[0669] The cells used were MDA-MB-231 / Luc breast adenocarcinoma epithelial cells (Cell Biolabs Inc. #AKR-231). These are derived from triple negative breast cancer (TNBC) and they stably express firefly luciferase. The MDA-MB-231 / Luc cell line was grown as adherent monolayers at 37°C in a humidified atmosphere (5% C02, 95% 02). The culture medium was DMEM medium (Wisent, #319-005-CL) supplemented with IX Non-Essential Amino Acids (NEAA) 100X solution (Hyclone TM , #30238.01) and 10% fetal bovine serum (FBS) (Hyclone TM , #SH30396.03). For experimental use, the cells were detached from the culture flasks by treatment with trypsin (Wisent, #325-042-CL) for 5-10 minutes, then diluted and neutralized by the addition of complete culture medium at a 10-fold dilution. The BioRad TC20 TMAn automated cell counter was used to assess cell counts and cell viability. For subcutaneous implantation in mice, MDA-MB-231 / Luc tumor cells were resuspended in the appropriate volume of HBSS (Sigma #H6648) implantation medium so that 150 μl of 5 x 10 6 cells / ml) were injected.

[0670] Animals

[0671] Sixty young adult female homozygous nude mice (Crl:CD1-Foxn1 nu ) from Charles River Canada Inc. (St-Constant, Quebec) were used for this study. Healthy mice were selected according to normal veterinary examination. Mice of comparable age (28-42 days) and body weight were retained for this study.

[0672] Mice were subcutaneously implanted with MDA-MB-231 / Luc cells as described above. Tumor growth was monitored and when the tumor volume reached 40-140 mm 3 or increased significantly for 2-3 days, mice were randomly assigned to one of the following groups: vehicle group, docetaxel group or one of 8 TH1902 formulation groups (6 mice per group) for further treatment. Experimental procedure

[0673] Mice were first anesthetized with isoflurane and oxygen. Electronic calipers were used for two-dimensional measurements during the study and tumor volume was calculated using the following formula: Tumor volume (mm 3 ) = 0.52 * a * b 2 where 0.52 is a constant for calculating the volume of an ellipsoid (π / 6), where "a" is the longest diameter and "b" is the shortest diameter [3].

[0674] Treatment was initiated when the tumor volume reached 40-140 mm 3 or increased significantly for 2-3 days. All treatments lasted 24 days, including 4 treatments; animals receiving Formulations 2 and 8 continued for an additional 2 treatments to extend exposure to TH1902 to day 38.

[0675] All mice were observed daily for changes in appearance and behavior and events were recorded as appropriate. Body weight was measured three times per week; their recording accuracy was 10 mg.

[0676] Once any tumor in the vehicle group reached 1000 mm 3 in size, all animals in the vehicle group were sacrificed. The docetaxel and 35 mg / kg TH1902 groups (docetaxel equimolar for comparison) were maintained for extended treatment and observation until their day 69 of sacrifice.

[0677] Data were analyzed by one-way ANOVA followed by Dunnett's test using the test formulation and docetaxel with vehicle treated animals, or (for growth curves comparing tumor volume or animal bioluminescence) by non-linear regression fit to Gompertz growth curves. Analysis was performed using GraphPad Prism software. A p-value of <0.05 was assumed to be statistically significant.

[0678] Results and Discussion

[0679] Tumor volume

[0680] All tumors were measured three times per week with a caliper. This continued for a total of 12 measurements over 24 days. After this time, animals were euthanized except for those treated with Formulations 2 and 8, which exhibited the greatest reduction in tumor volume. These animals were maintained and monitored for an additional two weeks. Measured tumor volumes can be seen in Figure 16 . As can be seen, the black and white circles represent animals treated with vehicle and free docetaxel at ¼ of its maximum tolerated dose (MTD), respectively; the tumor burden of mice treated with docetaxel appeared to grow slightly faster than that of control animals treated with vehicle alone. Of the 8 formulations, Formulations 3 appeared to have no effect on tumor inhibition. In contrast, Formulations 2 and 8 showed strong inhibition of tumor growth. The other 5 formulations exhibited moderate levels of tumor inhibition and were comparable. Formulations 2 and 8, which showed the strongest effect, contained slightly acidic solutions containing Tween-80 and glucose; Formulation 2 contained TH1902 with formate counterions, while Formulation 8 contained TH1902 with acetate counterions. The animals treated with Formulations 2 and 8 were monitored for an additional two weeks, during which time tumors treated with Formulation 8 exhibited slow tumor growth, while the tumor stasis observed with Formulation 2 remained unchanged. Formulations 2 and 8 showed statistically significant tumor growth inhibition compared to vehicle treated tumors, near stasis was observed in mice treated with Formulation 8 at day 24 (p=0.04), and a slight reduction in tumor volume was observed after treatment with Formulation 2 (p=0.01).

[0681] Figure 17 The strong inhibition of tumor volume growth induced by dilute TH1902 in Formulation 2 (8.75 mg / kg / week) was reproduced, and the body weight of mice treated with Formulation 2 is shown in Figure 18 . As can be seen, mice treated with Formulation 2 had no effect on their body weight. Similarly, no effect on body weight was seen in the other tested formulations (data not shown).

[0682] Example 3B: Formulation containing 17.5 mg / kg / week TH1902

[0683] Additional formulations were tested as described in Table 3 below. The concentration (Conc.) of TH1902 in the various formulations was assessed as a measure of solubility of TH1902 in the formulation.

[0684] Table 3: Additional TH1902 formulations

[0685]

[0686]

[0687] “-” indicates that the conjugated compound TH1902 was not soluble in the particular formulation.

[0688] The preferred formulations that exhibited solubility of 3 mg / mL or greater were subjected to xenograft tumor volume testing. More specifically, Formulations 1-7 described in Example 3A were tested at a TH1902 dose of 17.5 mg / kg / week according to the method described in Example 3A.

[0689] As shown in Table 5 below, all Formulations 1-7 were found to inhibit tumor volume compared to control after 6 treatments. Figure 19 Figure 20 Similarly, tumor progression in the various TH1902 formulations was shown. From these results, it can be seen that the formulations of the present application can be used to minimize, reduce, or decrease tumor regrowth.

[0690] Table 4 below summarizes the results of the studies based on the various formulations of Examples 3A and 3B.

[0691] Table 4: Results of studies of low and high dose TH1902

[0692]

[0693]

[0694] Example 4: Formulations in a clinical setting

[0695] By extrapolating from the previous study results to a clinical setting, a suggested formulation was provided in which 200 mg of the conjugated compound (e.g., TH1902) was dissolved in 20 mL of Tween® 80 (10%) in D5W (pH 3). The mixture was heated (10 min, 60 °C) and then transferred to a D5W infusion bag (pH 5). The concentration of the conjugated peptide was about 0.5-2 mg / mL and the concentration of Tween® 80 was about 0.5-2%. TM 80 (10%) in D5W (pH 3). The mixture was heated (10 min, 60 °C) and then transferred to a D5W infusion bag (pH 5). The concentration of the conjugated peptide was about 0.5-2 mg / mL and the concentration of Tween® 80 was about 0.5-2%. TM

[0696] Example 5A: Formulation composition of TH1902-injection concentrate

[0697] ​​Table 5 shows the components and concentrations of the TH1902 injection concentrate composition at 10 mg / mL.

[0698] Table 5. Composition of TH1902 injection concentrate 10 mg / mL

[0699]

[0700] The density of the formulation at 25 °C is 1.029 g / mL (Reference PPS Manual: LNB-20-028 p045).

[0701] The density of formic acid = 1.22 g / mL. The density of 99% formic acid = 1.213 g / mL.

[0702] Dissolution of API

[0703] A 1.5 liter scale-up batch of TH9102 injection 10 mg / mL was successfully manufactured following the execution of the approval protocol CSR0210-001.00. The mixing method specified in the protocol was based on a procedure previously developed for several small scale laboratory batches in FRD. This procedure relied on a carefully heated mix between 40-45 °C to achieve complete dissolution of the API and not to exceed this temperature range to avoid undesirable gelling or aggregation of the formulation. Based on the test results of the quality attributes of the drug product, it was concluded that this mixing procedure was reproducible.

[0704] Figure 21 A heating profile during TH1902 API dissolution for a R&D stability laboratory batch according to Example 5A is shown.

[0705] The preliminary activities for the formulation development of the TH1902 10 mg / mL injection concentrate drug product focused on optimizing a solution that could effectively dissolve the TH1902 API. Based on the results of the studies performed on excipient screening, additional excipient amounts (0% to 5% of glucose) and acid selection (HCI, citric acid, formic acid), the solution was finalized as an aqueous mixture of polysorbate 80 (10 w / v%), glucose (5 w / v%) and formic acid (0.04 v / v%). The next stage of formulation activities focused on developing a mixing procedure to effectively dissolve TH1902 at a concentration of 10 mg / mL in the final placebo. This mixing procedure has been demonstrated in multiple small scale laboratory batches using multiple batches of API. The pH of the formulation was also optimized in these studies. The final target pH value for TH1902 10 mg / mL was set at 4.3 ± 0.2. In addition, it was found that the mixing procedure was reproducible for two scale-up batches of 2.5 L and 1.0 L (R&D stability laboratory batches) size at the set target pH value.

[0706] Example 5B: Formulation composition of TH1902-injection concentrate

[0707] An alternative composition for TH1902 injection concentrate at 10 mg / mL is provided. Table 6 shows the components and concentrations.

[0708] Table 6. Composition of TH1902 injection concentrate 10 mg / mL

[0709]

[0710] Dissolution of API

[0711] Briefly, formulated TH1902 stock solution is prepared as a sterile aliquot of a 10 mg / mL frozen liquid solution (see below). On the day of animal dosing, the frozen aliquot is thawed at room temperature for 30 minutes and then diluted with sterile 5% dextrose injection USP (D5W) to the desired injection concentration (i.e., typically 5.4 mg / mL or 1.35 mg / mL).

[0712] Figure 22 A heating profile during dissolution of TH1902 API according to Example 5B is shown.

[0713] TH1902 frozen stock solution is prepared as follows:

[0714] 1. Prepare TH1902 diluent solution (Diluent) the day before dissolution. Diluent: 10% Tween 80 in D5W USP (w / v) with 0.04% formic acid (v / v), approximately pH 2.9. Place solution at room temperature until TH1902 dissolution (next day). TM 80 / 0.04% formic acid (v / v) in D5W USP (w / v), approximately pH 2.9. Place solution at room temperature until TH1902 dissolution (next day).

[0715] 2. Weigh 60 mg TH1902 API into a 14 ml screw-capped glass vial. Adjust TH1902 weight to reflect TH1902 purity according to the analytical certificate.

[0716] 3. Add 90% of the diluent solution required to prepare TH1902 10 mg / ml stock solution.

[0717] 4. Rotate the contents of the vial to form an opaque mixture and place a stir bar.

[0718] 5. Place the vial in a heating device (a glass water bath and a base to hold the vial with a thermometer and stir bar on a digital heating plate). Start mixing the contents of the vial.

[0719] 6. Gradually increase the temperature of the water bath in 5 °C increments every 30 minutes until the mixture becomes clear (temperature ramped to 45 °C over a period of approximately 165 to 180 minutes). Record the water bath temperature every 15 minutes.

[0720] 7. Let stand at room temperature for 30 minutes while gently swirling (cooling). Measure pH. Adjust pH to 4.3 ± 0.2 using dilute NaOH (0.1 N or less).

[0721] 8. Transfer the preparation to a graduated glass cylinder and bring to the final calculated volume with diluent solution.

[0722] 9. Transfer back into a 14 ml glass vial and mix slowly for 5 minutes at room temperature. Measure pH. The pH should be 4.3 ± 0.2.

[0723] 10. Filter sterilize into a new and sterile 14 ml glass vial with a PES 0.22 pm membrane. Check pH again. Perform UPLC analysis against TH1902 standard curve for quantification and purity assessment.

[0724] 11. Freeze aliquots of TH1902 stock solution (0.5 mL per aliquot in 4 mL glass vials) at -80 °C.

[0725] Figure 23 Representative UPLC analysis of TH1902 stock solution at 10 mg / ml after dissolution using in-house procedure is shown.

[0726] Advantageously, the formulations of Examples 5A-B are shown to provide a better injectable product appearance. Importantly, the heating profile indicates less heating required to obtain these formulations. Thus, higher stability of the formulations and better reproducibility of the method to obtain the formulations can be expected.

[0727] In vivo results obtained with TH1902 API dissolution (in-house procedure) method - Example 5B

[0728] In vivo results in endometrial cancer xenograft model (AN3-CA)

[0729] Three human sortilin-positive gynecological cancer cell lines (ovary: ES-2 and SKOV-3 / Luc, endometrium: AN3-CA) were used to evaluate the chemotherapeutic activity of TH1902 in vivo using xenograft models in immunodeficient mice. In the human AN3-CA endometrial xenograft tumor model, Figure 24), unlike docetaxel, 3.75 mg / kg TH1902 (same amount of docetaxel contained in the concentration) inhibited tumor growth. At the equivalent dose of docetaxel 15 mg / kg / week, both docetaxel and TH1902 administration led to complete cessation of tumor growth. The TH1902 formulation appeared to be more effective than docetaxel by inducing a strong regression of AN3-CA tumor volume. Indeed, 5 / 6 mice treated with the highest dose of TH1902 had prolonged tumor regression, while slow tumor recurrence was only observed in one mouse 30 days after the last treatment. Body weight of mice administered with docetaxel, TH1902 or vehicle was monitored as a general indicator of morbidity. As shown in Figure 24 , mice bearing AN3-CA tumors exhibited a slight increase in body weight, except for animals administered with either test article. On the other hand, at the MTD of docetaxel, there was more evidence of body weight loss associated with docetaxel, although animal body weight remained within the pre-set 20% body weight loss endpoint limit. Animals administered with TH1902 containing equivalent amounts of docetaxel maintained a fairly constant body weight throughout the experiment.

[0730] The effect of TH1902 or docetaxel on endometrial AN3-CA xenograft tumor model is shown in Figure 24 . For the purpose of Figure 24 A, mice bearing AN3-CA xenografts were repeatedly injected intravenously (arrows indicate days of injection) with vehicle or docetaxel (3.75 mg / kg / week, 15 mg / kg / week) or equivalent TH1902 doses (8.75 mg / kg / week and 35 mg / kg / week). After 2 cycles, the highest dose of docetaxel and TH1902 were both reduced by half (7.5 mg / kg / week and 17.5 mg / kg / week, respectively), as shown by the grey arrows. In Figure 24 B, the effect of TH1902 and docetaxel on tumor progression at day 14 was presented by subtracting the initial tumor volume at day 0 from the tumor volume measured at day 14. For Figure 25 C, mouse body weight was monitored during the study and was within acceptable ranges and within the -20% endpoint limit throughout all study periods. All data symbols shown represent mean ± standard error of the mean (SEM).

[0731] In vivo results in a colorectal xenograft model (HT-29)

[0732] Treatment of mice bearing HT29 colorectal xenograft tumors with low and high doses of docetaxel or TH1902 Figure 25). At the equivalent highest dose, the TH1902 formulation caused a strong inhibition of HT29 tumor growth. Thus, TH1902 in the current formulation appears to be more effective than docetaxel by inducing prolonged HT29 tumor progression.

[0733] Figure 25 The impact of TH1902 or docetaxel on a colorectal HT29 xenograft tumor model is shown. Mice bearing HT29 tumor xenografts were repeatedly injected intravenously (arrows indicate days of injection) with vehicle or with a low dose (A) or a high dose (B) of docetaxel or TH1902. Tumor growth was monitored over a period of 21 days and tumor volume was measured every 3-4 days. The results are shown in the graph. Figure 26 A) or high dose docetaxel or TH1902. Body weight of mice treated with equivalent low dose (Fig. C) or high dose (Fig. D) of docetaxel or TH1902 was monitored during the study and was within acceptable ranges and within the endpoint limit of -20% throughout the study. All data symbols shown represent mean ± standard error of the mean (SEM).

[0734] In vivo results in a pancreatic cancer xenograft model (PANC-1)

[0735] The sortilin-expressing pancreatic cancer cell line (PANC-1) was grown in vivo as subcutaneous tumor xenografts in immunocompromised nude mice. These animals were then used to assess the chemotherapeutic activity of vehicle, docetaxel and the peptide-drug conjugate TH1902 (at two different doses). Tumor growth was followed for 21 days in all five groups of mice; during this period, tumors in animals treated with vehicle only grew steadily and tumors in mice treated with 3.75 mg / kg docetaxel appeared very similar to those in mice treated with vehicle (A). Tumor growth reduction was associated with exposure to low dose TH1902 (8.75 mg / kg) and high dose docetaxel (15 mg / kg, which is the MTD). Exposure to high dose TH1902 (35 mg / kg) actually resulted in tumor size regression. Figure 26 A) Tumor growth reduction was associated with exposure to low dose TH1902 (8.75 mg / kg) and high dose docetaxel (15 mg / kg, which is the MTD). Exposure to high dose TH1902 (35 mg / kg) actually resulted in tumor size regression.

[0736] The two groups receiving low dose test article continued to receive weekly test article administration and tumor volume measurements for an additional 1 to 4 weeks to examine the long-term consequences of low dose treatment (B). Tumors continued to grow until the animals had to be euthanized due to tumor size, but clearly, low dose TH1902 administration inhibited tumor growth. Figure 26 B) Tumor growth reduction was associated with exposure to low dose TH1902 (8.75 mg / kg) and high dose docetaxel (15 mg / kg, which is the MTD). Exposure to high dose TH1902 (35 mg / kg) actually resulted in tumor size regression.

[0737] The growth curves of these tumors indicate that low dose administration of docetaxel and TH1902 had less effect on tumor volume than the higher doses. In addition, TH1902 appeared to be more effective than docetaxel in halting tumor growth and actually resulted in tumor regression when administered at the higher dose.

[0738] Tumor volumes of the five groups of mice on day 21 were compared by one-way ANOVA followed by Dunnett's multiple comparison test comparing the tumor size of each of the four test groups to the tumor size of the vehicle treated mice. As shown in Figure 26 C, the tumor sizes of mice carrying PANC-1 tumors could not be distinguished whether they were administered vehicle or low dose docetaxel. On the other hand, the tumor sizes of mice receiving low dose TH1902 or high dose docetaxel or TH1902 showed a significant reduction in tumor size and in the case of high dose TH1902 even elimination. These data demonstrate that TH1902 is superior to docetaxel in treating these pancreatic xenograft tumors.

[0739] Figure 26 The effects of TH1902 and docetaxel on a pancreatic tumor xenograft model are shown. Mice carrying a subcutaneous xenograft tumor of the pancreas were treated with TH1902, docetaxel or vehicle. PANC-1 tumor volume measurements of all 5 groups were recorded for three weeks and shown in Figure 26 A. Black arrows indicate the dates of test article administration. In Figure 26 B, the same data is shown but includes the extended results for mice administered low dose docetaxel and TH1902. All data symbols shown represent the mean ± SEM, n = 6 for all groups in graphs A and B. Black arrows indicate the days of test article administration for all 5 groups; gray arrows indicate administration to animals for only two of the low dose groups. For Figure 27 C, tumor progression on day 21 was then compared between each treatment group. Bars shown represent the mean ± SEM. Four asterisks indicate p < 0.0001.

[0740] In vivo results for a melanoma carcinoma xenograft model (SK-Mel-28) and a syngeneic melanoma model (B16-F10)

[0741] Two sortilin-expressing melanoma carcinoma cell lines (SK-MEL-28 and B16-F10) were used to monitor whether TH1902, when administered at 35 mg / kg / week, hinders cell growth compared to 15 mg / kg / week of unconjugated docetaxel. This is the maximum tolerated dose (MTD) for free docetaxel and the TH1902 formulation contains an equivalent amount of docetaxel in the peptide drug conjugate. Clearly, both docetaxel and TH1902 inhibited tumor growth in SK-MEL-28 xenografts, with TH1902 showing stronger inhibition ( Figure 27 A). This difference was quantified when the control group reached the tumor volume endpoint on day 42. In contrast to docetaxel, a significant regression of tumor volume was observed between control animals and animals treated with the TH1902 formulation ( Figure 27B). Body weight of mice treated with vehicle, docetaxel and TH1902 remained within -20% endpoint limit Figure 27 C).

[0742] Figure 27 The effect of TH1902 or docetaxel on melanoma SK-MEL-28 xenograft tumor model is shown. For Figure 27 A, mice bearing SK-MEL-28 xenografts were repeatedly injected intravenously (arrows indicate days of injection) with vehicle or vehicle containing equal amounts of docetaxel (15 mg / kg / week) or TH1902 (35 mg / kg / week). At Figure 27 B, the effect of TH1902 and docetaxel on tumor progression at day 42 is presented by subtracting the initial tumor volume at day 0 from the tumor volume measured at day 42. For Figure 28 C, body weight of mice treated with vehicle and equivalent doses of docetaxel or TH1902 was monitored during the study and was within acceptable range and -20% endpoint limit for all study periods. All data symbols shown represent mean ± standard error of the mean (SEM).

[0743] For the syngeneic B16-F10 melanoma tumor model, normal immunocompetent mice were implanted subcutaneously with murine B16-F10 cancer cells. Syngeneic mouse models consist of tumor tissue that has the same genetic background as the given immunocompetent mouse strain. Syngeneic mouse models provide an effective approach to study the performance of cancer therapies in the presence of a functional immune system. In a first study Figure 28 ), mice implanted with B16-F10 cancer cells were treated weekly with vehicle and equivalent doses of docetaxel or TH1902. Figure 28 Results in A show that this model is very aggressive and tumor growth is very rapid. In this very aggressive syngeneic melanoma tumor model, better efficacy of the TH1902 formulation was clearly observed compared to unconjugated docetaxel. At the study endpoint Figure 28 B, tumor regression was measured in mice treated with TH1902, which had no impact on body weight of the mice compared to docetaxel Figure 28 C). In addition, tumors were collected at day 14, aligned and photographed Figure 28 D). The pictures clearly indicate a huge difference in tumor size when treated with the TH1902 formulation compared to tumors treated with vehicle or docetaxel. All tumors treated with the TH1902 formulation were much smaller than tumors of the other two groups (vehicle and docetaxel).

[0744] Figure 28The effects of TH1902 or docetaxel on an syngeneic B16-F10 xenograft tumor model were demonstrated. For Figure 28 A. Immunoactive mice carrying B16-F10 xenografts were repeatedly injected intravenously (arrows indicate injection days) with a medium or a medium containing equivalent docetaxel (15 mg / kg / week) or TH1902 (35 mg / kg / week). Figure 28 In B, the effects of TH1902 and docetaxel on tumor progression on day 14 are presented by subtracting the initial tumor volume on day 0 from the tumor volume measured at the endpoint in the mediator group on day 14. For Figure 28 C. Monitor the body weight of mice treated with the mediator and equivalent doses of docetaxel or TH1902 during the study period, and ensure that body weight is within acceptable limits and -20% of the endpoint limit throughout the study period. Figure 29 D, Tumors were collected on day 14, aligned according to their treatment, and photographed. All data symbols shown represent mean ± standard error of mean (SEM).

[0745] Next, in the second study, a dose-response model based on the same gene B16-F10 melanoma was used. Figure 29 Three different equivalent doses of docetaxel and TH1902 were administered via IV bolus injection to immunocompetent mice carrying B16-F10 tumors. Mice were then treated with docetaxel at doses of 5 mg / kg every two weeks, 7.5 mg / kg every two weeks, and 10 mg / kg every two weeks, and with equivalent doses of TH1902 (11.5 mg / kg every two weeks, 17.25 mg / kg every two weeks, and 23 mg / kg every two weeks). Results clearly demonstrated that TH1902 induced stronger tumor growth inhibition at all doses compared to unconjugated docetaxel. Significant and durable regression was observed at the highest dose of TH1902 (23 mg / kg every two weeks). The equivalent dose of docetaxel (10 mg / kg every two weeks) had little effect on tumor growth.

[0746] Figure 29 This study demonstrates the dose-response study of TH1902 or docetaxel in an syngeneic B16-F10 xenograft tumor model. For Figure 29 A. Immunoactive mice carrying B16-F10 tumor xenografts were repeatedly injected intravenously (dashed lines indicate injection days) with either the mediator or equivalent increased doses of TH1902 and docetaxel. Mice were treated twice weekly with docetaxel at doses of 5 mg / kg, 7.5 mg / kg, and 10 mg / kg, and equivalent doses of TH1902 (11.5 mg / kg, 17.25 mg / kg, and 23 mg / kg). Figure 29In B, the effect of TH1902 and docetaxel on tumor progression at day 12 is presented by subtracting the initial tumor volume at day 0 from the tumor volume measured at day 12 when the tumors in the vehicle group reached the end point limit. Tumor regression was observed significantly with TH1902 formulation compared to docetaxel. For References C. Body weights of mice treated with vehicle and equivalent doses of docetaxel or TH1902 were monitored during the study and were within acceptable ranges and within the end point limit of -20% throughout the study.

[0747] The embodiments of the disclosure are presented in such a way in the present disclosure so as to demonstrate that each combination of the embodiments can be made where applicable. Thus, the embodiments have been presented in the specification in a manner equivalent to the presentation of dependent claims that are dependent on any one of the preceding claims (covering the previously presented embodiments) so as to demonstrate that they can be combined together in all possible ways. For example, all possible combinations between the embodiments and individual aspects presented in the present paragraph are hereby covered by the present disclosure when applicable.

[0748] ​

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Claims

1. A composition comprising a solubilizing agent polysorbate 80, glucose, and a conjugate compound or a pharmaceutically acceptable salt thereof, the conjugate compound being of the formula A-(B) as shown in n ​ wherein n is 1, 2, 3, or 4; A is a peptide compound of Formula (X): GVRAKAGVRN(Nle)FKSESY (X); and B is at least one anti-cancer agent linked to A, optionally linked at a free amine of the peptide compound, at an N-terminal position of the peptide compound, at a free-SH of the peptide compound, or at a free carboxyl of the peptide compound, wherein the anti-cancer agent is docetaxel, wherein at least one protecting group and / or at least one cysteine residue is optionally linked at the N-terminal and / or C-terminal to the peptide compound; wherein the conjugate compound or a pharmaceutically acceptable salt thereof is present in an amount of 0.9 w / w% to 1.1 w / w% based on the total weight of the composition; and wherein the solubilizing agent is present in an amount of 9% to 11% by weight per total volume of the composition; and wherein the composition is an aqueous solution having a pH of 4.0 to 4.

6.

2. The composition of claim 1, wherein the anti-cancer agent is linked to A at a free amine of a lysine residue of the peptide compound.

3. The composition of claim 1, wherein the peptide compound comprises the at least one protecting group, wherein the at least one protecting group is an acetyl group or a succinyl group.

4. The composition of claim 1, wherein the peptide compound comprises the at least one cysteine residue linked at the N-terminal and / or C-terminal to the peptide compound.

5. The composition of claim 4, wherein the anti-cancer agent is linked to the peptide compound at a free-SH of the peptide compound.

6. The composition of claim 1, wherein the peptide compound is represented by Formula (XXXIX): Acetyl-GVRAKAGVRN(Nle)FKSESY (XXXIX).

7. The composition of claim 1, wherein B is linked to A through a linker.

8. The composition of claim 7, wherein the linker is a cleavable linker.

9. The composition of claim 1, wherein the conjugate compound is represented by Formula (XIX): GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY - Formula (XIX).

10. The composition of claim 1, wherein the conjugate compound is represented by Formula (XXIII): Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY - Formula (XXIII).

11. The composition of claim 7, wherein the linker is selected from the group consisting of succinic acid and dimethyl glutaric acid.

12. The composition of claim 1, further comprising a buffering agent.

13. The composition of claim 12, wherein the buffering agent is an acetate buffer or a formate buffer.

14. The composition of claim 1, wherein the concentration of the dextrose is 2% to 8% by weight per total volume of the composition.

15. The composition of claim 1, wherein the composition is an aqueous solution having a pH of 4.3 ± 0.

2.

16. The composition of claim 1, comprising polysorbate 80, dextrose, formic acid, sodium hydroxide, and a diluent.

17. The composition of claim 16, wherein the concentration of the dextrose is 2% to 8% by weight of the total volume of the composition.

18. The composition of claim 16, wherein the formic acid is present in an amount of 0.02% to 0.06% by volume of the total volume of the composition.

19. The composition of claim 1, wherein the conjugate compound is in the form of a pharmaceutically acceptable acid addition salt.

20. The composition of claim 19, wherein the pharmaceutically acceptable acid addition salt is an acetate or formate salt.

21. Use of a composition as defined in any one of claims 1 to 20 in the manufacture of a medicament for the treatment of a Sortilin-expressing cancer or an aggressive cancer, wherein the Sortilin-expressing cancer or aggressive cancer is an ovarian cancer, an endometrial cancer, a breast cancer, a prostate cancer, a colorectal cancer, a lung cancer, a pancreatic cancer, a skin cancer, a brain cancer, or a urothelial cancer.

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