Sortilin-binding conjugate compounds, compositions, and their uses for treating cancer

Abstract

The present disclosure relates to compositions, processes, methods, and uses thereof comprising a solubilizing agent and a peptide compound and / or a conjugate compound for the treatment of cancer or invasive cancer. For example, the conjugate compound may have the formula A-(B)n, where A is a peptide compound and B is at least one therapeutic agent, and the peptide compound has the formula X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I) (SEQ ID NO: 1) (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II) (SEQ ID NO: 2) YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3) YKX 18 LRR(X 19 ) n PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4) IKLSGGVQAKAGVINMDKSESM(V) (SEQ ID NO: 5) IKLSGGVQAKAGVINMFKSESY(VI) (SEQ ID NO: 6) IKLSGGVQAKAGVINMFKSESYK(VII) (SEQ ID NO: 7) GVQAKAGVINMFKSESY(VIII) (SEQ ID NO: 8) GVRAKAGVRNMFKSESY(IX) (SEQ ID NO: 9) GVRAKAGVRN(Nle)FKSESY(X) (SEQ ID NO: 10) YKSLRRKAPRWDAPLRDPALRQLL(XI) (SEQ ID NO: 11) YKSLRRKAPRWDAYLRDPALRQLL(XII) (SEQ ID NO: 12) YKSLRRKAPRWDAYLRDPALRPLL(XIII) (SEQ ID NO: 13), wherein X1 to X 21 and n may have a variety of different values, and at least one protecting group and / or at least one labeling agent is optionally linked to said peptide compound at the N-terminus and / or C-terminus.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority from U.S. Provisional Patent Application No. 62 / 945,111, filed December 6, 2019, which is incorporated herein by reference in its entirety.

[0002] The present disclosure relates to peptide compounds, peptide conjugates, peptide compositions, and related methods and uses thereof. [Background technology]

[0003] According to a recent World Health Organization report, 8.2 million patients died from cancer in 2012 (1). Therefore, cancer is a continuing and growing health problem in both developing and developed countries. It is also estimated that the number of annual cancer cases will increase within the next 20 years (1). Common systemic treatments for cancer include surgery, endocrine therapy, chemotherapy, and radiation therapy (2). However, recent hopes are placed on the creation of "targeted therapeutic agents," which target specific molecular defects in cancer cells and are therefore more effective and less toxic than imprecise chemotherapy drugs (3).

[0004] It is currently estimated that when anticancer drugs are administered via classical formulations, approximately 95% of the therapeutic agent is taken up by cells in healthy tissue, whereas only approximately 2–5% effectively reaches the tumor. (4) Therefore, a challenge for any future successful personalized therapy approach will be to increase the selectivity of targeted therapy, in part through active transport of anticancer drugs to cancer cell compartments. (5–6)

[0005] Considering its role in ligand internalization and cellular trafficking, sortilin can be considered one of the cell's own shuttle systems (11). Recent studies have shown that sortilin plays a dual role in both endocytosis and receptor trafficking, enabling the sorting of ligands from the cell surface to specific subcellular compartments and the trafficking of pro-neurotrophins, such as the neuropeptides neurotensin (NT), proNGF, and proBDNF (8, 11-16). Sortilin expression is elevated in several human cancers, including breast, prostate, colon, pancreatic, skin, and pituitary cancers (17-20). Sortilin has also been reported to be overexpressed in ovarian cancer compared with healthy ovarian tissue (21, 22). Summary of the Invention

[0006] Accordingly, a first aspect is a composition comprising a solubilizing agent and a peptide compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein said peptide compound has at least 60% sequence identity to a compound selected from compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), and formula (XII); [Table 1] During the ceremony, 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; X 16 , X 17 , X 20 , and X 21 are independently selected from Q, P, Y, I and L; n is 0, 1, 2, 3, 4, or 5; When more than one X is present, each X is independently selected from any amino acid; X 19 is present more than once, each X is independently selected from any amino acid; wherein at least one protecting group and / or at least one labeling agent is optionally linked to said peptide at the N-terminus and / or C-terminus; Optionally, the peptide compound is cyclic.

[0007] Another embodiment is a composition comprising a solubilizing agent and a peptide compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the peptide compound has at least 80% sequence identity to a compound selected from the group consisting of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), and Formula (XII). [Table 2] During the ceremony, 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; X 16 , X 17 , X 20 , and X 21 are independently selected from Q, P, Y, I and L; n is 0, 1, 2, 3, 4, or 5; When more than one X is present, each X is independently selected from any amino acid; X 19is present more than once, each X is independently selected from any amino acid; wherein at least one protecting group and / or at least one labeling agent is optionally linked to said peptide at the N-terminus and / or C-terminus; Optionally, the peptide compound is cyclic.

[0008] In some embodiments, compositions are provided that include a solubilizing agent and a peptide compound, or derivative thereof, that targets the sortilin receptor.

[0009] In some embodiments, compositions are provided that include a solubilizing agent and a peptide compound, or a derivative thereof, for use in targeting a sortilin receptor.

[0010] In a further aspect, disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein said conjugate compound is A-(B) n and has the formula During the ceremony, n is 1, 2, 3, or 4; A is a peptide compound as defined herein, said peptide optionally protected by a protecting group; B is at least one therapeutic agent, and B is linked to A.

[0011] In a further aspect, disclosed herein is a composition comprising a solubilizing agent and a conjugate compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein said conjugate compound is A-(B) n and has the formula During the ceremony, n is 1, 2, 3, or 4; A is a peptide compound as defined herein, said peptide compound optionally protected by a protecting group; B is at least one therapeutic agent, and B is optionally linked to A at a free amine of said peptide compound, at the N-terminal position of said peptide compound, at a free -SH of said peptide compound, or at a free carboxyl of said peptide compound.

[0012] A further embodiment disclosed herein is a composition comprising a solubilizing agent and a conjugate compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein said conjugate compound is A-(B) n and has the formula During the ceremony, n is 1, 2, 3, or 4; A is a peptide compound as defined herein, said peptide optionally protected by a protecting group; B is at least one therapeutic agent, and B is linked to A at a free amine of a lysine residue of said peptide compound, optionally via a linker, or at the N-terminal position of said peptide compound, optionally via a linker.

[0013] Another embodiment disclosed herein is a composition comprising a solubilizing agent and a conjugate compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the conjugate compound is represented by formula (XXIII): It comprises a peptide compound having SEQ ID NO: 15, where each lysine residue has a docetaxel molecule linked to it. Formula (XXIII): Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY

[0014] Another embodiment disclosed herein is a composition comprising a solubilizing agent and a conjugate compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the conjugate compound is represented by the following formula (XXVIII): It comprises a peptide compound having SEQ ID NO: 15, where each lysine residue has a doxorubicin molecule linked to it. Formula (XXVIII): Acetyl-GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY

[0015] Another embodiment disclosed herein is a composition comprising a solubilizing agent and a conjugate compound, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the conjugate compound is represented by formula (LII): a peptide compound having SEQ ID NO: 24, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto; or The peptide compound has SEQ ID NO: 15, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, the cysteine ​​residue having an aldoxorubicin molecule linked thereto. Formula (LII): Acetyl-GVRAKAGVRN(Nle)FKSESYC (aldoxorubicin)

[0016] Another aspect disclosed herein is a composition comprising a solubilizing agent and a conjugated compound or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the conjugated compound is a compound of formula (XVI) below, comprising a peptide compound having SEQ ID NO: 15, wherein each lysine residue has a curcumin molecule linked thereto; and The peptide compound is selected from compounds of formula (XVII) below, including a peptide compound having SEQ ID NO: 16, wherein each lysine residue has a curcumin molecule linked thereto. Formula (XVI): Acetyl-GVRAK(curcumin)AGVRN(Nle)FK(curcumin)SESY Formula (XVII): Acetyl-YK(curcumin)SLRRK(curcumin)APRWDAPLRDPALRQLL

[0017] In another embodiment, the present invention provides a peptide compound, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, wherein the peptide has at least 60% sequence identity to a compound selected from the group consisting of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), and Formula (XIII), or ii) A-(B) n 1. A method of increasing the half-life and / or stability of a conjugate compound having the formula: During the ceremony, n is 1, 2, 3, or 4; A is the peptide compound, B is at least one therapeutic agent, and B is linked to A at a free amine of a lysine residue of said peptidic compound, optionally via a linker, or at the N-terminal position of said peptidic compound, optionally via a linker; Methods are provided that include combining the peptide or 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.

[0018] In another aspect, there is provided a method of increasing the half-life and / or stability of a peptide, a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein said peptide has at least 60% sequence identity to a compound selected from the group consisting of compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), and Formula (XIII), the method comprising conjugating the peptide compound to at least one molecule.

[0019] 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 defined herein.

[0020] In certain embodiments, there is provided a use of a composition as defined herein for treating cancer.

[0021] In some embodiments, there is provided a use of a composition as defined herein for targeting a sortilin receptor.

[0022] In one embodiment, there is provided a use of a composition as defined herein for the treatment of cancer or aggressive cancer.

[0023] In certain embodiments, there is provided a use of a composition as defined herein for the treatment of cancer or aggressive cancer in cancerous tissue or cells that express Sortilin.

[0024] In certain embodiments, there is provided the use of a composition as defined herein in the manufacture of a medicament for treating cancer.

[0025] In one embodiment, there is provided the use of a composition as defined herein in the manufacture of a medicament for targeting a sortilin receptor.

[0026] In one embodiment, there is provided the use of a composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer.

[0027] In certain embodiments, there is provided the 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 that express Sortilin.

[0028] In another aspect, there is provided the use of a composition as defined herein in the manufacture of a medicament for targeting a sortilin receptor.

[0029] In a further aspect, there is provided a liposome, graphene, nanotube or nanoparticle comprising a composition as defined herein.

[0030] In a further aspect, there is provided a liposome, graphene, nanotube or nanoparticle comprising a composition as defined herein for use in targeting a sortilin receptor. [Brief explanation of the drawings]

[0031] Further features and advantages of the present disclosure will become more readily apparent from the following description of specific embodiments, as illustrated by way of example in the accompanying schemes and drawings.

[0032] [Figure 1] This is a tissue immunohistochemistry microarray showing high expression of sortilin in human breast cancer (invasive ductal carcinoma and lymph node metastatic carcinoma). [Figure 2] 1 is a bar graph showing sortilin expression levels in invasive ductal carcinoma, lymph node metastatic carcinoma, and TNBC relative to normal tissues. [Figure 3] 1 is a graph showing survival in TNBC patients with high sortilin expression versus low sortilin expression. [Figure 4] 1 is a graph showing survival rates in TNBC with lymph node metastasis with high sortilin expression versus low sortilin expression. [Figure 5] 1 is a Western blot image showing that sortilin is highly expressed in different human TNBC cancer cell lines. [Figure 6] 1 is a bar graph showing inhibition of uptake of peptide TH19P01 by sortilin siRNA. [Figure 7] 1 is a bar graph showing apoptosis of MDA-MB-231 cells in docetaxel-treated and TH1902-treated cells as a function of concentration and time. [Figure 8]1 is a bar graph showing reversal of apoptosis in TH1902-treated MDA-MB-231 cells by sortilin ligand TH19P01, neurotensin, and progranulin. [Figure 9] 1 is a series of images showing immunostaining of α-tubulin in MDA-MB-231 cells treated with docetaxel or TH1902 versus control. [Figure 10] 1 is a graph showing cell migration inhibited by TH1902 in a sortilin-dependent manner. [Figure 11] 1 is a graph showing neutrophil counts as a function of the number of treatments with docetaxel or TH1902. [Figure 12] 1 is a graph showing the concentration of TH1902 and released docetaxel in the plasma of mice injected intravenously with TH1902 as a function of time. [Figure 13] 1 is a graph showing tumor volume in mice treated with vehicle, high docetaxel dose, or TH1902 (at the equivalent docetaxel dose) as a function of time. [Figure 14] 1 is a graph showing tumor volume in mice treated with vehicle, low docetaxel dose, or TH1902 (at the equivalent docetaxel dose) as a function of time. [Figure 15] 1 is a graph showing the stability of DoceKA (i.e., TH1902 conjugate) when formulated versus when dissolved in DMSO. [Figure 16] 1 is a graph showing MDA-MB-231 tumor volume in mice treated with vehicle, docetaxel, or various TH1902 formulations as a function of time. [Figure 17] 1 is a graph showing tumor volume in vehicle, docetaxel, or TH1902 (Formulation 2) treated mice as a function of time. [Figure 18] 1 is a graph showing the body weight of mice treated with vehicle, docetaxel, or TH1902 (Formulation 2) as a function of time. [Figure 19]1 is a graph showing MDA-MB231 tumor volume in mice treated with vehicle or various TH1902 formulations as a function of time. [Figure 20] 1 is a bar graph showing tumor progression in mice treated with vehicle or various TH1902 formulations (17.5 mg / kg / week). [Figure 21] 1 is a graph showing the heating profile during dissolution of TH1902 API for an R&D Stability lab batch (Example 5A). [Figure 22] 1 is a graph showing the heating profile during dissolution of TH1902 API according to an internal procedure (Example 5B). [Figure 23] 1 is a representative UPLC analysis of a stock solution of TH1902 at 10 mg / ml after dissolution per internal procedure (Example 5B). [Figure 24] 1 shows the results of an endometrial cancer xenograft model (AN3-CA) in mice treated with vehicle, low and high doses of docetaxel, or low and high doses of TH1902. A) is a graph showing tumor volume as a function of time, B) is a bar graph showing tumor progression at the study endpoint, and C) is a graph showing mouse body weight as a function of time. [Figure 25] 1 shows the results of a mouse colorectal cancer xenograft model (HT-29) treated with vehicle, docetaxel, or TH1902. A) is a graph showing tumor volume as a function of time at the low dose, B) is a graph showing tumor volume as a function of time at the high dose, C) is a graph showing mouse weight as a function of time at the low dose, D) is a graph showing mouse weight as a function of time at the high dose, E) is a bar graph showing tumor progression at the study endpoint at the low dose, and F) is a bar graph showing tumor progression at the study endpoint at the high dose. [Figure 26]

[0023] Figure 1 shows the results of a mouse pancreatic cancer xenograft model (PANC-1) treated with vehicle, low and high doses of docetaxel, or low and high doses of TH1902. (A) and (B) are graphs showing tumor volume as a function of time, and (C) is a bar graph showing tumor progression at the study endpoint. [Figure 27] 1 shows the results of a melanoma cancer xenograft model (SK-Mel-28) in mice treated with vehicle, low and high doses of docetaxel, or low and high doses of TH1902. A) is a graph showing tumor volume as a function of time, B) is a bar graph showing tumor progression at study endpoints, and C) is a graph showing mouse weight as a function of time. [Figure 28]

[0023] Figure 1 shows the results of a syngeneic melanoma tumor model (B16F10) in mice treated with vehicle, high-dose docetaxel, or high-dose TH1902. A) is a graph showing tumor volume as a function of time, B) is a bar graph showing tumor progression at the study endpoint, C) is a graph showing mouse body weight as a function of time, and D) is an image showing ex vivo tumors at the study endpoint. [Figure 29] 1 shows dose-response results for a mouse syngeneic melanoma tumor model (B16F10) treated with vehicle, docetaxel, or TH1902 at three equally escalating doses. A) is a graph showing tumor volume as a function of time, B) is a bar graph showing tumor progression at study endpoints, and C) is a graph showing mouse body weight as a function of time. DETAILED DESCRIPTION OF THE INVENTION

[0033] The term "peptide compound" as used herein refers to, for example, peptides derived from bacterial proteins or peptides derived from ligands of receptors that target receptors expressed on cancer cells, including multidrug-resistant cancer cells. For example, peptide compounds can be derived from bacterial proteins involved in cell penetration or sortilin ligands, such as progranulin and neurotensin. For example, peptide compounds can be cyclic. In certain embodiments, peptide compounds are linked (e.g., via a covalent bond, atom, or linker) to at least one therapeutic agent (e.g., an anticancer drug or a phytochemical), thereby forming a conjugate compound that can be used, for example, for the treatment of cancer or aggressive cancer. In certain other embodiments, peptide compounds can be used on the surface of liposomes. For example, peptide compounds can be used to coat liposomes, graphene, nanotubes, or nanoparticles that can be loaded with at least one therapeutic agent (e.g., an anticancer drug or a phytochemical, or a gene or siRNA).

[0034] The term "KBP family 1 peptide compound" refers to a peptide compound derived from a bacterial cell-permeable protein. For example, the KBP family 1 peptide compound may be derived from a protein having the amino acid sequence IKLSGGVQAKAGVINMDKSESM (SEQ ID NO: 5). Non-limiting examples of KBP family 1 peptide compounds are shown below. [Table 3]

[0035] As used herein, the peptide compound KBP-101 is represented by the amino acid sequence IKLSGGVQAKAGVINMDKSESM (SEQ ID NO: 5).

[0036] As used herein, the peptide compound KBP-102 is represented by the amino acid sequence succinyl-IKLSGGVQAKAGVINMFKSESY, which comprises the peptide sequence of SEQ ID NO: 6, to which the succinyl group is linked at the N-terminus.

[0037] As used herein, the peptide compound KBP-103 is represented by the amino acid sequence IKLSGGVQAKAGVINMFKSESYK (biotin), which comprises the peptide sequence of SEQ ID NO: 7, to which a biotin molecule is linked at its C-terminus.

[0038] As used herein, the peptide compound KBP-104 is represented by the amino acid sequence GVQAKAGVINMFKSESY (SEQ ID NO: 8).

[0039] As used herein, the peptide compound KBP-105 is represented by the amino acid sequence Acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14).

[0040] As used herein, the peptide compound KBP-106 is represented by the amino acid sequence Acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15).

[0041] As used herein, "TH19P01" or "TH19P01 peptide" is synonymous with the peptide compound KBP-106, represented by the sequence of SEQ ID NO:15.

[0042] The term "KBP family 2 peptide compound" refers to a peptide derived from the sortilin ligands 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 human progranulin, such as that having the amino acid sequence KCLRREAPRWDAPLRDPALRQLL (SEQ ID NO: 19), rat progranulin, such as that having the amino acid sequence KCLRKKTPRWDILLRDPAPRPLL (SEQ ID NO: 20), mouse progranulin, such as that having the amino acid sequence KCLRKKIPRWDMFLRDPVPRPLL (SEQ ID NO: 21), or neurotensin, such as that having the amino acid sequence XLYENKPRRPYIL (SEQ ID NO: 22). Non-limiting examples of KBP family 2 peptide compounds are shown below. [Table 4]

[0043] As used herein, the peptide compound KBP-201 is represented by the amino acid sequence Acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16).

[0044] As used herein, the peptide compound KBP-202 is represented by the amino acid sequence Acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17).

[0045] As used herein, the peptide compound KBP-203 is represented by the amino acid sequence Acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 18).

[0046] As used herein, the terms "sortilin" or "sortilin receptor" refer to a neuronal type 1 membrane glycoprotein encoded by the SORT1 gene, which belongs to the Vacuolar Protein Sorting 10 (Vps10) receptor family. Sortilin (also known as neurotensin receptor 3, accession number NP_002950, ​​incorporated herein by reference) is abundantly expressed in the central and peripheral nervous systems and in other tissue types. For example, sortilin expression is upregulated in many cancers, including ovarian, breast, colon, and prostate cancers. The encoded preproprotein is proteolytically processed by furin to generate the mature receptor with a molecular weight of 100–110 kDa. A truncated soluble form of sortilin (95 kDa) corresponding to its large luminal domain (i.e., extracellular domain or ectodomain) has also been described and has previously been detected in supernatant medium from cells overexpressing sortilin (48). The amino acid residues of Sortilin referenced herein correspond to their positions in 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.

[0047] The term "compound" as used herein 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 a compound, as previously set forth in this disclosure. The term "compound" also refers to a mixture of the various compounds disclosed herein.

[0048] The compounds of the present disclosure include prodrugs. Generally, such prodrugs are functional derivatives of these compounds that can be readily converted in vivo into the compound from which they are conceptually derived. Prodrugs of the compounds of the present disclosure can be conventional esters formed with available hydroxy or amino groups. 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 (e.g., an acid chloride in pyridine). Some common esters utilized as prodrugs include phenyl esters, aliphatic (C8-C9) esters, and esters of phenyl, aliphatic (C8-C9) esters. 24 ) esters, acyloxymethyl esters, carbamates, and amino acid esters. In certain cases, prodrugs of the compounds of the present disclosure are those in which one or more of the hydroxy groups in the compound is masked as a group that can be converted to a hydroxy group in vivo. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985.

[0049] Compounds of the present disclosure may also be included in radiolabeled forms, e.g., 2 H, 3 H, 14 C. 15Compounds labeled by incorporation into N, or 125 Radioactive halogens such as I. Radiolabeled compounds of the present disclosure can be prepared using standard methods known in the art.

[0050] As used herein, the term "analog" includes amino acid portions, extensions, substitutions, variants, modifications, or chemical equivalents of the disclosed peptides or antigens, and derivatives thereof, that perform substantially the same function in substantially the same way as the disclosed peptides or antigens. For example, analogs of the disclosed peptides and antigens include, but are not limited to, conservative amino acid substitutions. Analogs of the disclosed peptides and antigens also include additions and deletions to the disclosed peptides and antigens.

[0051] A "conservative amino acid substitution," as used herein, is one in which one amino acid residue is replaced with another without eliminating a desired property of the peptide or antigen.

[0052] As used herein, the phrase "derivative thereof" when referring to a compound means a derivative of the compound that has similar reactivity and can be used as a substitute for the compound to achieve the same desired result.

[0053] The term "cancer" as used herein refers to primary or secondary cancer, including non-metastatic and / or metastatic cancer. Reference to cancer includes reference to cancer tissue or cells. For example, cancer may be ovarian cancer, brain cancer, breast cancer (e.g., triple-negative breast cancer), melanoma, colorectal cancer, glioblastoma, liver cancer, lung cancer, prostate cancer, cervical cancer, head cancer, stomach cancer, kidney cancer, endometrial cancer, testicular cancer, 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 splenic cancer. The term "cancer" as used herein also includes any cancer associated with sortilin expression.

[0054] As used herein, the term "invasive cancer" refers to a cancer that has cancer cells that are rapidly dividing and growing. Invasive cancers may be, or are likely to be, invasive or metastatic, and are likely to spread to lymph nodes and / or other body organs. Reference to invasive cancer includes reference to invasive cancer tissue or cells. Invasive cancers may be any of the types of cancer described herein.

[0055] As used herein, the term "therapeutic agent" refers to an agent that can produce a therapeutic effect by inhibiting, suppressing, or reducing cancer in a subject, cancerous tissue, or cells (e.g., as determined by clinical symptoms or the amount of cancerous cells) compared to a control. Examples of therapeutic agents include, for example, anticancer agents and phytochemicals.

[0056] The term "anticancer drug" as used herein refers to a drug that can cause toxicity in cancer cells. For example, taxanes derived from the bark of the Pacific yew tree, Taxus brevifolia, can be used as anticancer drugs. Taxanes include, for example, docetaxel, paclitaxel, and cabazitaxel. Other anticancer drugs include, for example, anthracycline compounds that act by intercalating DNA. For example, anthracyclines include doxorubicin and aldoxorubicin.

[0057] As used herein, the term "docetaxel" or "doce" refers to an anticancer drug having the structure: [ka] Or its pharmaceutically acceptable salt, solvate or prodrug, and its mixture.For example, docetaxel can be conjugated to the peptide compound of the present disclosure at the 2-position of its side chain through the oxygen atom that is bonded to carbon atom.Docetaxel can be directly connected to peptide compound or through linker.

[0058] As used herein, the terms "doxorubicin," "dox," or "doxo" refer to an anticancer drug having the structure: [ka] Or its pharmaceutically acceptable salt, solvate or prodrug, and mixtures thereof.For example, doxorubicin can be conjugated to the peptide compound of the present disclosure at position 14 via the oxygen atom bonded to carbon atom.Doxorubicin can be linked to the peptide compound directly or via a linker.

[0059] As used herein, the term "cabazitaxel" or "cab" refers to an anticancer drug having the following structure: [ka] Or its pharmaceutically acceptable salt, solvate or prodrug, and mixtures thereof.For example, cabazitaxel can be conjugated to the peptide compound of the present disclosure at the 2-position of its side chain through the oxygen atom bonded to carbon atom.Cabazitaxel can be directly connected to peptide compound or via linker.

[0060] As used herein, the term "aldoxorubicin" or "aldo" refers to an anticancer agent having the structure: [ka] Or its pharmaceutically acceptable salt, solvate or prodrug, and mixtures thereof.For example, aldoxorubicin can be conjugated to the peptide compound of the present disclosure at the 13th position of its side chain via (6-maleimidocaproyl)hydrazone bonded to carbon.Aldoxorubicin can be linked to the peptide compound directly or via its linker.

[0061] As used herein, the term "phytochemical" refers to chemical compounds that naturally occur in plants and can be used to treat cancer. Examples of phytochemicals include curcumin. Curcumin (diferuloylmethane) is a yellow pigment found in turmeric spice (Curcuma longa), which has been associated with anti-inflammatory properties. Other phytochemicals with anti-inflammatory properties include omega-3, white willow bark, green tea, catechin, pycnogenol, Boswellia serrata resin, resveratrol, uncaria tomentosa, capsaicin, anthocyanins / anthocyanidins, flavanoids, olive oil compounds, chlorogenic acid, and sulforaphane.

[0062] As used herein, the term "curcumin" or "cur" refers to a phytochemical having the following structure: [ka] or its pharmaceutically acceptable salt, solvate or prodrug, and mixtures thereof. For example, curcumin can be conjugated to the peptide compound of the present disclosure via the oxygen atom of its phenolic group. Curcumin can be linked to the peptide compound directly or via a linker.

[0063] As used herein, the terms "conjugate compound," "peptide-drug conjugate," or "peptide conjugate" refer to a compound comprising a peptide compound disclosed herein linked to at least one therapeutic agent, optionally via a linker. A conjugate compound can have, for example, one, two, three, or four therapeutic agent molecules linked thereto. These one to four therapeutic agent molecules 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 via at least one covalent bond, at least one atom, or at least one linker. The conjugate compound can be used to treat cancer. Examples of conjugate compounds include, but are not limited to, the conjugate compounds shown below. [Table 5]

[0064] The term "conjugating" as used herein refers to the preparation of a conjugate, e.g., as defined above. Such an action involves linking a peptide compound, optionally via a linker, together with at least one therapeutic agent.

[0065] For example, below are general chemical formulas of some of the peptide-conjugate compounds disclosed herein:

[0066] Curcumin-peptide conjugate compounds: [ka]

[0067] For example, below are the chemical structures of some of the conjugate compounds disclosed herein. Docetaxel-peptide conjugate (DoceKA) (TH1902): [ka] Doxorubicin-peptide conjugate (DoxKA): [ka] Chemical formula:C 153 H 212 N 28 O 51 Molecular weight: 3259.52 KBC-106: [ka] Curcumin-peptide conjugates: KBC-201: [ka] KBP-106-Cys-Aldrubicin: [ka]

[0068] As used herein, the term "linker" refers to a chemical structure that links a peptide compound disclosed herein to at least one therapeutic agent. Linkers can be linked to peptide compounds at different functional groups on the peptide compound. For example, a linker can be linked to a peptide compound at a primary amine (amine (-NH). This group is present at the N-terminus of each polypeptide chain (referred to as an α-amine) and in the side chain of a lysine (Lys, K) residue (referred to as an ε-amine). For example, a linker can be linked to a peptide compound at a carboxyl (-COOH). This group is present at the C-terminus of each polypeptide chain and in the side chains of aspartic acid (Asp, D) and glutamic acid (Glu, E). For example, a linker can be linked to a peptide compound at a sulfhydryl (-SH). This group is present in the side chain of cysteine ​​(Cys, C). Often, a linker is linked to a peptide compound at a sulfhydryl (-SH). This group is present in the side chain of a tandem amino acid. As part of the secondary or tertiary structure of a protein, cysteines are linked together between their side chains via disulfide bonds (-SS-). To make them available for cross-linking by most types of reactive groups, they must be reduced to sulfhydryls. For example, a linker can be linked to a peptide compound at a carbonyl (-CHO). Ketone or aldehyde groups can be created in glycoproteins by oxidizing post-translational modifications (glycosylation) of polysaccharides with sodium metaperiodate. For example, the linker can be a cleavable linker. For example, the linker can be a non-cleavable linker.

[0069] The table below summarizes the reactivity classes and chemical groups of some major linkers for standard chemical conjugation. [Table 6]

[0070] For example, homobifunctional and heterobifunctional crosslinkers can be used. For example, disuccinimidyl suberate (DSS) is a homobifunctional crosslinker with identical amine-reactive NHS ester groups at both ends of a short spacer arm. For example, sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC) is a heterobifunctional crosslinker with an amine-reactive sulfo-NHS ester group at one end of a cyclohexane spacer arm and a sulfhydryl-reactive maleimide group at the opposite end. This allows for a sequential two-step conjugation procedure. Among the commercially available homobifunctional crosslinkers are BSOCOES (bis(2-[succinimidooxycarbonyloxy]ethyl) sulfone, DDPPB (1,4-di(3'-[2-pyridyldithio]-propionamido)butane), DSS (disuccinimidyl suberate), DST (disuccinimidyl tartrate), sulfo-DST (disulfodisuccinimidyl tartrate), DSP (dithiobis(succinimidyl propionate), DTSSP (3,3'-dithiobis(sulfosuccinimidyl propionate), EGS (ethylene glycol bis(succinimidyl succinate)), and BASED (bis(β-[4-azidosalicylamido]-ethyl) disulfide iodizable).

[0071] Peptide compounds can be conjugated via various linkers, such as sulfhydryl groups, amino groups (amines), or any suitable reactive group. The linker can be a covalent bond. The linker group can include a flexible arm, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 carbon atoms.

[0072] Exemplary linkers include, but are not limited to, pyridine disulfide, thiosulfonate, vinyl sulfonate, isocyanate, imidoester, diazine, hydrazine, thiol, carboxylic acid, multipeptide linker, and acetylene. Alternatively, other linkers that can be used include BS 3These include bis(sulfosuccinimidyl)suberate (a homobifunctional N-hydroxysuccinimide ester that targets accessible primary amines), NHS / EDC (N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (NHS / EDC allows primary amine groups to be conjugated with carboxyl groups)), sulfo-EMCS ([N-ε-maleimidocaproic acid]hydrazide (sulfo-EMCS is a heterobifunctional reactive group that is reactive toward sulfhydryl and amino groups)), and hydrazide (most proteins contain exposed carbohydrates, and hydrazides are useful reagents for linking carboxyl groups to primary amines).

[0073] A wide variety of activated carboxyl groups (e.g., esters) can be used as chemically reactive groups, provided that the hydroxyl moiety is physiologically acceptable to the extent necessary to modify the peptide compound to form a covalent bond. Specific examples of such agents include N-hydroxysuccinimide (NHS), N-hydroxysulfosuccinimide (sulfo-NHS), maleimidobenzoylsuccinimide (MBS), gamma-maleimidobutyryloxysuccinimide ester (GMBS), maleimidopropionic acid (MPA), maleimidohexanoic acid (MHA), and maleimidoundecanoic acid (MUA).

[0074] Primary amines are the primary target of NHS esters, which react with them to form covalent amide bonds. Accessible α-amine groups present at the N-terminus of proteins and the ε-amine of lysine react with NHS esters. Thus, the conjugated compounds disclosed herein can include linkers with NHS esters conjugated to the N-terminal amino acid of a peptide compound or the ε-amine of a lysine. An amide bond is formed when the NHS ester reacts with a primary amine to release N-hydroxysuccinimide. A succinimide-containing reactive group may be more simply referred to as a succinimidyl group. In some embodiments, the functional group on the peptide compound is a thiol group, and the chemically reactive group is a maleimide-containing group, such as gamma-maleimide-butyramide (GMBA or MPA). Such maleimide-containing groups may also be referred to herein as maleide groups.

[0075] Examples of the amine-amine linker include NHS esters and imide esters, examples of which are listed below. [Table 7]

[0076] The linker may also be a sulfhydryl-sulfhydryl linker such as maleimides and pyridyldithiols, listed below. [Table 8]

[0077] The linker may also be an amine-sulfhydryl linker, including NHS ester / maleimide compounds. Examples of these compounds are provided below. [Table 9]

[0078] Linkers are capable of reacting with amino groups and non-selective entities, including NHS ester / aryl azide and NHS ester / diazirine linkers, examples of which are listed below. [Table 10]

[0079] Exemplary amine-carboxyl linkers include carbodiimide compounds such as DCC (N,N-dicyclohexylcarbodiimide) and EDC (1-ethyl-3-[3-dimethylaminopropyl]carbodiimide). Exemplary sulfhydryl-nonselective linkers include pyridyldithiol / aryl azide compounds (e.g., APDP ((N-[4-(p-azidosalicylamido)butyl]-3'-(2'-pyridyldithio)propionamide)). Exemplary sulfhydryl-carbohydrate linkers include maleimide / hydrazide compounds (e.g., BMPH (N-[β-maleimidopropionic acid]hydrazide), EMCH ([N-ε-maleimidocaproic acid]hydrazide), MPBH4-(4-N-maleimidophenyl)butyric acid hydrazide), and KMUH (N-[κ-maleimidoundecanoic acid]hydrazide)), and pyridyldithiol / hydrazide compounds (e.g., PDPH (3-(2-pyridyldi)propionylhydrazide)). Exemplary carbohydrate-nonselective linkers include hydrazide / aryl azide compounds (e.g., ABH (p-azidobenzoylhydrazide)). Exemplary hydroxyl-sulfhydryl 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)).

[0080] The linker can connect 3 to 7 entities to generate branch points of varying complexity in the conjugated peptide compound. [Table 11]

[0081] TMEA and TSAT are accessible through a maleimide group bearing a sulfhydryl group. The hydroxyl and carboxyl groups of THPP can react with primary or secondary amines. Other useful linkers conform to the formula Y=C=NQAC(O)-Z, where Q is a homoaromatic or heteroaromatic ring system and A is a single bond or an unsubstituted or substituted divalent C1- 30 is a bridging group, Y is O or S, Z is Cl, Br, I, N, N-succinimidyloxy, imidazolyl, 1-benzotriazolyloxy, OAr (where Ar is an electron-deficient activated aryl group), or OC(O)R (where R is -AQN=C=Y or C4- 20 It is a tertiary alkyl (see U.S. Pat. No. 4,680,338).

[0082] Other useful linkers are of the formula [ka] wherein R1 is H, C1-6 alkyl, C2-6 alkenyl, C6- 12 aryl or alkynyl, or those coupled with a divalent organic -O-, -S-, or [ka] wherein R' is a C1-6 alkyl, a linking moiety, and R2 is H, C1- 12 Alkyl, C6~ 12 Aryl or C6~ 12 aralkyl, and R3 is [ka] or another chemical structure capable of delocalizing the lone pair of electrons of the adjacent nitrogen, and R4 is a pendant reactive group capable of linking R3 to a peptide compound or drug (see, e.g., U.S. Patent No. 5,306,809).

[0083] The linker may contain at least one amino acid residue and may be a peptide of at least or about 2, 3, 4, 5, 6, 7, 10, 15, 20, 25, 30, 40, or 50 amino acid residues. When the linker is a single amino acid residue, it can be any naturally occurring or non-naturally occurring amino acid (e.g., Gly or Cys). When the linker is a short peptide, it can have the sequence [Gly-Gly-Gly-Gly-Ser]. n The linker may be a glycine-rich peptide (which tends to be flexible) such as a peptide having the formula [XXXX-Gly] (see U.S. Pat. No. 7,271,149) or a serine-rich peptide linker (see U.S. Pat. No. 5,525,491), such as a peptide having the formula [XXXX-Gly] y wherein up to two of X are Thr, the remaining X 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 an α-helical linker (e.g., A(EAAAK) n A, where n is 1, 2, 3, 4, or 5.

[0084] The linker can be an aliphatic linker (e.g., having an amide bond to the polypeptide and an ester bond to the therapeutic agent). When an aliphatic linker is used, the aliphatic linker can be any length (e.g., C1 to C 20 ) and the chemical moieties (e.g., amino groups or carbamates) that they contain.

[0085] 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 may form an amide bond with the amino group of the amino acid residue, and the other carboxyl group may form an amide bond with, for example, the amino group of a peptide or a substituent. When the linker is Lys, Glu, or Asp, its carboxyl group may form an amide bond with the amino group of the amino acid residue, and the amino group may form an amide bond with, for example, the carboxyl group of a substituent. When Lys is used as a linker, an additional linker may be inserted between the ε-amino group of Lys and the substituent. The additional linker may be succinic acid, which can form an amide bond with the ε-amino group of Lys and the amino group present in the substituent. In one embodiment, the further linker is Glu or Asp (e.g., which forms an amide bond with the ε-amino group of Lys and another amide bond with a carboxyl group present in the substituent), i.e., the substituent is an Nε-acylated lysine residue.

[0086] 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.

[0087] The linker can provide a cleavable bond (e.g., a thioester bond) or a non-cleavable bond (e.g., a maleimide bond). For example, a cytotoxic protein can be attached to a linker that reacts with lysine residues in a polypeptide and modified free amines present at the amino terminus of the polypeptide. Thus, linkers useful in the present conjugate compounds can contain a group reactive with a primary amine on the polypeptide or modified polypeptide to which the therapeutic moiety is conjugated. More specifically, the linker can be selected from the group consisting of monofluorocyclooctyne (MFCO), bicyclo[6.1.0]nonyne (BCN), N-succinimidyl-S-acetylthioacetate (SATA), N-succinimidyl-S-acetylthiopropionate (SATP), maleimide, and dibenzocyclooctyne ester (DBCO ester). Useful cyclooctynes ​​within a given linker include OCT, ALO, MOFO, DIFO, DIBO, BARAC, DIBAC, and DIMAC.

[0088] The linker can include flexible arms, such as, for example, short arms (fewer than two carbon chains), medium-sized arms (two to five carbon chains), or long arms (three to six carbon chains).

[0089] Click chemistry can also be used for conjugation on peptides (DBCO, TCO, tetrazine, azide, and alkyne linkers). These linker families can be reactive to amine, carboxyl, and sulfhydryl groups. In addition, these linkers can be biotinylated, PEGylated, modified with fluorescent imaging dyes, or phosphoramidated for incorporation into oligonucleotide sequences.

[0090] The term "intermediate," as used herein, refers to a therapeutic agent that reacts with a linker, thereby forming an intermediate or activated form of the therapeutic agent. The intermediate can be reacted with a peptide compound disclosed herein, thereby forming a conjugate compound disclosed herein, which can be used to treat cancer or aggressive cancer.

[0091] The term "amino acid" refers to common natural (genetically encoded) or synthetic amino acids known to those skilled in the art, and their common derivatives. When applied to amino acids, "standard" or "proteinogenic" refers to the 20 genetically encoded amino acids in their natural configuration. Similarly, when applied to amino acids, "non-standard," "unnatural," or "unusual" refers to a wide selection of unnatural, rare, or synthetic amino acids, such as those described in Hunt, S., in Chemistry and Biochemistry of the Amino Acids, edited by Barrett, G.C., Chapman and Hall: New York, 1985. Some examples of non-standard amino acids include non-alpha-amino acids and D-amino acids.

[0092] The abbreviations used for amino acids and peptide designations follow the rules of the IUPAC-IUB Commission of Biochemical Nomenclature in 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, following 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, 2. nd edition, Portland Press, 1992, pp. 39-67. Extensions to this rule have been published in the JCBN / NC-IUB Newsletter 1985, 1986, and 1989. Biochemical Nomenclature and Related Documents, 2 ndedition, Portland Press, 1992, pp. 68-69.

[0093] The term "antagonist" refers to a compound that reduces at least some of the effect of an endogenous ligand of a protein, receptor, enzyme, interaction, or the like.

[0094] The term "inhibitor" refers to a compound that decreases the normal activity of a protein, receptor, enzyme, interaction, and the like.

[0095] 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 peptide compounds or peptide conjugates disclosed herein.

[0096] The term "mixture" as used herein refers to a composition containing two or more peptide compounds. In some embodiments, 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," this means that it can contain two or more "forms" of the peptide compound, such as salts, solvates, prodrugs, or, if applicable, stereoisomers of the peptide compound, in any ratio. Those skilled in the art will understand that the peptide compound in the mixture can also exist as a mixture of forms. For example, the peptide compound may exist as a hydrate of a salt 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 this application.

[0097] The term "modulator" refers to a peptide compound that has an effect on a biological or chemical process or mechanism. For example, a modulator may increase, promote, up-regulate, activate, inhibit, decrease, block, prevent, slow, desensitize, deactivate, down-regulate, etc. a biological or chemical process or mechanism. Thus, a modulator may 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.

[0098] The term "peptide" refers to a chemical compound containing at least two amino acids covalently linked together using an amide bond.

[0099] As used herein, the term "prodrug" refers to a derivative of the active form of a known compound or composition, which, upon administration to a subject, is gradually converted to the active form to provide a better therapeutic response and / or reduced toxicity levels. Generally, prodrugs are functional derivatives of the compounds disclosed herein that are readily convertible in vivo to the compound from which they are conceptually derived. Prodrugs include, but are not limited to, acyl esters, carbonates, phosphates, and urethanes. These groups are exemplary and not exhaustive; one of ordinary skill in the art can prepare other known types of prodrugs. Prodrugs can be formed, for example, at available hydroxy, thiol, amino, or carboxyl groups. For example, available OH or NH groups in the compounds of the present disclosure may be acylated using an activated acid in the presence of a base and, optionally, in an inert solvent (e.g., an acid chloride in pyridine). Some common esters utilized as prodrugs include phenyl esters, aliphatic (C1-C2) esters, and esters of phenyl, ... 24) esters, acyloxymethyl esters, carbamates, and amino acid esters. In certain cases, prodrugs of the compounds of the present disclosure are those in which hydroxy and / or amino groups in the compounds are masked as groups that can be converted to hydroxy and / or amino groups in vivo. Conventional procedures for the selection and preparation of suitable prodrugs are described, for example, in "Design of Prodrugs," edited by H. Bundgaard, Elsevier, 1985.

[0100] The term "protecting group" refers to any chemical compound that can be used to prevent a potentially reactive functional group, such as an amine, hydroxyl, or carboxyl, on a molecule 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 are found in Protective Groups in Organic Synthesis, edited by T.W. Greene and P.G. Wuts, John Wiley & Sons, New York, 4 thedition, 2006, 1082 pp, ISBN 9780471697541. Examples of amino-protecting groups include, but are not limited to, phthalimide, trichloroacetyl, benzyloxycarbonyl, tert-butoxycarbonyl, and adamantyloxycarbonyl. In some embodiments, the amino-protecting group is a carbamate amino-protecting group, defined as an amino-protecting group that forms a carbamate when attached to an amino group. In other embodiments, the aminocarbamate protecting group is allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), tert-butoxycarbonyl (Boc), and α,α-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, trimethylsilylethyl ester, and 2,2,2-trichloroethyl ester.

[0101] The term "sequence identity" as used herein refers to the percentage of sequence identity between two polypeptide sequences or two nucleic acid sequences. To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced into the first amino acid sequence or nucleic acid sequence for optimal alignment with the second amino acid or nucleic acid sequence). Then, the amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are compared. If a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules are identical at that position. The percent identity between two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical overlapping positions / total number of positions × 100%). In one embodiment, the two sequences are the same length. Determining the percent identity between two sequences can also be achieved using a mathematical algorithm. A preferred, non-limiting example of a mathematical algorithm utilized for comparing two sequences is the algorithm of Reference 52, modified as described in Reference 53. Such an algorithm is incorporated into the NBLAST and XBLAST programs of Reference 49. BLAST nucleotide searches can be performed, for example, with the NBLAST nucleotide program parameters set at score=100 and word length=12 to obtain nucleotide sequences homologous to the nucleic acid molecules of the present application. BLAST protein searches can be performed, for example, with the XBLAST program parameters set at score-50 and word length=3 to obtain amino acid sequences homologous to the protein molecules of the present disclosure. Gapped BLAST can be utilized as described in Reference 47 to obtain gapped alignments for comparison purposes. Alternatively, PSI-BLAST can be used to perform an iterated search that detects distant relationships between molecules (ibid.). When utilizing BLAST, Gapped BLAST, and PSI-Blast programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used (see, for example, the NCBI website).Another preferred, non-limiting example of a mathematical algorithm utilized for comparing sequences is the algorithm of Myers and Miller, 1988, CABIOS 4:11-17. Such an algorithm is incorporated into 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 can be determined using techniques similar to those described above, with or without allowing gaps. When calculating percent identity, typically, only exact matches are counted.

[0102] The phrase "consisting essentially of," as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and / or steps, as well as things that do not materially affect the basic and novel characteristics of the features, elements, components, groups, integers, and / or steps.

[0103] The expression "solid-phase chemistry" refers to the performance of chemical reactions in which one component of the reaction is covalently attached to a polymeric material (solid support, as defined below). Reaction methods for performing chemistry on the solid phase are more widely known and established outside the traditional fields of peptide and oligonucleotide chemistry (Solid-Phase Synthesis: A Practical Guide, edited by F. Albericio, CRC Press, 2000, 848 pp, ISBN: 978-0824703592, Organic Synthesis on Solid Phase, 2 ndedition, Florencio Zaragoza Dorwald, Wiley-VCH, 2002, 530 pp, ISBN: 3-527-30603-X, Solid-Phase Organic Synthesis: Concepts, Strategies, and Applications, edited by PHToy, Y. Lam, Wiley, 2012, 568 pp, ISBN: 978-0470599143).

[0104] The terms "solid support," "solid phase," or "resin" refer to a mechanically and chemically stable polymeric matrix utilized to perform solid-phase chemistry. This may be represented by the symbols "resin," "P-," or

number

[0105] Examples of suitable polymeric materials include, but are not limited to, polystyrene, polyethylene, polyethylene glycol (PEG, including but not limited to ChemMatrix® (Matrix Innovation, Quebec, Quebec, Canada, J. Comb. Chem. 2006, 8, 213-220)), polyethylene glycol grafted or covalently bonded to polystyrene (also called PEG-polystyrene, TentaGel™, Rapp, W.; Zhang, L.; Bayer, E. In Innovations and Perspectives in Solid Phase Synthesis. Peptides, Polypeptides and Oligonucleotides, edited by Epton, R.; SPCC Ltd.: Birmingham, UK; p 205), polyacrylate (CLEAR™), polyacrylamide, polyurethane, PEGA [polyethylene glycol poly(N,N dimethyl-acrylamide) copolymer, Tetrahedron Lett. 1992, 33, 3077-3080], cellulose, and the like. These materials may optionally contain additional chemical agents, such as polystyrene cross-linked with divinylvenethene (DVB, typically 0.1-5%, preferably 0.5-2%), to form cross-links and mechanically stabilize the structure. Non-limiting examples of such solid supports include aminomethylpolystyrene, hydroxymethylpolystyrene, benzhydrylaminepolystyrene (BHA), methylbenzhydrylamine (MBHA) polystyrene, and other polymeric backbones containing free chemical functional groups, most typically NH or -OH. The term is also meant to include "Ultraresins" with a high percentage ("loading") of these functional groups, such as those prepared from polyethyleneimine and cross-linking molecules (J. Comb. Chem. 2004, 6, 340-349). Upon completion of the synthesis, the resin is typically discarded, although it has been shown that it can be recycled (Tetrahedron Lett. 1975, 16, 3055).

[0106] Generally, materials used as resins are insoluble polymers, but certain polymers have different solubilities in different solvents, making them suitable for solid-phase chemistry. For example, polyethylene glycol can be used in this method because it is soluble in many organic solvents in which chemical reactions can be carried out, but insoluble in other solvents, such as diethyl ether. Thus, the reaction is carried out homogeneously in solution, and the polymeric product can then be precipitated by the addition of diethyl ether and processed as a solid. This has been called "liquid-phase" chemistry.

[0107] The term "pharmaceutically acceptable" means suitable for the treatment of a subject, such as an animal or a human.

[0108] The expression "pharmaceutically acceptable salt" means an acid addition salt or a base addition salt that is suitable or compatible for the treatment of a subject, such as an animal or a human.

[0109] As used herein, the phrase "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any compound of the present disclosure or any of its intermediates. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, as well as metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, formic acid, acetic acid, malic acid, tartaric acid, citric acid, ascorbic acid, monocarboxylic acids, dicarboxylic acids, and tricarboxylic acids, such as maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, and salicylic acid, and sulfonic acids, such as p-toluenesulfonic acid and methanesulfonic acid. Either monobasic or dibasic acid salts can be formed, and such salts can exist in either hydrated, solvated, or substantially anhydrous form. Generally, the acid addition salt of the compound of the present disclosure is more soluble in water and various hydrophilic organic solvents than their free base form, and generally shows a higher melting point.The selection of suitable salt will be known to those skilled in the art.Other pharmaceutically unacceptable salts, such as oxalates, can be used, for example, in the isolation of the compound of the present disclosure, for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0110] As used herein, the phrase "pharmaceutically acceptable base addition salt" refers to any non-toxic organic or inorganic base addition salt of any acid compound of the present disclosure or any of its intermediates. Acid compounds of the present disclosure that can form base addition salts include, for example, those in which COH is a functional group. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium, or barium hydroxide. Exemplary organic bases that form suitable salts include aliphatic, alicyclic, or aromatic organic amines such as methylamine, trimethylamine, and picoline, or ammonia. The selection of an appropriate salt will be known to those skilled in the art. Other non-pharmaceutically acceptable base addition salts may be used, for example, in the isolation of compounds or conjugate compounds of the present disclosure, for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

[0111] Formation of a desired compound salt is accomplished using standard techniques, for example, treating a neutral compound with an acid or base in a suitable solvent and isolating the formed salt by filtration, extraction, or any other suitable method.

[0112] The term "solvate" as used herein refers to a compound, or a pharmaceutically acceptable salt thereof, in which molecules of a suitable solvent are incorporated into the crystal lattice. A suitable solvent is physiologically tolerable at the administered dosage. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is called a "hydrate." The formation of solvates will vary depending on the compound and the solvate. Generally, solvates are formed by dissolving the compound in a suitable solvent and isolating the solvate by cooling or using an antisolvent. Solvates are typically dried or azeotroped under ambient conditions.

[0113] As used herein, the term "subject" includes all members of the animal kingdom, including mammals such as mice, rats, dogs, and humans.

[0114] The terms "suitable" and "appropriate" mean that the selection of particular groups or conditions will depend on the particular synthetic operation and identity of the molecule being performed, but that such selection is within the skill of one trained in the art. All process steps described herein are carried out under conditions suitable to provide the indicated product. Those skilled in the art will understand 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 an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product, and it is within the skill of the art to do so.

[0115] The phrases "therapeutically effective amount," "effective amount," or "sufficient amount" of a compound or composition of the present disclosure refer to an amount sufficient to produce beneficial or desired results, including clinical results, when administered to a subject, including a mammal, e.g., a human. Accordingly, a "therapeutically effective amount" or "effective amount" depends on the context in which it is applied. For example, in the context of treating cancer, it refers to the amount of a compound, peptide compound conjugate, or composition sufficient to achieve such treatment of cancer 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 various factors, such as the given drug, peptide compound conjugate, pharmaceutical formulation, route of administration, type of disease or disorder, and the identity of the subject or host being treated, but can nevertheless be routinely determined by one of ordinary skill in the art. Also, 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 cancer in a subject (e.g., as determined by clinical symptoms or the amount of cancerous cells) compared to a control.

[0116] As used herein, and as is well understood in the art, "treatment" or "treating" is an approach to obtain beneficial or desired results, including clinical results. Beneficial or desired clinical results can include, but are not limited to, reduced tumor progression, reduced tumor size, reduced tumor growth rate, reduced tumor invasiveness and metastatic potential, alleviation or amelioration of one or more symptoms or conditions, reduction in the extent of disease, stable (i.e., not worsening) disease state, prevention of disease spread, slowing or delaying disease progression, improvement or palliation of disease state, and remission (partial or total), whether detectable or not. "Treatment" or "treating" can also mean prolonging survival compared to expected survival if not receiving treatment.

[0117] As used herein, the term "tolerability" or "tolerated" refers to the degree to which a therapeutic agent can be tolerated or accepted by a subject treated with the therapeutic agent. For example, tolerability can be assessed by measuring different parameters, such as (i) the maintenance or absence of weight loss, (ii) the duration of tolerated treatment, and (iii) the reduction or absence of side effects, such as neutropenia. For example, it is well established that a therapeutic agent is tolerated by a subject if no weight loss is observed during treatment using such a therapeutic agent. For example, the conjugates (comprising at least one therapeutic agent) of the present disclosure can increase the tolerability of a given therapeutic agent because the conjugates are more selective for the receptor than the therapeutic agent taken alone. Unconjugated toxins may be too toxic to administer or use alone to a subject. Therefore, to increase tolerability, highly potent toxins can be used in drug conjugates. In some embodiments, the therapeutic agent is a toxin selected from the group consisting of maytansinoids, auristatins, calicheamicins, amatoxins, and amanitins.

[0118] As used herein, the term "administered" or "administering" means administering a therapeutically effective amount of a compound, peptide compound conjugate, or composition of the present application to a cell, either in vitro (e.g., in a cell culture) or in vivo (e.g., in a subject).

[0119] In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be inclusive 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 above also applies to words with similar meanings, such as "including," "having," and their derivatives. Finally, terms of degree, such as "substantially," "about," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified term so that the end result is not significantly altered. These terms of degree should be interpreted as including a deviation of at least ±5% of the modified term, if this deviation does not negate the meaning of the modified term.

[0120] As used herein and in 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 a mixture of two or more compounds. Also, it should be noted that the term "or" is generally used in its sense including "and / or" unless the context clearly dictates otherwise.

[0121] In compositions that include "additional" or "second" components, the second component, as used herein, is chemically distinct from the other or first component. The "third" component is distinct from the other, first, and second components, and further recited or "additional" components are similarly distinct.

[0122] It is intended that the definitions and embodiments described in particular sections are applicable to other embodiments described herein where they are suitable, as would be understood by one of ordinary skill in the art.

[0123] The recitation herein of numerical ranges by endpoints includes 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 understood that all numbers and fractions thereof are presumed to be modified by the term "about."

[0124] We have previously developed a platform that enables the delivery of therapeutic agents to cancer cells for novel therapies targeting primary and secondary tumors. This approach utilizes peptide compounds derived from bacterial proteins or ligands for receptors expressed on cancer cells (e.g., sortilin / syndecans).

[0125] Disclosed herein are compositions comprising a solubilizing agent and a peptide compound, as well as compositions comprising a solubilizing agent and a conjugate compound comprising at least one therapeutic agent linked to a peptide compound for use in treating cancer.

[0126] Thus, in a first aspect, there is provided a peptide compound having at least 60% sequence identity to a compound selected from the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII), [Table 12] During the ceremony, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X18 , and X 19 are independently selected from any amino acid; X 16 , X 17 , X 20 , and X 21 are independently selected from Q, P, Y, I and L; n is 0, 1, 2, 3, 4, or 5; When more than one X is present, each X is independently selected from any amino acid; X 19 is present more than once, each X is independently selected from any amino acid; wherein at least one protecting group and / or at least one labeling agent is optionally linked to said peptide at the N-terminus and / or C-terminus.

[0127] Another embodiment is a composition comprising a solubilizing agent and a peptide compound having at least 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 compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), and Formula (XIII), [Table 13] During the ceremony, 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 19are independently selected from any amino acid; X 16 , X 17 , X 20 , and X 21 are independently selected from Q, P, Y, I and L; n is 0, 1, 2, 3, 4, or 5; When more than one X is present, each X is independently selected from any amino acid; X 19 is present more than once, each X is independently selected from any amino acid; wherein at least one protecting group and / or at least one labeling agent is optionally linked to said peptide at the N-terminus and / or C-terminus.

[0128] Yet another embodiment 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 compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), and Formula (XIII), [Table 14] During the ceremony, 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; X 16 , X 17 , X 20 , and X 21 are independently selected from Q, P, Y, I and L; n is 0, 1, 2, 3, 4, or 5; When more than one X is present, each X is independently selected from any amino acid; X 19 is present more than once, each X is independently selected from any amino acid; wherein at least one protecting group and / or at least one labeling agent is optionally linked to said peptide at the N-terminus and / or C-terminus.

[0129] In some embodiments, the peptide compound targets the sortilin receptor. In some embodiments, the peptide compound is for use in targeting the sortilin receptor.

[0130] For example, the peptidic compound is a peptidic compound comprising: [Table 15]

[0131] For example, the peptidic compound is a peptidic compound consisting essentially of: [Table 16]

[0132] For example, the peptide compound is a peptide compound consisting of: [Table 17]

[0133] For example, peptide compounds include compounds selected from compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII). [Table 18] During the ceremony, 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; X 16 , X 17 , X 20 , and X 21 are independently selected from Q, P, Y, I and L; n is 0, 1, 2, 3, 4, or 5; When more than one X is present, each X is independently selected from any amino acid; X 19 is present more than once, each X is independently selected from any amino acid; wherein at least one protecting group and / or at least one labeling agent is optionally linked to said peptide at the N-terminus and / or C-terminus.

[0134] For example, the peptide compound may be 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% for a peptide compound selected from the peptide compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII). , 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.

[0135] 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 the peptide compound represented by Formula (I) or SEQ ID NO:1.

[0136] 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 the peptide compound represented by Formula (II) or SEQ ID NO:2.

[0137] 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 the peptide compound represented by Formula (III) or SEQ ID NO:3.

[0138] 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 the peptide compound represented by Formula (IV) or SEQ ID NO:4.

[0139] 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 the peptide compound represented by Formula (V) or SEQ ID NO:5.

[0140] 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 the peptide compound represented by Formula (VI) or SEQ ID NO:6.

[0141] 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 the peptide compound represented by Formula (VII) or SEQ ID NO:7.

[0142] 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 the peptide compound represented by Formula (VIII) or SEQ ID NO:8.

[0143] 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 the peptide compound represented by Formula (IX) or SEQ ID NO:9.

[0144] 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 the peptide compound represented by Formula (X) or SEQ ID NO:10.

[0145] 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 the peptide compound represented by Formula (XI) or SEQ ID NO:11.

[0146] 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 the peptide compound represented by Formula (XII) or SEQ ID NO:12.

[0147] 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 the peptide compound represented by Formula (XIII) or SEQ ID NO:13.

[0148] 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 the peptide compound represented by Formula (LI) or SEQ ID NO:23.

[0149] 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.

[0150] 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).

[0151] 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.

[0152] In one embodiment, at least one protecting group is linked to said peptide at the N-terminus and / or C-terminus.

[0153] In one embodiment, a succinyl group is linked to the peptidic compound, for example, the peptidic compound has a sequence of succinyl-IKLSGGVQAKAGVINMFKSESY, corresponding to SEQ ID NO: 6 and having a succinyl group linked thereto at its N-terminus.

[0154] In one embodiment, an acetyl group is linked 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).

[0155] In one embodiment, at least one labeling agent is linked to said peptide at the N-terminus and / or C-terminus.

[0156] Those skilled in the art will understand that commonly used labeling agents can be used. For example, the labeling agent is a vitamin. For example, the labeling agent is biotin. For example, the labeling agent is used as a fluorescent probe and / or an imaging agent.

[0157] In one embodiment, the peptidic compound is biotinylated, for example, the peptidic compound has the sequence IKLSGGVQAKAGVINMFKSESYK (biotin), which corresponds to SEQ ID NO: 7 and has a biotin molecule linked thereto at its C-terminus.

[0158] For example, the peptide compound is represented by the following formula (XXXVI): The peptide compound includes a peptide compound having SEQ ID NO: 6 linked at the N-terminus to a succinyl group. Formula (XXXVI): Succinyl-IKLSGGVQAKAGVINMFKSESY

[0159] In one embodiment, X 16 is independently selected from Q, P, Y, I, and L.

[0160] For example, X 16 is Q. For example, X 16 is P. For example, X 16 is Y. For example, X 16 is I.

[0161] In one embodiment, X 17 is independently selected from Q, P, Y, I, and L.

[0162] For example, X 17 is Q. For example, X 17 is P. For example, X 17 is Y. For example, X 17 is I.

[0163] In one embodiment, X 20 is independently selected from Q, P, Y, I, and L.

[0164] For example, X 20 is Q. For example, X 20 is P. For example, X 20 is Y. For example, X 20 is I.

[0165] In one embodiment, X 21 is independently selected from Q, P, Y, I, and L.

[0166] For example, X 21 is Q. For example, X 21 is P. For example, X 21 is Y. For example, X 21 is I.

[0167] In one embodiment, the peptide compound is selected from: [Table 19]

[0168] In one embodiment, the peptide compound can be modified at the C-terminus and / or N-terminus by adding one or more amino acid residues to obtain or increase preferential binding sites at the peptide termini. For example, the amino acid can be cysteine. For example, the amino acid can be lysine. For example, the amino acid can be cysteine ​​added to the C-terminus of the peptide. In one embodiment, the peptide compound is modified by adding a cysteine ​​to the C-terminus. In a specific embodiment, the peptide compound has a sequence of acetyl-GVRAKAGVRN(Nle)FKSESY, corresponding to SEQ ID NO: 15, and is modified by the addition of a cysteine ​​at the C-terminus.

[0169] The peptide compounds described herein can be linked, linked, mixed, or conjugated to small molecules, peptides, proteins, oligonucleotides, diagnostic agents, imaging or radionuclide agents, large molecules such as monoclonal antibodies, therapeutic agents, e.g., phytochemicals, or drug delivery systems including nanoparticles, liposomes, nanotubes, graphene particles loaded with therapeutic agents, imaging agents, genes, siRNA, etc. The resulting conjugated compounds can be used, for example, as monotherapy or combination therapy to treat cancer.

[0170] Thus, another aspect disclosed herein is a method for preparing a compound comprising: A-(B) n is a conjugate compound having the formula During the ceremony, n is 1, 2, 3, or 4; A is a peptide compound as defined herein, said peptide optionally protected by a protecting group; B is at least one therapeutic agent, and B is linked to A; Optionally, the peptide compound is cyclic.

[0171] Yet another embodiment disclosed herein is a method for preparing a compound comprising: A-(B) n is a conjugate compound having the formula During the ceremony, n is 1, 2, 3, or 4; A is a peptide compound as defined herein, said peptide compound optionally protected by a protecting group; B is at least one therapeutic agent, and B is optionally linked to A at a free amine of said peptide compound, at an N-terminal position of said peptide compound, at a free -SH of said peptide compound, or at a free carboxyl of said peptide compound; Optionally, the peptide compound is cyclic.

[0172] In some embodiments, the conjugated peptides described herein target the sortilin receptor. In some embodiments, the conjugated peptides described herein are for use in targeting the sortilin receptor.

[0173] Yet another embodiment disclosed herein is a method for preparing a compound comprising: A-(B) n is a conjugate compound having the formula During the ceremony, n is 1, 2, 3, or 4; A is a peptide compound as defined herein; B is at least one therapeutic agent, and B is linked to A at a free amine of a lysine residue of said peptidic compound, optionally via a linker, or at the N-terminal position of said peptidic compound, optionally via a linker; Optionally, the peptide compound is cyclic; For use in treating cancer or invasive cancer.

[0174] In certain embodiments, B is linked to A via a linker, optionally via a cleavable linker.

[0175] For example, at least one therapeutic agent is a phytochemical selected from curcumin, omega-3, white willow bark, green tea, catechin, pycnogenol, Boswellia serrata resin, resveratrol, uncaria tomentosa, capsaicin, anthocyanins / anthocyanidins, flavanoids, olive oil compounds, chlorogenic acid, and sulforaphane.

[0176] In certain embodiments, the therapeutic agent is a phytochemical or an anti-cancer agent.

[0177] In certain embodiments, the phytochemical is curcumin.

[0178] In certain embodiments, the conjugate compound is selected from: a compound of formula (XIV) below, comprising a peptide compound having SEQ ID NO: 10, wherein each lysine residue has a curcumin molecule linked thereto; and A compound of formula (XV) below, comprising a peptide compound having SEQ ID NO: 11, wherein each lysine residue has a curcumin molecule linked thereto. Formula (XIV): GVRAK(curcumin)AGVRN(Nle)FK(curcumin)SESY Formula (XV): YK(curcumin)SLRRK(curcumin)APRWDAPLRDPALRQLL

[0179] For example, the conjugate compound is represented by formula (XIV):

[0180] For example, the conjugate compound is represented by formula (XV):

[0181] In certain embodiments, the conjugate compound is selected from: a compound of formula (XVI) below, comprising a peptide compound having SEQ ID NO: 15, wherein each lysine residue has a curcumin molecule linked thereto; and A compound of formula (XVII) below, comprising a peptide compound having SEQ ID NO: 16, wherein each lysine residue has a curcumin molecule linked thereto. Formula (XVI): Acetyl-GVRAK(curcumin)AGVRN(Nle)FK(curcumin)SESY Formula (XVII): Acetyl-YK(curcumin)SLRRK(curcumin)APRWDAPLRDPALRQLL

[0182] For example, the conjugate compound is represented by formula (XVI):

[0183] For example, the conjugate compound is represented by formula (XVII):

[0184] In certain embodiments, the therapeutic agent is an anti-cancer agent.

[0185] In certain embodiments, the anticancer agent is docetaxel.

[0186] In certain embodiments, the conjugate compound is represented by formula (XIX): It comprises a peptide compound having SEQ ID NO: 10, where each lysine residue has a docetaxel molecule linked to it. Formula (XIX): GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY

[0187] In another embodiment, the conjugate compound is represented by the following formula (XXIII): It comprises a peptide compound having SEQ ID NO: 15, where each lysine residue has a docetaxel molecule linked to it. Formula (XXIII): Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY

[0188] In certain embodiments, the anti-cancer drug is doxorubicin.

[0189] In certain embodiments, the conjugate compound is represented by formula (XXVI): It comprises a peptide compound having SEQ ID NO: 10, where each lysine residue has a doxorubicin molecule linked to it. Formula (XXVI): GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY

[0190] In another embodiment, the conjugate compound is represented by the following formula (XXVIII): It comprises a peptide compound having SEQ ID NO: 15, where each lysine residue has a doxorubicin molecule linked to it. Formula (XXVIII): Acetyl-GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY

[0191] In certain embodiments, the anticancer agent is cabazitaxel.

[0192] In certain embodiments, the anticancer agent is aldoxorubicin.

[0193] In one embodiment, the conjugate compound is represented by formula (LI): a peptide compound having SEQ ID NO: 23, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto; or The peptide compound has SEQ ID NO: 10, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, the cysteine ​​residue having an aldoxorubicin molecule linked thereto. Formula (LI): GVRAKAGVRN(Nle)FKSESYC (aldoxorubicin)

[0194] In certain embodiments, the conjugate compound is represented by formula (LII): a peptide compound having SEQ ID NO: 24, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto; or The peptide compound has SEQ ID NO: 15, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, the cysteine ​​residue having an aldoxorubicin molecule linked thereto. Formula (LII): Acetyl-GVRAKAGVRN(Nle)FKSESYC (aldoxorubicin)

[0195] In certain embodiments, at least one therapeutic agent, B, is linked to a peptidic compound, A, at the free amine of the lysine residue of the peptidic compound via a linker.

[0196] In certain embodiments, at least one therapeutic agent, B, is linked to a peptidic compound, A, at the N-terminal position of said peptidic compound via a linker.

[0197] In certain embodiments, the linker is selected from succinic acid and dimethylglutaric acid linkers.

[0198] For example, the linker is a cleavable linker. For example, the linker is a non-cleavable linker.

[0199] For example, the conjugate compound can include a cleavable linker linking at least one therapeutic agent to the peptide compound, e.g., the at least one therapeutic agent can be released from the peptide compound by the action of an esterase on the ester bond.

[0200] For example, a therapeutic agent can be conjugated to a peptide compound by forming a bond, such as a peptide bond, to an available free amine on the peptide at a lysine or amino terminus.

[0201] In some embodiments, B is linked to A' via a linker, optionally via a cleavable or non-cleavable linker. In some embodiments, at least one therapeutic agent is an anti-cancer agent. In some embodiments, the anti-cancer agents are docetaxel, doxorubicin, cabazitaxel, aldoxorubicin, maytansinoids, auristatins, calicheamicins, amatoxins, amanitin, and oligopeptide mimetics (e.g., tubulysins). In some embodiments, at least one therapeutic agent is a phytochemical, optionally curcumin. In some embodiments, the anti-cancer agent is docetaxel. In some embodiments, the anti-cancer agent is doxorubicin. In some embodiments, the anti-cancer agent is cabazitaxel. In some embodiments, the anti-cancer agent is aldoxorubicin.

[0202] In some embodiments, the conjugate compound comprises one molecule of a therapeutic agent linked to a peptide compound. In some embodiments, the conjugate compound comprises at least one molecule of a therapeutic agent linked to a peptide compound. In some embodiments, the conjugate compound comprises up to eight molecules of a therapeutic agent linked to a peptide compound.

[0203] In some embodiments, the conjugate compound comprises two molecules of a therapeutic agent linked to a peptide compound. In some embodiments, the conjugate compound comprises three molecules of a therapeutic agent linked to a peptide compound. In some embodiments, the conjugate compound comprises four molecules of a therapeutic agent linked to a peptide compound. In some embodiments, the conjugate compound comprises 1 to 8 molecules of a therapeutic agent linked to a peptide compound.

[0204] In certain embodiments, the compounds described herein target the sortilin receptor. In certain embodiments, the compounds described herein are for use in targeting the sortilin receptor.

[0205] In some embodiments, the compounds described herein are for the treatment of cancer or aggressive cancer.

[0206] For example, sortilin-expressing cells are immune cells, optionally macrophages, CD4+, CD8+, B220+, bone marrow-derived cells basophils, eosinophils, and cytotoxic T lymphocytes, natural killer (NK) cells, T helper type 1 (Th1) cells.

[0207] For example, sortilin-expressing cells are cancer cells, optionally ovarian cancer cells, endometrial cancer cells, breast cancer cells (e.g., triple-negative breast cancer cells, optionally HCC1599, HCC1937, HCC1143, MDA-MB468, HCC38, HCC70, HCC1806, HCC1187, DU4475, BT-549, Hs578T, MDA-MB231, MDA-MB436, MDA-MB1 57, MDA-MB453, BT-20, or HCC1395 cells), prostate cancer cells, colorectal cancer cells, lung cancer cells, pancreatic cancer cells, skin cancer cells, brain (glioma) cancer cells, urinary tract cancer cells, carcinoid cancer cells, kidney cancer cells, testicular cancer cells, pituitary cancer cells, and blood cancer cells, such as bone marrow cancer cells, diffuse large B-cell lymphoma cancer cells, myeloma cancer cells, or chronic B-cell leukemia cancer cells.

[0208] For example, the sortilin-expressing cell is a cancer cell, optionally an ovarian cancer cell, an endometrial cancer cell, a breast cancer cell (e.g., a triple-negative breast cancer cell), a prostate cancer cell, a colorectal cancer cell, a lung cancer cell, a pancreatic cancer cell, a skin cancer cell, a brain (glioma) cancer cell, a urinary tract cancer cell, a carcinoid cancer cell, a kidney cancer cell, a testicular cancer cell, a pituitary cancer cell and a blood cancer cell, such as a bone marrow cancer cell, a diffuse large B-cell lymphoma cancer cell, a myeloma cancer cell, or a chronic B-cell leukemia cancer cell.

[0209] 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.

[0210] The conjugate compounds disclosed herein can also be used to transport therapeutic agents into cells because they are not substrates for efflux pumps, such as the P-glycoprotein membrane transport pump, which extrude other therapeutic agents from multidrug-resistant cells.

[0211] In one embodiment, a method for obtaining a peptide compound is provided, comprising: i) providing a library of binder peptides; and ii) selecting a sortilin-binding peptide from the library by affinity selection using a target; The target is immobilized on a solid support; The target is composed of an amino acid sequence set forth in any one of SEQ ID NOs: 25 to 50, an analog thereof, or a fragment thereof; A method is provided wherein the target interacts with a sortilin-binding peptide.

[0212] In a further aspect, there is provided a method of preparing a conjugate compound conjugate disclosed herein, the method comprising: reacting a linker with said therapeutic agent to obtain an intermediate; optionally purifying said intermediate; reacting said intermediate with a peptide compound to obtain said conjugate compound; optionally purifying the conjugate compound conjugate; Methods are provided in which a therapeutic agent is linked to a peptide compound at the free amine of a lysine residue or at the N-terminus, and the peptide compound comprises 1, 2, 3, or 4 therapeutic agent molecules linked thereto.

[0213] For example, the peptide compound may have one therapeutic agent molecule linked thereto. For example, the peptide compound may have two therapeutic agent molecules linked thereto. For example, the peptide compound may have three therapeutic agent molecules linked thereto. For example, the peptide compound may have four therapeutic agent molecules linked thereto.

[0214] For example, the linker is succinic acid. For example, the linker is a dimethylglutarate linker.

[0215] In one embodiment, the peptide compound is protected at the N-terminus prior to reacting with the intermediate.

[0216] For example, a protecting group such as FMOC can be added as a protecting group to the free amine on the therapeutic agent before being incorporated by a linker.After its synthesis, the conjugate compound can be deprotected from the protecting group.For example, the conjugate compound containing the protecting agent FMOC can be deprotected using piperidine.Those skilled in the art will easily understand that other known chemical reagents can be used to deprotect the conjugate compound.

[0217] For example, the N-terminus of a therapeutic peptide compound may be capped by acetylation thereof, thereby providing an irreversible protecting group at the N-terminus.

[0218] In certain embodiments, the intermediate is activated before reacting with the peptide compound.

[0219] For example, the intermediate is activated prior to reacting the compound with a coupling agent 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).

[0220] For example, an intermediate containing a therapeutic agent linked to a linker can be activated with the peptide coupling reagent TBTU prior to conjugation with a peptide compound.

[0221] In one embodiment, the conjugate compound is purified after its synthesis.

[0222] The peptide compounds disclosed herein are useful in the context of fusion proteins. For example, fusion proteins can be engineered by fusing the peptide compounds (e.g., peptide compounds) disclosed herein to one or more proteins, or portions thereof, such as functional domains. Fusion proteins 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 include a linker connecting the proteins.

[0223] Commonly used protein expression systems include those derived from bacteria, yeast, baculovirus / insect, plant and mammalian cells, and more recently, filamentous fungi such as Myceliophthora thermophile.

[0224] One aspect disclosed herein is a composition comprising a solubilizing agent and a liposome, graphene, nanotube, or nanoparticle comprising at least one peptide compound as defined herein, for use in treating cancer.

[0225] One aspect disclosed herein is a composition comprising a solubilizing agent and a liposome, graphene, nanotube, or nanoparticle comprising at least one peptide compound defined herein that targets a sortilin receptor.

[0226] One aspect disclosed herein is a composition comprising a solubilizing agent and a liposome, graphene, nanotube, or nanoparticle comprising at least one peptide compound as defined herein for use in targeting a sortilin receptor.

[0227] Another aspect is a composition comprising a solubilizing agent and a liposome, graphene, nanotube, or nanoparticle coated with at least one compound as defined herein, for use in treating cancer.

[0228] Another embodiment is a composition comprising a solubilizing agent and a liposome, graphene, nanotube, or nanoparticle coated with at least one compound defined herein that targets a sortilin receptor.

[0229] Another aspect is a composition comprising a solubilizing agent and a liposome, graphene, nanotube, or nanoparticle coated with at least one compound as defined herein for use in targeting a sortilin receptor.

[0230] Another aspect is a composition for use in treating cancer, comprising a solubilizing agent and liposomes, graphene, nanotubes, or nanoparticles loaded with at least one therapeutic agent, gene, or siRNA, wherein said liposomes or said nanoparticles are coated with at least one compound as defined herein.

[0231] Various embodiments of liposomes, nanotubes, graphene, or nanoparticles can be envisioned by those skilled in the art. For example, liposomes or nanoparticles can contain at least one compound disclosed herein coated on the surface of the liposomes or nanoparticles and a therapeutic agent, such as an anticancer drug, within the liposomes or nanoparticles. For example, liposomes or nanoparticles can contain at least one compound disclosed herein coated on the surface of the liposomes or nanoparticles and a therapeutic agent, such as an anticancer drug, within the liposomes or nanoparticles. For example, liposomes or nanoparticles can contain at least one peptide compound disclosed herein coated on the surface of the liposomes or nanoparticles and a therapeutic agent, such as an anticancer drug, within the liposomes or nanoparticles. For example, liposomes or nanoparticles can contain at least one conjugate compound disclosed herein coated on the surface of the liposomes or nanoparticles and a therapeutic agent, such as an anticancer drug, within the liposomes or nanoparticles. For example, liposomes or nanoparticles may contain at least one compound (cmopound) disclosed herein coated on the surface of the liposome or nanoparticle, and a therapeutic agent, e.g., an anticancer drug, within the liposome or nanoparticle. Additionally, in some embodiments, the compounds described herein can be associated, linked, or linked with one or more other compounds to form multimers, such as dimers, trimers, or tetramers, as well as branched peptides; optionally, the peptide compounds are cyclic. Such compounds can be linked together, for example, via covalent bonds, atoms, or linkers. For example, a multimer contains more than one compound. Methods for producing multimeric (e.g., dimeric, trimeric) forms of peptide compounds are described in U.S. Patent No. 9,161,988, the entire contents of which are incorporated herein by reference.

[0232] 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 cell that expresses sortilin 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.

[0233] In some embodiments, the solubilizer is present in an amount of about 5% to about 15% by weight per total volume of the composition. In other embodiments, the solubilizer is present in an amount of about 8% to about 12% by weight per total volume of the composition. In other embodiments, the solubilizer is present in an amount of about 9% to about 11% by weight per total volume of the composition. In other embodiments, the solubilizer is present in an amount of about 10% by weight per total volume of the composition.

[0234] In some embodiments, the conjugate 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 embodiments, the conjugate 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 embodiments, the conjugate 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 embodiments, the conjugate 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 embodiments, the conjugate 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.

[0235] In some embodiments, the composition further comprises a solution suitable for injection, present at about 1% to about 10% by weight per total volume of the composition. In some embodiments, the composition further comprises a solution suitable for injection, present at about 2% to about 8% by weight per total volume of the composition. In some embodiments, the composition further comprises a solution suitable for injection, present at about 3% to about 7% by weight per total volume of the composition. In some embodiments, the composition further comprises a solution suitable for injection, present at about 4% to about 6% by weight per total volume of the composition. In some embodiments, the composition further comprises a solution suitable for injection, present at about 5% by weight per total volume of the composition.

[0236] In some embodiments, the solubilizing agent is polysorbate (Tween™), polyethylene glycol (15)-hydroxystearate (Solutol™), dimethyl sulfoxide (DMSO), water-soluble organic solvents (polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerin, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide), non-ionic surfactants (Cremophor™ EL, Cremophor™ RH 40, Cremophor™ RH 60, d-α-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol™ HS 15, sorbitan monooleate, poloxamer 407, Labrafil™ M-1944CS, Labrafil™ M-2125CS, Labrasol™, Gellucire™ 44 / 14, Softigen™ 767, 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 coconut and palm oils). seed oil medium chain triglycerides), organic liquids / semi-solids (beeswax, d-α-tocopherol, oleic acid, medium chain monoglycerides and diglycerides), cyclodextrins (α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutylether-β-cyclodextrin), phospholipids (hydrogenated soy phosphatidylcholine, distearoylphosphatidylglycerol, L-α-dimyristoylphosphatidylcholine, L-α-dimyristoylphosphatidylglycerol).

[0237] In some embodiments, the polysorbate is polysorbate 20, polysorbate 40, polysorbate 60, or polysorbate 80.

[0238] In some embodiments, the compositions of the present application further comprise a buffer selected from acetate buffer, borate buffer, citrate buffer, glycine buffer, HEPES buffer, phosphate buffer, Tris buffer, AES, ammonia, AMP, AMPD, AMPSO, BES, bicine bicarbonate, BIS-Tris BIS-Tris-propane borate, cacodylate, CAPS, CAPSO carbonate, CHES, citrate, DIPSO, formate, glycine lysylglycine HEPES, HEPPS, EPPS HEPPSO imidazole malate, maleic acid, MES, MOPS, MOPSO phosphate, PIPES, POPSO, phosphate, pyridine succinate, TAPS, TAPSO, taurine, TEA, TES, Tricine, Tris, and mixtures thereof.

[0239] In some embodiments, the compositions of the present application further comprise dextrose solution (e.g., D5W), sodium lactate solution (lactated Ringer's solution), saline, water, ethanol, acetic acid, formic acid, sodium hydroxide, and mixtures thereof.

[0240] In some embodiments, the composition is an aqueous solution having a pH of about 3 to about 5. In some embodiments, the composition is an aqueous solution having a pH of about 3.5 to about 4.5. In some embodiments, the composition is an aqueous solution having a pH of about 3.75 to about 4.25. In some embodiments, the composition is an aqueous solution having a pH of about 3.8 to about 4.1.

[0241] In some embodiments, the composition comprises polysorbate, dextrose solution, formic acid, sodium hydroxide, and optionally water.

[0242] In some embodiments, the polysorbate is present in an amount of about 5% to about 15% by weight per total volume of the composition. In other embodiments, the polysorbate is present in an amount of about 8% to about 12% by weight per total volume of the composition. In other embodiments, the polysorbate is present in an amount of about 9% to about 11% by weight per total volume of the composition. In other embodiments, the polysorbate is present in an amount of about 10% by weight per total volume of the composition.

[0243] In some embodiments, the dextrose 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 embodiments, the dextrose 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 embodiments, the dextrose solution has a concentration of about 5% and is present in an amount of about 5% by weight per total volume of the composition.

[0244] In some embodiments, 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 embodiments, 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 embodiments, formic acid is present in an amount of about 0.04% by volume per total volume of the composition.

[0245] In some embodiments, 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 embodiments, the sodium hydroxide is in a solution having a concentration of about 0.1N to about 1N. In some embodiments, the sodium hydroxide is in a solution having a concentration of about 0.1N. In some embodiments, the sodium hydroxide is in a solution having a concentration of about 1N. In some embodiments, 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 embodiments, the sodium hydroxide solution is present in an amount such that the composition has a pH of about 4.3.

[0246] In some embodiments, the composition comprises polysorbate 80 present in an amount of about 10% by weight per total volume of the composition, a dextrose 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 solution having a concentration of about 0.1 N to about 1 N and present in an amount such that the composition has a pH of about 4.1 to about 4.5, and optionally water or a diluent.

[0247] In certain embodiments, methods are provided for treating cancer or aggressive cancer, comprising administering to a subject in need thereof a therapeutically effective amount of at least one composition or compound defined herein.

[0248] In another aspect, provided is a method of treating cancer or aggressive cancer in a subject having cancerous tissue or cells that express Sortilin, comprising contacting said cancerous tissue or cells with at least one compositon or compound defined herein.

[0249] In another aspect, provided is a method of treating cancer or aggressive cancer in a subject having cancerous tissue or cells that express Sortilin, comprising contacting said cancerous tissue or cells with at least one composition or compound defined herein.

[0250] In another aspect, provided is a method of treating cancer or aggressive cancer in a subject having cancerous tissue or cells that express Sortilin, comprising contacting said cancerous tissue or cells with at least one composition or compound defined herein.

[0251] 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 defined herein.

[0252] In some embodiments, the composition is administered at a dose of about 1 to about 100 mg / kg / week. In some embodiments, the composition is administered at a dose of about 2 to about 40 mg / kg / week. In other embodiments, the composition is administered at a dose of about 5 to about 10 mg / kg / week. In other embodiments, the composition is administered at a dose of about 5 to about 25 mg / kg / week. In other embodiments, the composition is administered at a dose of about 10 to about 20 mg / kg / week. In other embodiments, the composition is administered at a dose of about 10 to about 75 mg / kg / week. In other embodiments, the composition is administered at a dose of about 35 to about 50 mg / kg / week.

[0253] In some embodiments, the composition is administered at a dose of about 3 to about 300 mg / kg / 3 weeks. In other embodiments, the composition is administered at a dose of about 6 to about 240 mg / kg / 3 weeks. In other embodiments, the composition is administered at a dose of about 15 to about 30 mg / kg / 3 weeks. In other embodiments, the composition is administered at a dose of about 15 to about 75 mg / kg / 3 weeks. In other embodiments, the composition is administered at a dose of about 30 to about 60 mg / kg / 3 weeks. In other embodiments, the composition is administered at a dose of about 30 to about 225 mg / kg / 3 weeks. In other embodiments, the composition is administered at a dose of about 105 to about 150 mg / kg / 3 weeks.

[0254] In some embodiments, dosage is expressed in terms of the active ingredient in the composition.For example, in the case of an exemplary formulation comprising the conjugate compound of docetaxel (TH1902), about 44% of the total weight of the conjugate compound corresponds to 1 molecule of docetaxel.In other words, 1 equivalent of docetaxel by weight corresponds to about 2.33 times the weight of conjugate TH1902, that is, 1g of docetaxel=about 2.33g of TH1902.

[0255] In some embodiments, the composition contains from about 3 to about 300 mg / mm 2 In other embodiments, the composition is administered at a dose of about 5 to about 210 mg / mm 2In other embodiments, the composition is administered at a dose of about 75 to about 150 mg / mm 2 In other embodiments, the composition is administered at a dose of about 10 to about 300 mg / mm 2 In other embodiments, the composition is administered at a dose of about 30 to about 150 mg / mm 2 It is administered at a dose of 0.001 mg / week.

[0256] In some embodiments, the composition contains about 10 to about 1000 mg / mm 2 In other embodiments, the composition is administered at a dose of about 15 to about 500 mg / mm 3. 2 In other embodiments, the composition is administered at a dose of about 10 to about 250 mg / mm 3. 2 In other embodiments, the composition is administered at a dose of about 10 to about 500 mg / mm 3. 2 In other embodiments, the composition is administered at a dose of about 50 to about 450 mg / mm 3. 2 It is administered at a dose of 1 / 3 weeks.

[0257] In some embodiments, the composition prevents tumor growth or progression for a period of at least 10 days after treatment. In some embodiments, the composition prevents tumor growth or progression for a period of at least 20 days after treatment. In other embodiments, the composition prevents tumor growth or progression for a period of at least 30 days after treatment. In other embodiments, the composition prevents tumor growth or progression for a period of at least 40 days after treatment.

[0258] In some embodiments, the composition prevents tumor growth or progression for a period of about 10 to about 50 days after treatment. In other embodiments, the composition prevents tumor growth or progression for a period of about 10 to about 25 days after treatment. In other embodiments, the composition prevents tumor growth or progression for a period of about 10 to about 20 days after treatment. In other embodiments, the composition prevents tumor growth or progression for a period of about 10 to about 15 days after treatment.

[0259] In some embodiments, the composition is effective in reducing tumor size for a period of at least 10 days after treatment. In other embodiments, the composition is effective in reducing tumor size for a period of at least 20 days after treatment. In other embodiments, the composition is effective in reducing tumor size for a period of at least 30 days after treatment. In other embodiments, the composition is effective in reducing tumor size for a period of at least 40 days after treatment.

[0260] In some embodiments, the composition is effective in reducing tumor size for a period of about 10 to about 50 days after treatment. In other embodiments, the composition is effective in reducing tumor size for a period of about 10 to about 25 days after treatment. In other embodiments, the composition is effective in reducing tumor size for a period of about 10 to about 20 days after treatment. In other embodiments, the composition is effective in reducing tumor size for a period of about 10 to about 15 days after treatment.

[0261] In some embodiments, the subject is a mammal. In some embodiments, the subject is an animal. In some embodiments, the subject is a human.

[0262] In another embodiment, there is provided a method of increasing the stability and / or bioavailability of a therapeutic agent, comprising: Obtaining a composition or conjugate compound disclosed herein, wherein said composition or conjugate compound comprises said therapeutic agent; and administering a therapeutically effective amount of the composition or conjugated compound to a subject in need thereof.

[0263] In another embodiment, there is provided a method of increasing the stability and / or bioavailability of a therapeutic agent, comprising: conjugating said therapeutic agent with a peptide compound as defined herein to obtain a conjugate compound; and administering a therapeutically effective amount of the conjugated compound to a subject in need thereof.

[0264] In another embodiment, i) a peptide compound having at least 60% sequence identity to a compound selected from the compounds of formula (I), formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), formula (IX), formula (X), formula (XI), formula (XII), and formula (XIII), or ii) A-(B) n 1. A method of increasing the half-life and / or stability of a conjugate compound having the formula: During the ceremony, n is 1, 2, 3, or 4; A is the peptide compound, B is at least one therapeutic agent, and B is linked to A at a free amine of a lysine residue of said peptidic compound, optionally via a linker, or at the N-terminal position of said peptidic compound, optionally via a linker; Methods are provided that include combining the peptide or conjugate compound with a solubilizing agent to increase 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.

[0265] In another aspect, there is provided a method of increasing the half-life and / or stability of a peptide having at least 60% sequence identity to a compound selected from compounds of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), Formula (VIII), Formula (IX), Formula (X), Formula (XI), Formula (XII), and Formula (XIII), said method comprising conjugating the peptide compound to at least one molecule.

[0266] 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.

[0267] For example, the at least one molecule is selected from small molecules, peptides, proteins, oligonucleotides, diagnostic agents, imaging or radionuclide agents, large molecules such as monoclonal antibodies, therapeutic agents, imaging agents, genes, drug delivery systems including siRNA-loaded nanoparticles, liposomes, nanotubes, graphene particles.

[0268] For example, the conjugated peptide has a half-life that is increased by 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 unconjugated version of the same peptide.

[0269] The conjugate compounds disclosed herein may also provide better tolerability compared to unconjugated therapeutic agents.For example, in the international application WO2017 / 088058 (filed on November 24, 2016, entitled "PEPTIDE COMPOUNDS AND CONJUGATE COMPOUNDS FOR THE TREATMENT OF CANCER THROUGH RECEPTOR-MEDIATED CHEMOTHERAPY"), which is published in its entirety and is incorporated herein by reference, it has been shown that peptide-drug conjugates are better tolerated compared to unconjugated therapeutic agents at equivalent doses due to specific receptor targeting.In particular, in vivo studies have shown that treatment with conjugated compounds has little effect on the body weight of tested mice, thus indicating the tolerability of conjugated compounds.

[0270] For example, a method of increasing the tolerability of a therapeutic agent, comprising: conjugating a therapeutic agent to a peptide compound or peptides disclosed herein to obtain a conjugate compound; and Provided herein are methods comprising administering a therapeutically effective amount of a conjugate compound to a subject in need thereof.

[0271] For example, a method of increasing the tolerability of a therapeutic agent, comprising: Obtaining a conjugate compound disclosed herein, wherein the conjugate compound comprises a therapeutic agent; and Provided herein are methods comprising administering a therapeutically effective amount of a conjugate compound to a subject in need thereof.

[0272] For example, there is provided the use of a compound or composition as defined herein to increase the tolerability of a therapeutic agent.

[0273] In another aspect, there is provided a use of a compound or composition defined herein for treating cancer.

[0274] In another aspect, there is provided a use of a compound or composition as defined herein for targeting a sortilin receptor.

[0275] In another aspect, there is provided the use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer.

[0276] In another aspect, there is provided a use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer involving sortilin expression.

[0277] In another aspect, there is provided a use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer in cancerous tissue or cells that express Sortilin.

[0278] In another embodiment there is provided a use of a compound or composition as defined herein for the treatment of cancer or aggressive cancer in CD133 positive cells.

[0279] In another aspect, there is provided a use of a compound or composition as defined herein to increase the stability and / or bioavailability of at least one therapeutic agent.

[0280] In another aspect, there is provided a use of a compound or composition as defined herein for increasing the stability and / or bioavailability of at least one peptide compound.

[0281] In another aspect, there is provided a use of a compound or composition as defined herein for minimizing, reducing or diminishing tumor regrowth.

[0282] In another aspect, there is provided the use of a compound or composition as defined herein in the manufacture of a medicament for treating cancer.

[0283] In another aspect, there is provided the use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer.

[0284] In another aspect, there is provided the use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of a cancer associated with sortilin expression or an aggressive cancer.

[0285] In another aspect, there is provided the use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer in cancerous tissue or cells that express Sortilin.

[0286] In another aspect there is provided the use of a compound or composition as defined herein in the manufacture of a medicament for the treatment of cancer or aggressive cancer in CD133 positive cells.

[0287] In another aspect, there is provided the use of a compound or composition as defined herein in the manufacture of a medicament for minimizing, reducing or diminishing tumor regrowth.

[0288] For example, at least one therapeutic compound included in the conjugate compound and / or used in the manufacture of a medicament for treating cancer is an anti-cancer drug, e.g., the anti-cancer drug is selected from docetaxel, cabazitaxel, aldoxorubicin, maytansinoids, auristatins, calicheamicins, amatoxins, amanitins, and doxorubicin.

[0289] For example, at least one therapeutic compound included in the conjugate compound and / or used in the manufacture of a medicament for treating cancer is a phytochemical, e.g., the phytochemical is curcumin.

[0290] For example, the phytochemical may be selected from curcumin, omega-3, white willow bark, green tea, catechin, pycnogenol, Boswellia serrata resin, resveratrol, uncaria tomentosa, capsaicin, anthocyanins / anthocyanidins, flavanoids, olive oil compounds, chlorogenic acid, and sulforaphane.

[0291] In another embodiment, there is provided a use of a compound or composition disclosed herein to treat cancer in combination with therapeutic agents such as cytotoxic drugs, toxins and anti-cancer peptides, immunomodulators such as anti-PD1 and anti-PDL1, anti-cancer delivery systems, anti-angiogenic agents, and / or radiation therapy.

[0292] In further embodiments, there is provided the use of a compound or composition disclosed herein to target the sortilin receptor in combination with therapeutic agents such as cytotoxic drugs, toxins and anti-cancer peptides, immunomodulators such as anti-PD1 and anti-PDL1, anti-cancer delivery systems, anti-angiogenic agents, and / or radiation therapy.

[0293] Further provided is a method of preparing a composition of the present application, the method comprising preparing a diluent solution containing a solubilizing agent, adding a conjugate compound to the diluent solution in an amount sufficient to obtain a desired concentration, heating the solution to solubilize the conjugate 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 make up the final volume of the composition.

[0294] Further embodiments of the present disclosure are described with reference to the following examples, which should be understood to be for the purpose of illustrating embodiments of the present disclosure and are not intended to limit the scope of the present disclosure. [Example]

[0295] Example 1: Docetaxel-peptide conjugates for sortilin-positive triple-negative breast cancer Receptor-mediated therapy using jugate Introduction Taxanes are a class of widely used chemotherapy molecules that prevent the depolymerization of microtubules and therefore inhibit cell division. Examples of taxanes include paclitaxel and docetaxel. These taxanes are used to treat various cancers, including breast cancer.

[0296] Sortilin is a molecule found on the cell surface and within intracellular membranes of multiple tissues. It functions as a receptor for several peptide molecules and plays a poorly understood role in targeting the intracellular trafficking of membrane vesicles. Sortilin is overexpressed in many forms of cancer, including breast, ovarian, endometrial, lung, melanoma, colorectal, and pancreatic cancer. Sortilin has been found to be overexpressed in 79% of invasive ductal breast cancers and 59% of triple-negative breast cancers (TNBC). TNBC accounts for 15-20% of breast cancer cases worldwide and remains the most lethal subgroup of breast cancer. BC is considered more aggressive and difficult to treat than other breast cancers. Of women treated for TNBC, 42% experience rapid recurrence, with a peak incidence three years after diagnosis. Currently, no targeted therapies are approved for the treatment of TNBC. Therefore, the main treatment options for patients with TNBC are surgery, anthracycline and taxane chemotherapy, and radiation therapy.

[0297] The TH19P01 peptide has been developed that specifically binds to the extracellular surface of sortilin, allowing it to be internalized by the protein and deliver it to the cellular moiety to which the peptide is attached. One molecule being investigated is TH1902, which contains two molecules of docetaxel ester linked to a peptide and has shown considerable potential as a chemotherapeutic agent when tested in cell culture and human xenografts in nude mice.

[0298] High sortilin expression in human breast cancer As shown in Figures 1 and 2, high sortilin expression in human breast cancers (invasive ductal carcinoma, lymph node metastatic carcinoma, and triple-negative breast cancer) was demonstrated using immunohistochemical staining. The highest expression levels were detected in lymph node metastases. As shown in Figure 3, Kaplan-Meier curves indicate that high sortilin gene expression is associated with poor prognosis in TNBC patients with advanced stage 3 or 4 disease (n = 161 cases). As shown in Figure 4, Kaplan-Meier analysis of TNBC patients with lymph node metastasis (n = 72 cases) indicates that high sortilin gene expression dramatically impacts patient survival. Figure 5 is a Western blot showing that sortilin is highly expressed in different human TNBC cancer cell lines.

[0299] Sortilin-mediated chemotherapy internalization, proliferation, migration, and apoptosis In vitro testing of the TH19P01 peptide and TH1902 conjugate compounds was performed. As shown in Figure 6, sortilin siRNA inhibits the uptake of the peptide TH19P01. TH1902 was shown to have potent antiproliferative activity in MDA-MB-231 breast cancer cells, with an aH IC of 0.19 ± 0.09 nM compared to 0.56 ± 0.19 nM for docetaxel. 50 In addition, TH1902-induced apoptosis of MDA-MB-231 cells was found to be stronger than that of docetaxel (Figure 7) and was found to be reversed by the sortilin ligand TH19P01, neurotensin, and progranulin (Figure 8). TH1902 was also found to alter MDA-MB-231 microtubule polymerization, as shown by immunostaining of α-tubulin (Figure 9). Cell migration was also found to be inhibited by TH1902 in a sortilin-dependent manner (Figure 10).

[0300] In vivo validation of safety: Evaluation of neutropenia in TH1902-treated mice One of the more common oncologic emergencies associated with the use of taxanes in chemotherapy is febrile neutropenia (5 × 10 8 / L and is expected to worsen).

[0301] Fifteen young adult female homozygous athymic mice (Crl:CD1-Foxn1 nu Mice (ages 4-6 weeks) received six consecutive treatments of docetaxel or TH1902 (equivalent to a docetaxel dose of 15 mg / kg / week). As shown in Figure 11, docetaxel administration induced a rapid decline in neutrophil levels as early as 4 days after the first dose of docetaxel. This level continued to decline as docetaxel administration continued. While the decline in neutrophil counts after docetaxel test article administration was statistically significant both after the first and third injections, there was no apparent change in neutrophil counts in mice receiving the TH1902 test article at any measurement time (up to 6 cycles, total dose of 195 mg / kg), nor was there any significant change in neutrophil counts in animals receiving vehicle alone (data not shown). These results indicated that TH1902 may be useful in preventing or reducing neutropenia, a side effect commonly observed with docetaxel treatment. In addition, no weight loss was observed in TH1902-treated mice (data not shown).

[0302] Additionally, mouse plasma levels of TH1902 and docetaxel were evaluated in TH1902-treated mice. As shown in Figure 12, high plasma concentrations of TH1902 were measured after intravenous bolus injection (50 mg / kg). Very low concentrations of docetaxel released from TH1902 were measured in mouse plasma, whereas approximately 15-20% of the docetaxel concentration was measured when administered as free drug.

[0303] In vivo validation of efficacy: Potent inhibition of TNBC tumor growth in MDA-MB-231 subcutaneous xenografts Group 1 mice implanted with MDA-MB-231 subcutaneous xenografts received a high dose of docetaxel (15 mg / kg), TH1902 (equivalent to the docetaxel dose), or vehicle (see Figure 13). Group 2 mice implanted with MDA-MB-231 subcutaneous xenografts received a low dose of docetaxel (3.75 mg / kg, 1 / 4 MTD), TH1902 (equivalent to the docetaxel dose), or vehicle (see Figure 14). In Group 1 (high dose), TH1902 was found to provide better and more sustained efficacy in terms of tumor growth inhibition. In Group 2 (low dose), significant improvement in efficacy was observed with TH1902 when administered at a lower dose compared to docetaxel. In addition, a higher cumulative injected dose was seen for TH1902 compared to docetaxel alone (up to 2-fold).

[0304] conclusion TH1902 demonstrated improved tolerability (lower toxicity) and improved efficacy (stronger inhibition of TNBC tumor growth) compared with docetaxel alone (at comparable doses). Other breast cancer types that express sortilin may potentially benefit from TH1902.

[0305] Example 2: Increased in vitro stability of formulated TH1902 in mouse plasma Additional studies were conducted to study the stability of formulated TH1902 in mouse plasma. TH1902 was dissolved in DMO or formulated with a solubilizer (formulation: DMSO / Solutol™ HS15 / Tween™-80 / EtOH / Sol.Ac.Ac. / D5W / water in the following V / V ratio: 5 / 6 / 2.5 / 0.75 / 0.005 / 69 / 16.75). TH1902 was incubated in mouse plasma at 37°C for the indicated time. Plasma proteins were precipitated by adding 4 volumes of ACN (87%) with formic acid (0.125%), followed by centrifugation (10,000 rpm x 5 min). The supernatant was injected into UPLC / MS. The peak area corresponding to TH1902 was calculated and compared to time 0. Results were expressed in terms of stability (%) as a function of time, as shown in Figure 15. As can be seen, TH1902 dissolved in DMSO had a half-life of 5 hours, while TH1902 formulated with a solubilizer had a half-life of 30 hours.

[0306] Example 3: Improved formulation of TH1902 Example 3A: Formulation containing 8.75 mg / kg / week of TH1902 Introduction A key factor in the development of any pharmaceutical product is the formulation of the administered product, which refers to the collection of chemicals present with the test article, which may affect solubility, stability, pH, or other properties that may affect the drug's bioavailability and activity.

[0307] the purpose The objective was to compare tumor growth inhibition when different formulations of TH1902 (8.75 mg / kg / week) were injected into the human subcutaneous tumor model MDA-MB-231 / Luc (a triple-negative breast cancer that constitutively expresses luciferase) xenografts grown in nude mice to identify the optimal formulation.

[0308] method Compound characterization TH1902 and docetaxel (supplied by Wonda Science Inc.) were used. Docetaxel (having a molecular weight of 808 g / mol) was formulated in EtOH / Tween™-80 / D5W (1:1:78). Specifically, 2.5 mg of docetaxel was dissolved in 40 μl of ethanol, and then 40 μl of Tween™-80 was added, followed by 3120 μl of D5W. TH1902 (having a molecular weight of 3704 g / mol) was formulated as described further below. Both treatments were administered intravenously once a week for 6 weeks. The treatment doses were 8.75 mg / kg (concentration 1.35 mg / mL) for TH1902 and 3.75 mg / kg (concentration 0.625 mg / mL) for docetaxel.

[0309] Eight different formulations containing TH1902 were tested. For formulations 7 and 8 (described below), TH1902 was loaded onto an HPLC column, then washed with 0.25 M ammonium acetate, washed with 2% acetic acid, and eluted with 50% acetonitrile, 2% acetic acid. The eluate (TH1902 with acetate counterions) was lyophilized until use in formulations 7 and 8. The various TH1902 formulations are detailed below in Tables 20 and 21. [Table 20] [Table 21] JPEG0007811908000037.jpg154170

[0310] Tumor cell preparation The cells used were MDA-MB-231 / Luc epithelial breast adenocarcinoma (Cell Biolabs Inc. #AKR-231). These cells were derived from triple-negative breast cancer (TNBC) and stably express firefly luciferase. The MDA-MB-231 / Luc cell line was grown as an adherent monolayer at 37°C in a humidified atmosphere (5% CO2, 95% O2). The culture medium was DMEM medium (Wisent, #319-005-CL) supplemented with 1x non-essential amino acid (NEAA) 100x solution (Hyclone™, #30238.01) and 10% fetal bovine serum (FBS) (Hyclone™, #SH30396.03). For experimental use, cells were detached from the culture flask by treatment with trypsin (Wisent, product number 325-042-CL) for 5-10 min, then diluted 10-fold and neutralized by adding complete culture medium. Cell number and cell viability were assessed using a BioRad TC20™ automated cell counter. For subcutaneous implantation in mice, 5 × 10 cells were used. 6 MDA-MB-231 / Luc tumor cells were resuspended in the appropriate volume of HBSS (Sigma no. H6648) transplantation medium for injection in 150 μl (3.33×10 7 cells / ml).

[0311] animal In this study, 60 young adult female homozygous nude mice (Crl:CD1-Foxn1) obtained from Charles River Canada Inc. (St-Constant, Quebec) were used. nu ) were used. Healthy mice were selected based on routine veterinary examination. Mice of comparable age (28–42 days) and weight were maintained for this study.

[0312] Mice were subcutaneously implanted with MDA-MB-231 / Luc cells as described above. Tumor growth was monitored until tumor volumes reached 40–140 mm. 3When the sigma reached 0.05 or 2-3 days after a significant increase, the mice were randomly assigned to a vehicle group, a docetaxel group, or one of eight TH1902 formulation groups (6 mice per group) for further treatment.

[0313] First, mice were anesthetized with isoflurane and oxygen. During the study, two-dimensional measurements were taken using electronic calipers, 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 the ellipsoid (π / 6), "a" is the longest diameter, and "b" is the shortest diameter [3].

[0314] Treatment is for tumors with a volume of 40 to 140 mm 3 Treatment was initiated when the TH1902 count reached 0.05 or 2-3 days after a significant increase. All treatments continued for 24 days and included four treatments. Animals receiving formulations 2 and 8 continued two additional treatments to extend their exposure to TH1902 to day 38.

[0315] All mice were observed daily for changes in appearance and behavior, and events were recorded when appropriate. Body weight was measured three times a week and recorded to the nearest 10 mg.

[0316] All animals in the vehicle group had tumors of 1000 mm 3 The docetaxel and 35 mg / kg TH1902 group (equimolar to docetaxel to allow for comparison) was maintained for long-term treatment and observation until day 69, when they were euthanized.

[0317] Data were analyzed using vehicle- versus test formulation- and docetaxel-treated animals by either one-way ANOVA followed by Dunnett's test, or by nonlinear regression fitting to Gompertz growth curves (to compare growth curves for tumor volume or animal bioluminescence). Analysis was performed using GraphPad Prism software. Statistical significance was assumed for p<0.05.

[0318] Results and Discussion Tumor volume All tumors were measured three times weekly using calipers. This resulted in a total of 12 measurements within 24 days. Animals were then euthanized, except for those treated with formulations 2 and 8, which showed the greatest reduction in tumor volume. These animals were maintained and monitored for an additional two weeks. The 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 1 / 4 of its maximum tolerated dose (MTD), respectively. The docetaxel-treated mice have tumor burdens that appear to grow slightly faster than those of control animals treated with vehicle alone. Of the eight formulations, formulation 3 appears to have no effect on tumor inhibition. In contrast, formulations 2 and 8 show potent inhibition of tumor growth. The other five formulations show intermediate levels of tumor inhibition and are comparable. Formulations 2 and 8, showing the strongest effects, comprise a slightly acidic solution containing Tween-80 and dextrose; Formulation 2 contains TH1902 with a formate counterion, while Formulation 8 contains TH1902 with an acetate counterion. Animals treated with Formulations 2 and 8 were monitored for an additional two weeks, during which time tumors treated with Formulation 8 showed slower tumor growth, while the tumor stasis observed with Formulation 2 remained unchanged. Formulations 2 and 8 showed statistically significant inhibition of tumor growth compared to vehicle-treated tumors, with a near-steady state observed in mice treated with Formulation 8 at day 24 (p=0.04), and a slight decrease in tumor volume after treatment with Formulation 2 (p=0.01).

[0319] The strong inhibition in tumor volume growth induced by diluted TH1902 (8.75 mg / kg / week) in Formulation 2 is reproduced in Figure 17, and the weights of mice treated with Formulation 2 are shown in Figure 18. As can be seen, treatment of mice with Formulation 2 did not affect their body weight. Similarly, no effect on body weight was observed with the other formulations tested (data not shown).

[0320] Example 3B: Formulation containing 17.5 mg / kg / week of TH1902 Additional formulations were tested as described below in Table 22. The concentration (Conc.) of TH1902 in the various formulations was evaluated as a measure of the solubility of TH1902 in the formulation. [Table 22] A "-" indicates that the conjugated compound TH1902 was not soluble in the particular formulation.

[0321] Preferred formulations demonstrated soubility of 3 mg / mL or greater and 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.

[0322] As can be seen from Figure 19, after six treatments, all formulations 1-7 were found to inhibit tumor volume compared to the control. Figure 20 similarly shows tumor progression in various TH1902 formulations. These results demonstrate that the formulations of the present application are useful in minimizing, reducing, or slowing tumor regrowth.

[0323] Table 23 below summarizes the results of the studies of Examples 3A and 3B based on various formulations. [Table 23]

[0324] Example 4: Formulation in clinical practice Extrapolating previous research findings to clinical practice, a proposed formulation is provided in which 200 mg of conjugated compound (e.g., TH1902) is dissolved in 20 mL of Tween™ 80 (10%) in D5W (pH 3). The mixture is heated (10 min, 60°C) and then transferred to a D5W infusion bag (pH 5). The concentration of the conjugated peptide is approximately 0.5-2 mg / mL, and the concentration of Tween™ is approximately 0.5-2%.

[0325] Example 5A: Pharmaceutical Composition for TH1902 - Injection Concentrate Table 24 shows the components and concentrations of the 10 mg / mL TH1902 injectable concentrate composition.

[0326] [Table 24] The density of the formulation is 1.029 g / mL at 25°C (reference PPS Notebook: LNB-20-028 p045). Density of formic acid = 1.22 g / mL. Density of 99% formic acid = 1.213 g / mL.

[0327] Dissolution of API A 1.5-liter scale-up batch of TH9102 Injection 10 mg / mL was successfully prepared by executing approved protocol CSR0210-001.00. The compounding method specified in this protocol was based on a procedure previously developed for several small-scale laboratory batches of FRD. This procedure relied on careful heating of the compounding mixture between 40 and 45°C to achieve complete dissolution of the API, and this temperature range was not exceeded to avoid undesirable gelation or aggregation of the compound. Based on the test results for pharmaceutical quality attributes, it is concluded that the compounding procedure was reproducible.

[0328] FIG. 21 shows the heating profile during dissolution of an R&D Stability lab batch of TH1902 API according to Example 5A.

[0329] Initial formulation development work for the TH1902 10 mg / mL injectable concentrate drug product focused on optimizing a solution capable of effectively dissolving the TH1902 API. Based on the results of studies conducted on excipient screening, additional excipient amounts (0–5% dextrose), and acid selection (HCl, citric acid, formic acid), the solution was finalized as an aqueous mixture of polysorbate-80 (10% w / v), dextrose (5% w / v), and formic acid (0.04% v / v). The next phase of formulation work focused on developing a compounding procedure for effective dissolution of TH1902 at the 10 mg / mL concentration in the finished placebo. This compounding procedure was demonstrated in multiple small-scale laboratory batches using several API lots. The pH value 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. Furthermore, the compounding procedure was found to be reproducible for two scaled-up batches of 2.5 L and 1.0 L (R&D stability lab batch) sizes at the set target pH value.

[0330] Example 5B: Pharmaceutical Composition for TH1902 - Injection Concentrate An alternative composition of a 10 mg / mL injectable concentrate of TH1902 is provided. Table 25 shows the components and concentrations.

[0331] [Table 25]

[0332] Dissolution of API Briefly, formulated TH1902 stock solutions were prepared as sterile aliquots of a 10 mg / mL frozen liquid solution (see below). On the day of animal dosing, the frozen aliquots were thawed at room temperature for 30 minutes and then diluted with sterile 5% Dextrose Injection USP (D5W) to the desired concentration for injection (i.e., typically 5.4 or 1.35 mg / mL).

[0333] FIG. 22 shows the heating profile during dissolution of TH1902 API according to the internal procedure, according to Example 5B.

[0334] A TH1902 frozen stock solution was prepared as follows. 1. Make TH1902 diluent solution (Diluent) the day before dissolution. Diluent: 10% Tween™ 80 (w / v) in D5W USP with 0.04% formic acid (V / V), pH approximately 2.9. Keep the solution at room temperature until TH1902 dissolution (next day). 2. Weigh 60 mg of TH1902 API into a 14 ml glass vial with a screw cap. Adjust the weight of TH1902 to reflect the purity of the TH1902 according to the Certificate of Analysis. 3. Add 90% of the diluent solution required to prepare a TH1902 10 mg / ml stock solution. 4. Swirl the contents of the bottle to form an opaque mixture and place a stir bar. 5. Place the bottle into a heating device (glass water bath, platform to hold the vial with thermometer, and stir bar on a digital heating plate). Begin mixing the contents of the bottle. 6. Gradually increase the temperature of the water bath in 5°C increments every 30 minutes until the mixture becomes clear (the temperature will increase to 45°C over a period of approximately 165-180 minutes). Record the temperature of the water bath every 15 minutes. 7. Allow to cool at room temperature for 30 minutes with gentle swirling. Measure pH. Adjust pH to 4.3 ± 0.2 with dilute NaOH (0.1 N or less). 8. Transfer the formulation to a graduated glass cylinder and bring to the final calculated volume with diluent solution. Transfer back to the 9.14 ml glass vial and mix gently for 5 minutes at room temperature. Measure the pH. The pH should be 4.3 ± 0.2. 10. Sterilize through a PES 0.22 μm membrane and filter into a new sterile 14 ml glass vial. Check the pH again. Perform UPLC analysis against a TH1902 standard curve for quantification and purity assessment. 11. Freeze aliquots of TH1902 stock solution (0.5 mL per aliquot in 4 mL glass vials) at -80°C.

[0335] A representative UPLC analysis of a stock solution of TH1902 at 10 mg / ml after dissolution using an in-house procedure is shown in FIG.

[0336] Advantageously, the formulations of Examples 5A-B were shown to provide a better appearance of the injectable product. Importantly, the heating profile indicates that less heating is required to obtain these formulations. Thus, greater stability of the formulations and better reproducibility of the methods for obtaining them can be expected.

[0337] In vivo results obtained by method of TH1902 API dissolution (internal procedure) - Example 5B In vivo results of the endometrial cancer xenograft model (AN3-CA) Three human sortilin-positive gynecological cancer cell lines (ovarian: ES-2 and SKOV-3 / Luc, endometrial: 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), 3.75 mg / kg of TH1902 (a concentration containing the same amount of docetaxel) inhibited tumor growth, unlike docetaxel. At an equivalent dose of 15 mg / kg / week of docetaxel, both docetaxel and TH1902 administration caused complete cessation of tumor growth arrest. TH1902 formulation appears 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 experienced prolonged tumor regression, while one mouse showed slow tumor recurrence 30 days after the last treatment. The body weight of mice administered docetaxel, TH1902, or vehicle was monitored as an overall indicator of morbidity. As shown in Figure 24, mice bearing AN3-CA tumors showed slight weight gain, except for animals administered any of the test articles. Meanwhile, at the MTD for docetaxel, animal weights remained within the pre-set 20% weight loss endpoint limit, although there was greater evidence of docetaxel-related weight loss. Animals administered TH1902 containing an equivalent amount of docetaxel maintained a fairly constant weight throughout the experiment.

[0338] The effects of TH1902 or docetaxel on the endometrial AN3-CA xenograft tumor model are shown in Figure 24. For the purposes of Figure 24A, mice bearing AN3-CA xenografts were repeatedly intravenously injected 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) (arrows indicate injection days). After two cycles, the maximum doses of docetaxel and TH1902 were both halved (7.5 mg / kg / week and 17.5 mg / kg / week, respectively), as indicated by the gray arrows. In Figure 24B, the effects of TH1902 and docetaxel on tumor progression on day 14 are shown by subtracting the initial tumor volume on day 0 from the tumor volume measured on day 14. For Figure 24C, mouse body weights were monitored throughout the study and were within the acceptable range and the -20% endpoint limit during all studies. All data symbols shown represent the mean ± standard error of the mean (SEM).

[0339] In vivo results of a colorectal cancer xenograft model (HT-29) Mice bearing HT29 colorectal xenograft tumors were treated with low and high doses of docetaxel or TH1902 (Figure 25). At the equivalent highest dose, the TH1902 formulation caused potent inhibition of HT29 tumor growth. Thus, TH1902 in its current formulation appears to be more effective than docetaxel at inducing long-term HT29 tumor progression.

[0340] Figure 25 shows the effects of TH1902 or docetaxel on a colorectal HT29 xenograft tumor model. Mice bearing HT29 tumor xenografts were repeatedly injected intravenously with vehicle or vehicle containing low (Figure 25A) or high doses of docetaxel or TH1902 (arrows indicate injection days). The body weights of mice treated with equivalent low (Figure C) or high (Figure D) doses of docetaxel or TH1902 were monitored throughout the study and remained within the acceptable range and the -20% endpoint limit during all studies. All data symbols shown represent the mean ± standard error of the mean (SEM).

[0341] In vivo results of a pancreatic cancer xenograft model (PANC-1) A sortilin-expressing pancreatic cancer cell line (PANC-1) was grown in vivo as subcutaneous tumor xenografts in immunodeficient nude mice. These animals were then used to evaluate the chemotherapeutic activity of vehicle, docetaxel, and the peptide-drug conjugate TH1902 at two different doses. Tumor growth in all five groups of mice was followed for 21 days. During this time, there was steady tumor growth in animals treated with vehicle alone, while tumors in mice treated with 3.75 mg / kg docetaxel appeared very similar in size to those in vehicle-treated mice (Figure 6A). Decreased tumor growth was associated with exposure to both low-dose TH1902 (8.75 mg / kg) and high-dose docetaxel (15 mg / kg, its MTD). Exposure to high-dose TH1902 (35 mg / kg) actually resulted in tumor size regression.

[0342] The two groups receiving the low dose of test article continued to receive weekly test article treatment and tumor volume measurements for an additional 1-4 weeks to examine the long-term consequences of low-dose treatment (Figure 6B). Tumor growth continued until the animals had to be euthanized due to tumor size, and it is clear that the low dose of TH1902 inhibited tumor growth.

[0343] These tumor growth curves show that low doses of both docetaxel and TH1902 have less impact on tumor volume than higher doses. In addition, TH1902 appears to be more effective than docetaxel at halting tumor growth and actually causing tumor regression when administered at higher doses.

[0344] Tumor volumes at day 21 were compared for the five groups of mice using one-way ANOVA followed by Dunnett's multiple comparison test. Tumor size in each of the four test groups was compared to tumor size in vehicle-treated mice. As shown in Figure 6C, tumor size in mice bearing PANC-1 tumors was indistinguishable between those treated with vehicle and those treated with low-dose docetaxel. In contrast, tumor size in mice receiving either low-dose TH1902 or high-dose docetaxel or TH1902 showed significant reductions in tumor size, and even remission in the case of high-dose TH1902. These data confirm that TH1902 is superior to docetaxel in treating these pancreatic xenograft tumors.

[0345] Figure 26 shows the effects of TH1902 and docetaxel on a pancreatic tumor xenograft model. Mice bearing subcutaneous pancreatic xenograft tumors were treated with TH1902, docetaxel, or vehicle. PANC-1 tumor volume measurements from all five groups were recorded for 3 weeks and are shown in Figure 26A. Black arrows indicate the day of test article administration. In Figure 26B, the same data are shown in this panel, but with extended results for mice administered low doses of docetaxel and TH1902. All data symbols shown represent the mean ± SEM for all groups in panels A and B, n = 6. Black arrows indicate the day of test article administration for all five groups, while gray arrows indicate administration only to animals in the two low-dose groups. For Figure 26C, tumor progression on day 21 was then compared between each treatment group. Bars shown represent the mean ± SEM. A quadruple asterisk indicates p<0.0001.

[0346] In vivo results of melanoma cancer xenograft model (SK-Mel-28) and syngeneic melanoma model (B16-F10) Two sortilin-expressing melanoma cancer cell lines (SK-MEL-28 and B16-F10) were used to monitor whether TH1902 inhibited cell growth when administered at 35 mg / kg / week compared to unconjugated docetaxel at 15 mg / kg / week. This is the maximum tolerated dose (MTD) of free docetaxel, and the TH1902 formulation contains an equivalent amount of docetaxel within this peptide-drug conjugate. It is clear that both docetaxel and TH1902 inhibited tumor growth in SK-MEL-28 xenografts, with TH1902 demonstrating stronger inhibition (Figure 27A). This difference was quantified when the control group reached the tumor volume endpoint on day 42. In contrast to docetaxel, significant regression of tumor volume was observed between control animals and animals treated with the TH1902 formulation (Figure 27B). Body weights of vehicle-, docetaxel-, and TH1902-treated mice remained within the -20% endpoint limit (Figure 27C).

[0347] Figure 27 shows the effect of TH1902 or docetaxel on the melanoma SK-MEL-28 xenograft tumor model. For Figure 27A, mice bearing SK-MEL-28 xenografts were repeatedly intravenously injected with vehicle or vehicle containing equivalent doses of docetaxel (15 mg / kg / week) or TH1902 (35 mg / kg / week) (arrows indicate the days of injection). In Figure 27B, the effect of TH1902 and docetaxel on tumor progression on day 42 is shown by subtracting the initial tumor volume on day 0 from the tumor volume measured on day 42. For Figure 27C, the body weights of mice treated with vehicle and equivalent doses of docetaxel or TH1902 were monitored throughout the study and remained within the acceptable range and the -20% endpoint limit throughout the study. All data symbols shown represent the mean ± standard error of the mean (SEM).

[0348] For the syngeneic B16-F10 melanoma tumor model, normal immunocompetent mice were subcutaneously implanted with murine B16-F10 cancer cells. Syngeneic mouse models consist of tumor tissue with the same genetic background as a given immunocompetent mouse strain. Syngeneic mouse models provide an effective approach to studying how cancer therapy functions in the presence of a functional immune system. In the first study (Figure 28), mice implanted with B16-F10 cancer cells were treated weekly with vehicle and equivalent doses of either docetaxel or TH1902. The results in Figure 28A show that this model is highly aggressive, with tumors growing very rapidly. In this highly aggressive melanoma syngeneic tumor model, the superior efficacy of the TH1902 formulation was clearly observed compared to unconjugated docetaxel. At the study endpoint of day 14 (Figure 28B), tumor regression was measured in TH1902-treated mice, in contrast to docetaxel, without affecting mouse body weight (Figure 28C). Additionally, tumors were collected, aligned, and photographed on day 14 (Figure 28D). The photographs clearly show the significant difference in size of tumors treated with the TH1902 formulation compared to those treated with vehicle or docetaxel. All tumors treated with the TH1902 formulation were much smaller than tumors from the other two groups (vehicle and docetaxel).

[0349] Figure 28 shows the effect of TH1902 or docetaxel on a syngeneic B16-F10 xenograft tumor model. For Figure 28A, immunocompetent mice bearing B16-F10 xenografts were repeatedly intravenously injected with vehicle or vehicle containing equivalent doses of docetaxel (15 mg / kg / week) or TH1902 (35 mg / kg / week) (arrows indicate injection days). In Figure 28B, the effect of TH1902 and docetaxel on tumor progression on day 14 is shown by subtracting the initial tumor volume on day 0 from the tumor volume measured on day 14, when tumors in the vehicle group reached the endpoint limit. For Figure 24C, the body weights of mice treated with vehicle and equivalent doses of docetaxel or TH1902 were monitored throughout the study and remained within the acceptable range and the -20% endpoint limit throughout the entire study. For Figure 28D, tumors were harvested on day 14, aligned according to their treatment, and photographed. All data symbols shown represent the mean ± standard error of the mean (SEM).

[0350] Next, a dose-response study was performed in a second study using a syngeneic B16-F10 melanoma tumor model (Figure 29). Immunocompetent mice bearing B16-F10 tumors were administered three different equivalent doses of docetaxel and TH1902 by intravenous bolus injection. The mice were then treated with 5, 7.5, and 10 mg / kg / biweekly docetaxel and equivalent TH1902 doses (11.5, 17.25, and 23 mg / kg / biweekly). The results clearly show that TH1902 induced much stronger tumor growth inhibition at all doses compared to unconjugated docetaxel. A clear and prolonged regression was observed at the highest dose of TH1902 (23 mg / kg / biweekly). An equivalent dose of docetaxel (10 mg / kg / biweekly) had only a slight effect on tumor growth.

[0351] Figure 29 shows a dose-response study of TH1902 or docetaxel on a syngeneic B16-F10 xenograft tumor model. For Figure 29A, immunocompetent mice bearing B16-F10 xenografts were repeatedly injected intravenously with vehicle or equivalent increasing doses of TH1902 and docetaxel (arrows indicate injection days). Mice were treated twice weekly with 5, 7.5, and 10 mg / kg docetaxel and equivalent TH1902 (11.5, 17.25, and 23 mg / kg). In Figure 29B, when tumors in the vehicle group reached the endpoint limit, the effect of TH1902 and docetaxel on tumor progression on day 12 is shown by subtracting the initial tumor volume on day 0 from the tumor volume measured on day 12. In contrast to docetaxel, tumor regression was clearly observed with the TH1902 formulation. For Figure 29C, the body weights of mice treated with vehicle and equivalent doses of docetaxel or TH1902 were monitored throughout the study and remained within the acceptable range and the -20% endpoint limit during all studies.

[0352] The embodiments of the present disclosure are presented in this manner to show that, where applicable, all combinations of embodiments can be made. Thus, these embodiments are presented in the description in a manner equivalent to making dependent claims for all embodiments that depend on any of the preceding claims (covering previously presented embodiments), thereby demonstrating that they can be combined together in all possible ways. For example, where applicable, all combinations between the embodiments and various aspects presented in the paragraphs of this specification are covered by the present disclosure herein. 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Claims

1. A composition comprising polysorbate 80, a dextrose solution, and a conjugate compound or a pharmaceutically acceptable salt or solvate thereof, Polysorbate 80 is present in an amount of 8% to 12% by weight per total volume of the composition; the dextrose solution is present in an amount such that the concentration of dextrose is 4% to 6% by weight per total volume of the composition; The conjugate compound is A-(B) n and has the formula During the ceremony, n is 1, 2, 3, or 4; A is a peptide compound, B is at least one anticancer drug optionally linked to A at a free amine of said peptide compound, at an N-terminal position of said peptide compound, at a free —SH of said peptide compound, or at a free carboxyl of said peptide compound, wherein the at least one anticancer drug is docetaxel; the peptide compound has at least 90% sequence identity to the sequence GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 10); A composition wherein at least one protecting group and / or at least one cysteine ​​residue is optionally linked to said peptide compound at the N-terminus and / or C-terminus.

2. 2. The composition of claim 1, wherein at least one anticancer drug is linked to A at a free amine of a lysine residue of the peptide compound.

3. The composition of claim 1 or 2, wherein at least one anticancer drug is linked to A via a linker.

4. The composition of claim 3 , wherein the linker is a cleavable linker.

5. The composition according to any one of claims 1 to 4, wherein the peptide compound consists of the amino acid sequence of SEQ ID NO:

10.

6. The composition of any one of claims 1 to 5, wherein the peptide compound comprises at least one protecting group, and at least one protecting group is acetyl or succinyl.

7. The composition of any one of claims 1 to 6, wherein the peptide compound is represented by formula (XXXIX): Formula (XXXIX): Acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15).

8. The composition of any one of claims 1 to 7, wherein the peptide compound comprises at least one cysteine ​​residue linked to said peptide compound at the N-terminus or C-terminus.

9. 9. The composition of claim 8, wherein the at least one anti-cancer agent is linked to the peptide compound at a free --SH of the peptide compound.

10. the conjugate compound is 2. The composition of claim 1, comprising a peptide compound having SEQ ID NO: 10, wherein each lysine residue has a docetaxel molecule linked thereto, represented by formula (XIX): Formula (XIX): GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY

11. the conjugate compound is 2. The composition of claim 1, comprising a peptide compound having SEQ ID NO: 15, wherein each lysine residue has a docetaxel molecule linked thereto, and is represented by the following formula (XXIII): Formula (XXIII): Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY

12. The composition of claim 4 , wherein the linker is selected from succinic acid and dimethylglutaric acid.

13. The composition of any one of claims 1 to 12, further comprising a buffer.

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

15. The composition according to any one of claims 1 to 14, wherein the composition is an aqueous solution having a pH of 3.5 to 4.

5.

16. 16. The composition of any one of claims 1 to 15, wherein the polysorbate 80 is present in an amount of 9% to 11% by weight based on the total volume of the composition.

17. 17. The composition of any one of claims 1 to 16, wherein the conjugate compound is present in an amount of 0.1 w / w% to 5 w / w%, based on the total weight of the composition.

18. 18. The composition of claim 17, wherein the conjugate compound is present in an amount of 0.5% to 2.5% w / w, based on the total weight of the composition.

19. 19. The composition of claim 17 or 18, wherein the conjugate compound is present in an amount of 0.8 w / w% to 1.2 w / w%, based on the total weight of the composition.

20. 20. The composition of any one of claims 1 to 19, comprising polysorbate, dextrose solution, formic acid, sodium hydroxide, and water or a diluent.

21. The composition of any one of claims 1 to 20, wherein the conjugate compound is in the form of a pharmaceutically acceptable acid addition salt.

22. 22. The composition of claim 21, wherein the pharmaceutically acceptable acid addition salt is an acetate or formate salt.

23. 23. The composition of any one of claims 1 to 22 for use in the treatment of a sortilin-expressing cancer.

24. 24. The composition for use of claim 23, wherein the sortilin-expressing cancer is ovarian cancer, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, pancreatic cancer, skin cancer, brain cancer, urinary tract cancer, carcinoid cancer, kidney cancer, testicular cancer, pituitary cancer or blood cancer.

25. 23. Use of a composition according to any one of claims 1 to 22 in the manufacture of a medicament for the treatment of a sortilin-expressing cancer.

26. 26. The use of claim 25, wherein the sortilin-expressing cancer is ovarian cancer, endometrial cancer, breast cancer, prostate cancer, colorectal cancer, lung cancer, pancreatic cancer, skin cancer, brain cancer, urinary tract cancer, carcinoid cancer, kidney cancer, testicular cancer, pituitary cancer or blood cancer.

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