Methods and compounds for targeting sortilin receptors and inhibiting angiogenic mimicry

Abstract

The present disclosure relates to peptide compounds and conjugated compounds, processes, methods and uses thereof for treating cancer or invasive cancer. For example, the compound may include a compound of the following 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 APRW 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), where X1 to X 21 and n can have various values, and wherein at least one protecting group and / or at least one labeling agent is optionally linked to the peptide compound at the N- and / or C-terminus for inhibiting angiogenic mimicry and / or treating cancer.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 62 / 722,726 filed on August 24, 2018 and U.S. Provisional Application No. 62 / 804,063 filed on February 11, 2019, both of which are incorporated herein by reference in their entirety. Technical Field

[0003] The present disclosure relates to methods and compositions for targeting sortilin receptors and inhibiting angiogenic mimicry. Background Art

[0004] According to a recent report by the World Health Organization, 8.2 million people died of cancer in 2012 (1). Cancer is therefore a growing health problem in both developing and developed countries. It is estimated that the number of cancer cases per year will increase over the next two decades (1). The general treatments commonly used for cancer are surgery, endocrine therapy, chemotherapy, and radiotherapy (2). However, a recent hope has been placed on the development of "targeted therapies" that target specific molecular defects in cancer cells and have the potential to be more effective and less toxic than imprecise chemotherapeutic agents (3).

[0005] Currently, when anticancer drugs are administered via classical formulations, it is estimated that approximately 95% of the therapeutic agent is taken up by cells within healthy tissue, while only approximately 2%-5% effectively reaches the tumor (4). Therefore, the challenge for any future successful personalized therapeutic approach is to increase the selectivity of targeted therapies, in part through active transport of anticancer drugs to the cancer cell compartment (5-6).

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

[0007] Vascular mimicry has been implicated in tumor malignancy, including invasion and metastasis. Vascular mimicry has been associated with a more aggressive tumor phenotype and poor 5-year overall survival in cancer patients (24). Vascular mimicry is described as a process by which cancer cells establish alternative blood perfusion pathways through endothelial-free mechanisms (25, 29). In addition, vascular mimicry also provides cancer cells with potential routes for dissemination (42). In 1999, patterned vessel-like channel structures were observed in highly invasive and metastatic human melanomas in which erythrocytes were detected (28). No endothelial cells were detected in these channels by light microscopy, transmission electron microscopy, or immunohistochemistry for the endothelial cell markers CD34 and CD31.

[0008] Vascular mimicry plays an important role in tumor growth (42), and it has been similarly characterized in ovarian cancer, breast cancer, lung cancer, liver cancer, colorectal cancer, prostate cancer, bladder cancer, kidney cancer, sarcoma, and glioma (43, 29, 44). Survival analysis showed that patients with vascular mimicry in their tumors had poor clinical outcomes compared with patients whose tumors did not exhibit vascular mimicry. A meta-analysis evaluating the effect of vascular mimicry on the survival of patients with 15 malignancies showed that vascular mimicry was associated with a more aggressive tumor phenotype and poor 5-year overall survival (24, 43). In recent years, it has been reported that cancer stem cells (CSCs) and epithelial to endothelial transition (a subtype of epithelial to mesenchymal transition) can accelerate vascular mimicry by stimulating cancer cell plasticity, remodeling of the extracellular matrix, and connecting vascular mimicry pathways to host vasculature (45).

[0009] Ovarian cancer is one of the first cancers in which vasculogenic mimicry was described and associated with decreased overall survival of patients (43). A retrospective study conducted in 120 ovarian cancer samples showed that 43% of all tested tissues involved vasculogenic mimicry (46). In the same study, CD133 expression, one of the most reliable cell surface markers for cancer stem cells, was found in 47% of ovarian cancer tissues. The presence of both vasculogenic mimicry and CD133-positive expression is associated with advanced tumors, high-grade ovarian cancer, and chemotherapy non-responsiveness, leading to poor prognosis in ovarian cancer patients. In breast cancer, vasculogenic mimicry has been reported to be highest in triple-negative breast cancer (TNBC) samples (30). In the latter study, CD133+ cells with CSC characteristics were associated with vasculogenic mimicry in TNBC. Moreover, in TNBC, CD133 expression and vasculogenic mimicry are closely related, as it is suggested that a highly plastic CSC subpopulation within TNBC-derived MDA-MB-231 cells triggers vasculogenic mimicry and the formation of 3D tubular structures in vitro. Summary of the invention

[0010] Thus, a first aspect is a peptide compound having at least 60% sequence identity with a compound selected from the group consisting of compounds of formula (A)-(C), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI) and (XII):

[0011] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO: 1)

[0012] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II) (SEQ ID NO: 2)

[0013] YKX 13 LRRX 14 APRW 15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3)

[0014] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4)

[0015] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO: 5)

[0016] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO: 6)

[0017] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0018] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO: 8)

[0019] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0020] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO: 1 0)

[0021] YKSLRRKAPRWDAPLRDPALRQLL(XI)(SEQ ID NO: 11)

[0022] YKSLRRKAPRWDAYLRDPALRQLL(XII)(SEQ ID NO: 1 2)

[0023] YKSLRRKAPRWDAYLRDPALRPLL(XIII)(SEQ ID NO: 1 3)

[0024] in

[0025] 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 independently selected from any amino acids;

[0026] X 16 , X 17 , X 20 and X 21 independently selected from Q, P, Y, I and L;

[0027] n is 0, 1, 2, 3, 4, or 5;

[0028] When X9 is present more than once, each of said X9 is independently selected from any amino acid;

[0029] When X 19 When present more than once, each of said X9 is independently selected from any amino acid;

[0030] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide at the N- and / or C-terminus,

[0031] Optionally, the peptide compound is cyclic,

[0032] For inhibiting vasculogenic mimicry and / or treating cancer.

[0033] In another aspect is a peptide compound having at least 80% sequence identity with a compound selected from the group consisting of compounds of Formula (A)-(I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), and (XII):

[0034] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO:1)

[0035] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II)(SEQ ID NO:2)

[0036] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L(III)(SEQ ID NO:3)

[0037] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV)(SEQ ID NO:4)

[0038] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO:5)

[0039] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO:6)

[0040] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0041] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO:8)

[0042] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0043] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO:1 0)

[0044] YKSLRRKAPRWDAPLRDPALRQLL(XI)(SEQ ID NO:11)

[0045] YKSLRRKAPRWDAYLRDPALRQLL(XII)(SEQ ID NO:1 2)

[0046] YKSLRRKAPRWDAYLRDPALRPLL(XIII)(SEQ ID NO: 1 3)

[0047] in

[0048] 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 independently selected from any amino acids;

[0049] X 16 , X 17 , X 20 and X 21 independently selected from Q, P, Y, I and L;

[0050] n is 0, 1, 2, 3, 4, or 5;

[0051] When X9 is present more than once, each of said X9 is independently selected from any amino acid;

[0052] When X 19 When present more than once, each of said X9 is independently selected from any amino acid;

[0053] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide at the N- and / or C-terminus,

[0054] Optionally, the peptide compound is cyclic,

[0055] For inhibiting vasculogenic mimicry and / or treating cancer.

[0056] In one aspect, a compound, a peptide compound or a derivative thereof is provided, which specifically binds to a polypeptide having an amino acid sequence as shown in any one of SEQ ID NOs: 25-50, an analogue or a fragment thereof, for use in inhibiting angiogenic mimicry.

[0057] In one aspect, a compound, a peptide compound or a derivative thereof targeting a sortilin receptor is provided.

[0058] In one aspect, a compound, a peptide compound or a derivative thereof for targeting a sortilin receptor is provided.

[0059] In one aspect, a compound, a peptide compound or a derivative thereof is provided which binds at least 2, optionally at least 4, consecutive amino acid residues as shown in any one of SEQ ID NOs: 25-50, an analogue or a fragment thereof.

[0060] In another aspect disclosed herein is a compound having the formula A-(B) n The conjugated compound

[0061] in

[0062] n is 1, 2, 3, or 4;

[0063] A is a peptide compound as defined in the present disclosure, wherein the peptide is optionally protected by a protecting group; and

[0064] B is at least one therapeutic agent, wherein B is linked to A,

[0065] For inhibiting vasculogenic mimicry and / or treating cancer.

[0066] In another aspect disclosed herein is a compound having the formula A-(B) n The conjugated compound

[0067] in

[0068] n is 1, 2, 3, or 4;

[0069] A is a peptide compound as defined in the present disclosure, wherein the peptide compound is optionally protected by a protecting group; and

[0070] B is at least one therapeutic agent, wherein B is optionally linked to A at a free amine of the peptide compound, at the N-terminal position of the peptide compound, at a free -SH of the peptide compound, or at a free carboxyl group of the peptide compound,

[0071] For inhibiting vasculogenic mimicry and / or treating cancer.

[0072] Another aspect disclosed herein is a compound having the formula A-(B) n The conjugated compound

[0073] in

[0074] n is 1, 2, 3, or 4;

[0075] A is a peptide compound as defined in the present disclosure, wherein the peptide is optionally protected by a protecting group; and

[0076] B is at least one therapeutic agent, wherein 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,

[0077] For inhibiting vasculogenic mimicry and / or treating cancer.

[0078] Another aspect disclosed herein is a conjugated compound represented by formula (XXIII):

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

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

[0081] Another aspect disclosed herein is a conjugated compound represented by formula (XXVIII):

[0082] Acetyl-GVRAK(Adriamycin)AGVRN(Nle)FK(Adriamycin)SESY-Formula (XXVIII)

[0083] It comprises the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a doxorubicin molecule attached thereto.

[0084] Another aspect disclosed herein is a conjugated compound represented by formula (LII):

[0085] Acetyl-GVRAKAGVRN(Nle)FKSESYC(aldoxorubicin)-Formula (LII)

[0086] It comprises the peptide compound having SEQ ID NO: 24, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto, or

[0087] It comprises the peptide compound having SEQ ID NO: 15, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, and wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto.

[0088] Another aspect disclosed herein is a conjugated compound selected from the group consisting of compounds of formula (XVI) and formula (XVII):

[0089] Acetyl-GVRAK(Curcumin)AGVRN(Nle)FK(Curcumin)SESY-Formula (XVI)

[0090] It comprises the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a curcumin molecule attached thereto; and

[0091] Acetyl-YK(Curcumin)SLRRK(Curcumin)APRWDAPLRDPALRQLL-Formula (XVII)

[0092] It comprises the peptide compound having SEQ ID NO: 16, wherein each lysine residue has a curcumin molecule attached thereto.

[0093] Another aspect disclosed herein is an isolated antibody that specifically binds to a polypeptide having an amino acid sequence as shown in any one of SEQ ID NOs: 25-50, an analog or a fragment thereof, for use in inhibiting angiogenic mimicry.

[0094] Another aspect disclosed herein is an isolated antibody targeting a sortilin receptor.

[0095] Another aspect disclosed herein is an isolated antibody for targeting a sortilin receptor. Another aspect disclosed herein is an isolated antibody that binds to at least 2, optionally at least 4, consecutive amino acid residues as shown in any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof.

[0096] Another aspect disclosed herein is a conjugated antibody having the formula A'-(B)n,

[0097] in

[0098] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0099] A' is an isolated antibody as defined in the present disclosure, wherein the isolated antibody is optionally protected by a protecting group; and

[0100] B is at least one therapeutic agent, wherein B is optionally linked to A' at a free amine of the isolated antibody, at the N-terminal position of the isolated antibody, at a free -SH of the isolated antibody, or at a free carboxyl group of the isolated antibody,

[0101] Used to inhibit vasculogenic mimicry.

[0102] In another aspect disclosed herein, a conjugated antibody having the formula A'-(B)n,

[0103] in

[0104] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

[0105] A' is an isolated antibody as defined in the present disclosure, wherein the isolated antibody is optionally protected by a protecting group; and

[0106] B is at least one therapeutic agent, wherein B is linked to A' at a free amine of a lysine residue of said isolated antibody, optionally through a linker, or at the N-terminal position of said isolated antibody, optionally through a linker,

[0107] Used to inhibit vasculogenic mimicry.

[0108] In one aspect, a conjugated antibody targeting a Sortilin receptor is provided.

[0109] In one aspect, a process for preparing a conjugated compound or a conjugated antibody disclosed in the present disclosure is provided, the process comprising:

[0110] reacting a linker and the at least one therapeutic agent together to obtain an intermediate;

[0111] optionally purifying the intermediate;

[0112] reacting the intermediate with the peptide compound to obtain the conjugated compound or conjugated antibody, wherein the at least one therapeutic agent is linked to the peptide compound or isolated antibody via the linker; and

[0113] optionally purifying the conjugated compound or conjugated antibody;

[0114] wherein the at least one therapeutic agent is linked to the peptide compound or the isolated antibody at a free amine of a lysine residue or at the N-terminus; and wherein the peptide compound comprises 1, 2, 3, or 4 therapeutic agent molecules linked thereto, or the isolated antibody comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 therapeutic agent molecules linked thereto.

[0115] In one aspect, there is provided a method of inhibiting vasculogenic mimicry, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound, isolated antibody or antibody conjugate as defined herein.

[0116] In another aspect, there is provided a method of inhibiting vasculogenic mimicry in a cell expressing Sortilin, the method comprising contacting the cell with at least one compound, isolated antibody or antibody conjugate as defined herein.

[0117] In another aspect, there is provided a method of treating cancer or aggressive cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound, isolated antibody or antibody conjugate as defined herein.

[0118] Also provided is a method for making an isolated antibody, wherein the isolated antibody specifically binds to an isolated polypeptide comprising a sequence as shown in any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof, by the following steps: i) immunizing an animal with an immunogenic form of the isolated polypeptide; ii) screening an expression library; or iii) using phage display.

[0119] In one aspect, a method of inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin is provided, the method comprising contacting the cancer tissue cell with at least one compound, isolated antibody or antibody conjugate as defined herein, wherein the inhibiting angiogenic mimicry comprises: causing a reduction in the length of angiogenic mimicry tubes in the cancer tissue or the cell expressing Sortilin that is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45% or about 30% to about 40% greater than that of untreated cancer tissue or cell expressing Sortilin.

[0120] In one aspect, a method of inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin is provided, the method comprising contacting the cancer tissue cell with at least one compound, isolated antibody or antibody conjugate as defined herein, wherein the inhibiting angiogenic mimicry comprises: reducing the number of angiogenic mimicry rings in the cancer tissue or the cell expressing Sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45% or about 30% to about 40% compared to untreated cancer tissue or cells expressing Sortilin.

[0121] In one aspect, a method of inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin is provided, the method comprising contacting the cancer tissue cell with at least one compound, isolated antibody or antibody conjugate as defined herein, wherein the inhibition of angiogenic mimicry comprises: causing a reduction in the length of angiogenic mimicry tubes in the cancer tissue or cell expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times, or about 1.2 to about 2.0 times greater than in a cancer tissue or cell expressing Sortilin treated with the at least one therapeutic agent. A reduction of at least 2 times greater means, for example, that if the length of angiogenic mimicry tubes is reduced by 10% in a cancer tissue or cell expressing Sortilin treated with the at least one therapeutic agent, the length of angiogenic mimicry tubes is reduced by at least 20% in a cancer tissue or cell expressing Sortilin treated with the at least one compound, isolated antibody or antibody conjugate as described herein.

[0122] In one aspect, a method of inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin is provided, the method comprising contacting the cancer tissue cell with at least one compound, isolated antibody or antibody conjugate as defined herein, wherein the inhibiting angiogenic mimicry comprises: causing a reduction in the number of angiogenic mimicry rings in the cancer tissue or the cell expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times, or about 1.2 to about 2.0 times greater than in a cancer tissue or cell expressing Sortilin treated with the at least one therapeutic agent. A reduction of at least 2 times greater means, for example, that if angiogenic mimicry rings are reduced by 10% in a cancer tissue or cell expressing Sortilin treated with the at least one therapeutic agent, then angiogenic mimicry rings are reduced by at least 20% in a cancer tissue or cell expressing Sortilin treated with at least one compound, isolated antibody or antibody conjugate as described herein.

[0123] In one aspect, a method of inhibiting angiogenic mimicry in cancer tissue or cells expressing sortilin is provided, the method comprising contacting the cancer tissue cells with at least one compound, isolated antibody or antibody conjugate as defined herein, wherein the cells expressing sortilin 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.

[0124] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein for inhibiting vasculogenic mimicry.

[0125] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein for targeting a Sortilin receptor.

[0126] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein for inhibiting angiogenic mimicry in cancer tissue or cells expressing Sortilin.

[0127] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein for treating cancer or an aggressive cancer.

[0128] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein for treating cancer or invasive cancer in cancer tissue or cells expressing Sortilin.

[0129] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein in the manufacture of a medicament for inhibiting angiogenic mimicry.

[0130] In one aspect, there is provided use of at least one compound, isolated antibody or antibody conjugate as defined herein in the manufacture of a medicament for targeting a Sortilin receptor.

[0131] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein in the manufacture of a medicament for inhibiting angiogenic mimicry in cancer tissue or cells expressing Sortilin.

[0132] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein in the manufacture of a medicament for treating cancer or an aggressive cancer.

[0133] In one aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein in the manufacture of a medicament for treating cancer or invasive cancer in cancerous tissue or cells expressing Sortilin.

[0134] In one aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for causing a reduction in the length of angiogenic mimetic tubes in cancer tissue or cells expressing sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45% or about 30% to about 40% greater than untreated cancer tissue or cells expressing sortilin.

[0135] In one aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for reducing the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45% or about 30% to about 40% compared to untreated cancer tissue or cells expressing Sortilin.

[0136] In one aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for causing a reduction in the length of angiogenic mimetic tubes in cancer tissue or cells expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times or about 1.2 to about 2.0 times greater than in cancer tissue or cells expressing Sortilin treated with the at least one therapeutic agent.

[0137] In one aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein, for causing a reduction in the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times or about 1.2 to about 2.0 times greater than in cancer tissue or cells expressing Sortilin treated with the at least one therapeutic agent.

[0138] In one aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for inhibiting angiogenic mimicry in a cell expressing Sortilin, wherein the cell expressing Sortilin is an immune cell, optionally a macrophage, CD4+, CD8+, B220+, a cell of bone marrow origin, a basophil, an eosinophil and a cytotoxic T lymphocyte, a natural killer (NK) cell, a T helper type 1 (Th1) cell.

[0139] In one aspect, a process for preparing a conjugate compound or an antibody conjugate disclosed in the present disclosure is provided, the process comprising:

[0140] reacting a linker and the at least one therapeutic agent together to obtain an intermediate;

[0141] optionally purifying the intermediate;

[0142] reacting the intermediate with the peptide compound or the isolated antibody to obtain the conjugate compound or antibody conjugate, wherein the at least one therapeutic agent is linked to the peptide compound or the isolated antibody via the linker; and

[0143] optionally purifying the conjugated compound;

[0144] wherein the at least one therapeutic agent is linked to the peptide compound or the isolated antibody at a free amine of a lysine residue or at the N-terminus; and wherein the peptide compound comprises 1, 2, 3, or 4 therapeutic agent molecules linked thereto, or the isolated antibody comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 therapeutic agent molecules linked thereto.

[0145] In another aspect, a method of increasing the stability and / or bioavailability of a therapeutic agent is provided, the method comprising:

[0146] obtaining the conjugated compound disclosed herein, wherein the conjugated compound comprises the therapeutic agent, and

[0147] A therapeutically effective amount of the conjugate compound is administered to a subject in need thereof.

[0148] In another aspect, a method of increasing the stability and / or bioavailability of a therapeutic agent is provided, the method comprising:

[0149] conjugating the therapeutic agent to a peptide compound as defined herein to obtain a conjugated compound, and

[0150] A therapeutically effective amount of the conjugate compound is administered to a subject in need thereof.

[0151] In a further aspect there is provided a use of a conjugated compound as defined herein for increasing the stability and / or bioavailability of said at least one therapeutic agent.

[0152] In another aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein in the manufacture of a medicament for inhibiting angiogenic mimicry.

[0153] In another aspect, there is provided the use of at least one compound, isolated antibody or antibody conjugate as defined herein in the manufacture of a medicament for targeting a Sortilin receptor.

[0154] In another aspect, provided herein is a method of increasing the tolerability of a therapeutic agent, the method comprising:

[0155] conjugating the therapeutic agent to a peptide compound disclosed herein to obtain a conjugated compound, and

[0156] A therapeutically effective amount of the conjugate compound is administered to a subject in need thereof.

[0157] In another aspect, provided herein is a method of increasing the tolerability of a therapeutic agent, the method comprising:

[0158] Obtaining the conjugate compound or antibody conjugate disclosed herein, wherein the conjugate compound or antibody conjugate comprises a therapeutic agent, a linker, wherein the antibody conjugate targets Sortilin.

[0159] A therapeutically effective amount of the conjugate compound or the antibody conjugate is administered to a subject in need thereof.

[0160] For example, provided is a use of a conjugated compound or antibody conjugate disclosed herein for increasing the tolerability of a therapeutic agent.

[0161] In another aspect, there is provided a liposome, graphene, nanotube or nanoparticle comprising at least one compound, isolated antibody or antibody conjugate as defined herein for inhibiting angiogenic mimicry.

[0162] In another aspect, there is provided a liposome, graphene, nanotube or nanoparticle comprising at least one compound, isolated antibody or antibody conjugate as defined herein for targeting a Sortilin receptor.

[0163] In a further aspect, there is provided a liposome, graphene, nanotube or nanoparticle coated with at least one compound, isolated antibody or antibody conjugate as defined herein for inhibiting angiogenic mimicry.

[0164] In a further aspect, there is provided a liposome, graphene, nanotube or nanoparticle coated with at least one compound, isolated antibody or antibody conjugate as defined herein for targeting a Sortilin receptor. BRIEF DESCRIPTION OF THE DRAWINGS

[0165] Further features and advantages of the present disclosure will become more apparent from the following description of specific embodiments, which are illustrated by way of example in the accompanying scheme and drawings, in which:

[0166] FIG1 is a representation of the prior art depicting a graph showing the percentage of human cancers presenting vasculogenic mimicry (VM) from ref 24 (n=3062 clinical cases). Expression of vasculogenic mimicry is associated with advanced tumors, high-grade cancers, and chemotherapy non-response. In various cancers, vasculogenic mimicry is also associated with shorter overall survival. Abbreviations: BDMT: bidirectionally differentiated malignant tumor; HCC: hepatocellular carcinoma; NSCLC: non-small cell lung cancer; OLSCC: oral / laryngeal squamous cell carcinoma.

[0167] FIG2 is a representation of the prior art, depicting a graph showing the percentage of breast cancers with vasculogenic mimicry (VM). In breast cancer, the presence of vasculogenic mimicry is highest in triple negative (TN) breast cancer patients compared to luminal or HER2+ positive breast cancer. Vasculogenic mimicry may represent an important survival mechanism that results in the failure of current anti-angiogenic therapies to completely eradicate tumors (30).

[0168] FIG3 is a representation of the prior art showing an in vitro 3D reconstruction using X-ray microtomography of angiogenic mimicry of SKOV3 ovarian cancer cells (from ref. 31). The reconstruction of the 4-day 3D culture landscape of ovarian cancer cells on artificial matrigel is clearly visible, showing elevated structures with a tubular appearance (panel a). The structure within the white rectangle is shown at a higher magnification in panels b and c, where arrows indicate tubular-looking structures protruding above the flattened cell aggregates. A cross-section of this structure is shown to demonstrate the gas-filled space with an estimated diameter of 50 μm (panel c).

[0169] Figure 4 shows prior art confocal microscopy of angiogenic mimetic tubular structures using SKOV3 (from ref. 31) expressing green fluorescent protein (GFP). Panel a: Confocal microscopy Z-stack reconstruction showing the presence of cells containing tubular structures. The Z-stack shows a continuous upper monolayer [1], as well as a central wall structure with a hollow center [2] and a continuous lower monolayer [3]. Panel b: Computer generated cross section clearly showing tubular structures containing lumens.

[0170] Figure 5 The ES-2 ovarian cancer cells formed 3D tubular structures. Tube-like structures in ES-2 ovarian cancer cells were rapidly formed and observed within 4 hours after being seeded on the artificial basement membrane.

[0171] Fig. 6A , Figure 6B , Figure 6C and Fig.6D showed that sortilin was detected in 3D tubular structures of ES-2 ovarian cancer cells. More specifically, Fig. 6A ES-2 ovarian cancer cells seeded on Matrigel are shown. After 12 hours, Sortilin was detected in 3D tubular structures by confocal microscopy using rabbit anti-Sortilin antibody. Figure 6B A control with only secondary anti-rabbit antibody is shown. Overall results indicate that ( Fig. 6A ) in the Sortilin assay is specific. Figure 6C and Fig.6D Shown are DAPI staining of ES2 cancer cell nuclei within 3D tubular structures under the conditions used for anti-SORT1 and secondary antibody detection.

[0172] Fig. 7A and Figure 7BThe effect of sortilin gene silencing on vasculogenic mimicry formation is shown. ES-2 ovarian cancer cells were transfected with scrambled siRNA (siScrambled) or specific SORT1 siRNA (siSORT1) and seeded on artificial basement membrane. After 12 hours, 3D tubular structures were observed in ES-2 cancer cells transfected with scrambled siRNA. ES-2 transfected with specific SORT1 siRNA did not form 3D tubular structures. The total tube length and total number of rings were quantified by Wimasis image analysis software, and the results showed that these structures were inhibited by more than 90% when sortilin expression was reduced due to siSORT1 (n=4).

[0173] Fig. 8A and Figure 8B To show the effect of doxorubicin conjugate (DoxKA) on vasculogenic mimicry. More specifically, Fig. 8A ES2 ovarian cancer cells were seeded on Matrigel in the presence of increasing concentrations of DoxKA, doxorubicin, or doxorubicin liposomes (doxorubicin encapsulated in liposomes). After 12 hours, 3D tubular structures were inhibited by DoxKA, but not by doxorubicin or doxorubicin liposomes alone. Figure 8B Quantification of total ring number and total tube length by Wimasis image analysis software is shown, and these structures are inhibited at low nM concentrations of DoxKA.

[0174] Fig. 9 The effect of Aldoxorubicin conjugates (AldoxKA) on vasculogenic mimicry is shown. Aldoxorubicin, a doxorubicin derivative, was conjugated to the Katana peptide via an acidic pH-sensitive linker. ES-2 ovarian cancer cells were seeded on an artificial Matrigel in the presence of increasing concentrations of AldoxKA. After 12 hours, 3D tubular structures were inhibited by AldoxKA, but not by doxorubicin alone (see Figure 8).

[0175] Fig. 10A and Fig. 10B The effect of docetaxel conjugate (DoceKA) on vasculogenic mimicry is shown. ES-2 ovarian cancer cells were seeded on Matrigel in the presence of docetaxel or DoceKA. After 12 hours, DoceKA showed a stronger inhibitory effect on 3D tubular structure than docetaxel alone at docetaxel equivalent concentrations (600 pM; Fig. 10A Quantification of total ring number and total tube length revealed that these structures were inhibited at low nM concentrations of DoceKA ( Fig. 10B ).

[0176] Fig.11Showing the effect of curcumin conjugate (CurKA) on vasculogenic mimicry. ES-2 ovarian cancer cells were seeded on Matrigel in the presence of curcumin or CurKA. After 12 hours, CurKA showed a stronger inhibitory effect on 3D tubular structures at curcumin equivalent concentrations than curcumin alone. The total number of rings and total tube length showed that these structures were inhibited at nM concentrations of CurKA.

[0177] Fig.12 Figure 2 shows the inhibitory effect of anti-sortilin (anti-SORT1) mAb on vasculogenic mimicry. ES-2 ovarian cancer cells were seeded on Matrigel in the presence of vehicle (control), mouse IgG (12 nM), or anti-SORT1 mAb (12 nM). Images were taken after 4 and 12 hours. Anti-SORT1 mAb inhibited the formation of 3D tubular structures and had a strong effect on total tube length and number of rings (n=2).

[0178] Fig.13A , Figure 1 3B, Fig. 13C and Fig.13D 1 shows a series of graphs showing the binding and internalization of anti-SORT1 mAb to ES-2 ovarian cancer cells. FIG. 1 3A shows anti-sortilin antibody labeling using the Alexa Fluor 488 protein labeling kit from Invitrogen. Human ES-2 ovarian cancer cells were incubated with anti-sortilin-Alexa 488 (1 μg / ml) at 4°C for 30 minutes and then trypsinized or not to assess cell surface binding. The results clearly show that the major portion of the fluorescent signal is caused by binding to the sortilin receptor on the cell surface, as trypsinization reduced the fluorescence level by more than 90%. Fig. 13B Shown is the binding of anti-sortilin-Alexa488 (1 μg / ml, 30 min) on the cell surface of human ES-ovarian cancer cells in the presence of sortilin ligands (neurotensin (NT) and progranulin (PGRN)) and Katana peptides (KBP106 and KBP201). Fig. 13C Anti-sortilin antibodies were shown to be internalized into ES-2 cancer cells. In this experiment, binding of anti-sortilin-Alexa488 antibodies (1 μg / ml, 30 minutes) on human ES-2 ovarian cancer cells was first performed at 4°C, then the cells were washed to remove unbound fluorescent antibodies, and the cells were incubated at 37°C for 1 or 2 hours and then trypsinized. The fluorescence associated with internalized fluorescent anti-sortilin-Alexa488 was then quantified by flow cytometry. The results showed that approximately 50% of the anti-sortilin-Alexa488 initially bound to the cell surface was internalized within 2 hours. Fig.13DDisplay as Fig. 13C The internalization of anti-sortilin-Alexa 488 was measured at increasing concentrations as described in. The results showed that the internalization of the anti-sortilin-Alexa 488 fluorescent conjugate increased with increasing concentrations of the fluorescent conjugate and was saturable.

[0179] Fig.14 Schematic diagram showing the different regions of Sortilin and the regions for generating anti-Sortilin antibodies used in the present disclosure.

[0180] Figure 1 5 shows the inhibitory effect of anti-sortilin antibodies on vasculogenic mimicry in ovarian cancer cells. Inhibitory effect of anti-sortilin (anti-SORT1) mAbs on vasculogenic mimicry. ES-2 ovarian cancer cells were seeded on artificial Matrigel in the presence of vehicle (control), mouse IgG (12 nM), or anti-SORT1 mAb #1 (12 nM) or anti-SORT1 mAb #2 (12 nM). Images were taken at 0 and 12 hours after antibody treatment. The results show that anti-SORT1 mAb inhibits the formation of 3D tubular structures and has a strong effect on total tube length and number of rings (n=2).

[0181] Fig.16A and Fig. 16B To show the effect of anti-sortilin antibodies on vasculogenic mimicry in ES-2 ovarian cancer cells. More specifically, Fig.16A Anti-sortilin mAbs #1 and #2 are shown to reduce the total number of angiogenic mimetic rings. Figure 1 6B shows that anti-sortilin mAbs #1 and #2 reduce the total angiogenic mimetic tube length. Anti-sortilin mAb #2, generated against the extracellular amino acid sequence of sortilin (300-422), strongly inhibits angiogenic mimetic.

[0182] Fig.17A , Fig. 17B , Fig. 17C and Fig.17D The histological features of sortilin expression in normal and breast cancer cells and the assessment of Alexa488-labeled KA-peptide uptake in MDA-MB-231 cells are shown. More specifically, Fig.17A IS is an immunohistochemical technique that shows the lack of Sortilin expression in normal adjacent tissues, and its overexpression in stage IIIC invasive ductal carcinoma (IDC) and lymph node metastatic carcinoma (LNMC). The intensity of Sortilin staining was evaluated using the IS method. Fig. 17B Shown is the distribution of Sortilin in normal tissue versus IDC and LNMC breast tumors. Fig. 17CGene silencing of Sortilin was performed as described in the Methods section and validated by immunoblotting using anti-SORT1 antibody. Uptake of 200 nM Alexa488-labeled KA-peptide was then performed in control (siScrambled) or Sortilin-deficient (siSORT1) MDA-MB-231 cancer cells. Fig.17D Depicted are the uptake of 200 nm Alexa 488-labeled KA-peptide also evaluated in the absence (white bars) or presence (black bars) of excess unlabeled KA-peptide (50 μM), neurotensin (10 μM) or progranulin (1 nM) in MDA-MB-231 cells.

[0183] Figure 1 8A illustrates the synthesis of docetaxel-Katana peptide conjugate. Diisopropylethylamine (DIEA; 0.21 ml, 1.2mmol) was added dropwise to a suspension of docetaxel (0.81g, 1.0mmol) and succinic anhydride (105mg, 1.05mmol) in DMSO (5ml) under stirring. The mixture was stirred at room temperature and monitored by UPLC-MS. After 2 hours, the reaction was complete. The solvent was removed, and the resulting residue was dissolved in dichloromethane and loaded on a Biotage silica gel column for purification. DoceSuOH was obtained in the form of a white powder after freeze drying, with a UPLC-MS purity of >95%. DIEA (0.234mmol) was added dropwise to a solution of DoceSuOH (213mg, 0.234mmol) and TBTU (75mg, 0.234mmol) in DMSO (3-4ml) to pre-activate DoceSuOH. The completion of pre-activation was monitored by UPLC-MS, and then a solution of kA-peptide (120 mg, 0.062 mmol) in dimethyl sulfoxide (0.2 ml) was added. The mixture was stirred at room temperature. The reaction was monitored by UPLC-MS until completion. The reaction mixture was purified using a 3ORPC resin column and an AKTA purifier system (10% to 80% ACN) to obtain KA(SuDoce)2 or DoceKA in the form of a white powder after lyophilization. Figure 1 8B illustrates that the purity of the conjugate evaluated by UPLC-MS purity is greater than 95%.

[0184] Fig.19 Depict the in vitro anticancer properties of DoceKA on MDA-MB-231 breast cancer cells determined using [3H]-thymidine incorporation assays. For each drug concentration, a [3H]-thymidine graph incorporated was plotted. IC50 values ​​(nM) were calculated using GraphPad Prism software. The IC50 value for DoceKA was 0.38 nM, and the IC50 value for docetaxel was 0.68 nM. Fig.19is a set of graphs depicting the cell cycle distribution of MDA-MB231 cells determined based on cellular DNA content using flow cytometry after treatment with 2 μM docetaxel or 1 μM DoceKA for 24 hours.

[0185] Fig. 20A and Fig. 20B To illustrate the effect of sortilin gene silencing on the anti-migratory potential of DoceKA. More specifically, Fig. 20A To characterize the effect of docetaxel on the migration of MDA-MB-231 cells, and Fig. 20B Depict the effect of DoceKA on MDA-MB-231 cell migration after siRNA-mediated gene silencing of sortilin. Transfected cells were pre-incubated with DoceKA (1 μM) or unconjugated docetaxel (2 μM) for 2 hours. Cells were then harvested and their migration potential was assessed in real time using an Xcelligence instrument.

[0186] Fig.21A , Fig. 21B and Fig. 21C The cell death induction effect of docetaxel and DoceKA conjugate in MDA-MB-231 cells was demonstrated. MDA-MB-231 cells were treated with control (vehicle) or increasing concentrations of docetaxel or DoceKA for 5 hours. The cells were then harvested and the apoptosis rate was determined after staining with annexin V-FITC and propidium iodide (PI). The cells were analyzed by flow cytometry. More specifically, Fig.21A Depicted MDA-MB-231 cells were treated with control (vehicle), 10 μM docetaxel, or 5 μM DoceKA for 24 hours, and cell morphology was examined under a light microscope. Fig. 21B is a line graph showing the percentage of apoptotic cell death based on different concentrations of DoceKA and docetaxel. Fig. 21C Figure 2. Excess free KA-peptide (50 μM) or sortilin ligands, neurotensin (10 μM) or progranulin (1 nM) compete for DoceKA uptake in MDA-MB-231 cells. After 5 h of incubation, cells were stained with Annexin V-FITC / PI. Fig.21A shown.

[0187] Fig.22A and Fig. 22B This study illustrates the molecular mechanism by which DoceKA induces cell death in MDA-MB-231 cells. Fig.22A Illustrate an immunoblot experiment showing the expression levels of IL-6, survivin, BcI-xi, and mutant p53 in MDA-MB-231 cells after treatment with docetaxel and DoceKA. GAPDH was used as a control. Fig. 22BData are representative of three independent experiments, and bar graphs show densitometric quantification of IL-6, survivin, Bcl-xL, and p53 expression compared to GAPDH. The mean of the control group was set to 1.0.

[0188] Fig.23A and Fig. 23B To characterize the effect of DoceKA on tubulin polymerization. More specifically, Fig.23A Cells treated with vehicle (DMSO), 2 μM docetaxel or 1 μM DoceKA for 24 hours, fixed and immunostained with anti-a-tubulin antibody and imaged using confocal microscopy are shown. DNA was stained with DAPI and cells were visualized using confocal microscopy. Representative cells for each condition are shown. Fig. 23B Description: The effects of docetaxel (2 μM) and DoceKA (1 μM) on the polymerization of purified tubulin were examined in vitro in a fluorescence-based polymerization assay. Paclitaxel (2 μM) and vinblastine (2 μM) were added as controls for tubulin polymerizing and tubulin depolymerizing agents, respectively. Assembly of tubulin into microtubules was determined by an increase in fluorescence emission (Ex. 340-360 nm ± 20 nm; Em. 410-460 nm ± 20 nm).

[0189] Fig.24A Residual tumor burden after untreated (vehicle), docetaxel-treated (Docetaxel), or docetaxel conjugate-treated (DoceKA) is depicted. Fig. 24B Tumor size is shown for untreated, docetaxel-treated, or DoceKA-treated patients 14 days and 74 days after treatment. Fig.24C Describes the residual tumor burden after 74 days of docetaxel or DoceKA treatment.

[0190] Fig.25A and Fig.25B To characterize the effects of DoceKA on the MDA-MB231 TNBC xenograft model. More specifically, Fig.25A Figure 3. Tumor volumes of mice treated with docetaxel or DoceKA. Mice treated with docetaxel received 3 treatments at 15 mg / kg / week (MTD). Mice treated with DoceKA received 5 treatments at the equivalent dose of docetaxel. Fig.25B The body weight of mice at different time points after treatment with docetaxel or DoceKA is depicted. Mice treated with docetaxel received 3 treatments at 1.5 mg / kg / week (MTD). Mice treated with DoceKA received 5 treatments at the equivalent dose of docetaxel. One mouse was sacrificed on day 15 due to toxicity (body weight: -25%).

[0191] Fig.26A and Fig.26B Depicting the DoceKA dose response in the MDA-MB231 TNBC model. More specifically, Fig.26A Describe the effect of different doses of DoceKA treatment on tumor volume. Fig.26B Depicted are the effects of different doses of DoceKA on tumor volume progression at day 15 after treatment.

[0192] Fig.27A , Fig.27B and Fig.27C DoceKA showed no effect on blood cells in nude mice. Fig.27A To illustrate the effects of three treatments with different concentrations of docetaxel or DoceKA on lymphocytes. Fig.27B To describe the effects of three treatments with different concentrations of docetaxel or DoceKA on platelets. Fig.27C Illustrated are the effects on neutrophils after 3 treatments with different concentrations of docetaxel or DoceKA. IP indicates intraperitoneal administration, while IV indicates intravenous delivery.

[0193] Fig.28 Depicting preliminary toxicity data of DoceKA, specifically neutrophil counts (g / L) after DoceKA treatment at different doses of docetaxel or DoceKA. Docetaxel induced a dramatic decrease in neutrophil counts four days after a single injection at the maximum tolerated dose; whereas neutrophil counts remained within the normal range even after six DoceKA injections.

[0194] Fig.29A Plasma concentrations of DoceKA and released docetaxel (BDL) calculated at progressive time intervals are presented. Fig.29B PK in CD-1 mice is illustrated. DoceKA (20 mg / kg) was administered intravenously to mice. Plasma was collected at different time points. DoceKA and released docetaxel were extracted with acetonitrile. DoceKA and released docetaxel were quantified by UPLC / MS using paclitaxel as an internal standard: 2 μl and 10 μl of supernatant were directly injected for DoceKA and docetaxel without lyophilization. The released docetaxel concentration was below the limit of quantification (LOQ) of docetaxel at 0.083, 0.25 and 4 hours. At a docetaxel dose of 20 mg / kg, the reported Cmax was approximately 20 μg / ml or 25 μM.

[0195] Fig.30 The expression of sortilin in human ovarian cancer and normal tissues analyzed by immunohistochemistry is shown in Figure 3. The expression of sortilin gradually increases from normal cells to benign cells, to borderline cells, to malignant cells, and to metastatic cells.

[0196] Fig.31A Demonstrates the expression of sortilin in human ovarian cancer and normal tissues measured using immunohistochemistry. Fig.31B Delineate Sortilin expression in normal, benign, low-grade serous carcinoma, high-grade serous carcinoma, clear cell carcinoma, mucinous carcinoma, endometrioid carcinoma, transitional cell carcinoma, borderline, metastatic cells, as well as germ cells and other non-epithelial cells.

[0197] Fig.32 The expression of the human ovarian cancer Sortilin gene is described in a cDNA tissue microarray (OriGene). Specifically, it uses qPCR to quantify the expression of the Sortilin gene in healthy tissue and grade I to IV ovarian tumors.

[0198] Fig.33A is a series of immunohistochemical images of normal breast tissue and breast cancer tissue exposed to anti-SORT1 mAB. Fig.33B To characterize the expression of sortilin in normal tissue, invasive ductal carcinoma, and lymph node metastatic carcinoma tissue.

[0199] Fig.34 Immunohistochemistry images depicting invasive ductal carcinoma (stage IIIC), associated lymph node metastases, and adjacent normal tissues from three different patients. IHC samples were stained with anti-SORT1 mAb.

[0200] Fig.35A Immunohistochemistry images depicting sortilin in melanoma. Specifically, the images show sortilin in normal tissue and melanoma stage II, II, and IV tumors. Fig.35B The expression of sortilin in normal tissues and stage I to IV melanoma tissues is depicted in bar graph format.

[0201] Fig.36 is a series of images showing sortilin in normal tissue and in melanoma stage II, II, and IV tumors.

[0202] Fig.37A and Fig.37B To characterize the immunohistochemistry of sortilin in uterine cancer. More specifically, Fig.37A Composed of images of Sortilin in normal tissue, endometrial cancer tissue, and cervical cancer tissue. Fig.37B is a graphic representation of the expression of sortilin in normal tissues, endometrial cancer tissues, and cervical cancer tissues.

[0203] Fig.38A and Fig.38B To characterize the immunohistochemistry of sortilin in lung cancer. More specifically, Fig.38A Comprised of images of Sortilin in normal and cancerous lung tissue. Fig.38B is a graphic representation of the expression of sortilin in normal and cancerous lung tissue.

[0204] Fig.39 is a series of immunoblot images illustrating the expression of Sortilin in several different cancer cell lines (ovarian, breast, brain, and other cancers).

[0205] Fig.40A and Fig.40B Confocal microscopy images depicting 3D tubular structures in OVCAR-3 ovarian cancer cells. Sortilin was detected using a rabbit anti-sortilin antibody. More specifically, Fig.40A There are three panels, the first image depicts the staining of sortilin present in the cells, the second image depicts the Hoechst staining of the cell nuclei, and the last image depicts the first two images merged. Fig.40B There are three panels, the first image depicts staining of control antibodies present in cells, the second image depicts Hoechst staining of cell nuclei, and the last image depicts the first two images merged. These results indicate that sortilin-positive cells contribute to angiogenic mimicry in vitro.

[0206] Fig.41A , Fig.41B and Fig.41C To illustrate the inhibitory effect of docetaxel conjugate (DoceKA) on vasculogenic mimicry in ES-2 ovarian cancer cells. More specifically, Fig.41A Illustrated are the total rings present when different concentrations of docetaxel or DoceKa are present. Fig.41B The total tube length present in the presence of different concentrations of docetaxel or DoceKa is illustrated. Fig.41C Illustrated are the percentage of branch points present in the presence of different concentrations of docetaxel or DoceKa. These figures demonstrate that low pM concentrations of DoceKA inhibit vasculogenic mimicry in ES-2 ovarian cancer cells.

[0207] Fig.42A , Fig.42B , Fig.42C , Fig.42D , Fig.42E and Fig.42F To characterize the effects of sortilin gene silencing on in vitro vasculogenic mimicry in TNBC-derived MDA-MB231 cells. More specifically, Fig.42A Illustrated are MDA-MB231 cells transiently transfected with scrambled siRNA (siScrambled) at 0 hours. Fig.42B Illustrated are MDA-MB231 cells transiently transfected with specific Sortilin siRNA (siSortilin) ​​at 0 hours. Fig.42CIllustration of MDA-MB231 cells transiently transfected with scrambled siRNA (siScrambled) at 24 hours. Fig.42D Description: MDA-MB231 cells were transiently transfected with specific sortilin siRNA (siSortilin) ​​at 24 hours. Fig.42E is a bar graph depicting the percentage of total rings for siScrambled and siSortilin cells over 24 hours. Fig.42F is a bar graph depicting the average ring area percentage of siScrambled cells and siSortilin cells over 24 hours.

[0208] Fig.43A and Fig.43B To characterize the inhibition of MDA-MB231 vasculogenic mimicry by DoceKA. More specifically, Fig.43A Illustrated are the effects of different concentrations of docetaxel (upper panels) and DoceKa (lower panels) administered to cells. Fig.43B is a graph illustrating the total number of rings present in cells when exposed to different concentrations of docetaxel and DoceKA.

[0209] Fig.44A Illustration of vasculogenic mimicry in ES-2 ovarian cancer cells at 0, 2, 6, 12, and 24 hours. Fig.44B Gene expression of sortin (SORT1), CD133, and MMP9 is depicted at 0, 2, 6, 12, and 24 hours. CD133 is one of the most commonly used markers to isolate cancer stem cell (CSC) populations from tumors. CD133+ cancer cells (CSCs) are positively correlated with vasculogenic mimicry formation, locoregional recurrence, and distant metastasis.

[0210] Fig.45A Illustration of the vasculogenic mimicry of MDA-MB-231 TNBC cells at 0, 2, 6, 12, and 24 hours. Fig.45B Gene expression of Sortilin (SORT1), CD1 33, and MMP9 at 0, 2, 6, 12, and 24 hours is depicted.

[0211] Fig.46A and Fig.46B To characterize the inhibition of vasculogenic mimicry in ES-2 ovarian cancer cells by anti-sortilin antibodies. More specifically, Fig.46A Depicted are images taken after 12 hours of ES-2 ovarian cancer cells in the presence of rabbit IgG, anti-SORT1 rabbit pAb, mouse IgG, and anti-SORT1 mouse mAb. Fig.46BIllustrated are the total number of rings present at hour 12 for cells exposed to rabbit IgG, anti-sortilin rabbit pAb, mouse IgG, and anti-sortilin mAb. Anti-SORT1 mAb inhibited the formation of 3D tubular structures and had a strong effect on total tube length and number of rings.

[0212] Fig.47 Depicted are images of panels of ES-2 ovarian cancer cells at 0 and 12 hours in the presence of varying concentrations of control or anti-SORT1 antibodies.

[0213] Fig.48A and Fig.48B To illustrate the effect of anti-sortilin on vasculogenic mimicry in ES-2 ovarian cancer cells. Fig.48A Depicted are the total number of rings present in cells at different concentrations of anti-SORT1 antibody. Fig.48B Illustrated is the percentage proliferation of cells exposed to different concentrations of anti-SORT1 antibody compared to a control group not exposed to anti-sortilin.

[0214] Fig.49 are images of panels illustrating exposure of ES-2 ovarian cancer cells to different concentrations of Katana peptide (KBP106) alone at exposure times of 0 and 24 hours. Under the same experimental conditions as for the Katana conjugate, the peptide (KBP106) had no significant effect on vasculogenic mimicry at 50 μM.

[0215] Fig.50 are images of panels illustrating ES-2 ovarian cancer cells exposed to KBP106 peptide and doxorubicin conjugate (KBB106). Fig.50 Images depicting ES-2 ovarian cancer cells exposed to different concentrations of KBP106 peptide and KBB106 at 0 and 24 hours of exposure. Addition of excess KBP106 is shown to reverse the inhibition of angiogenic mimicry caused by KBB106. Although KBP106 had no effect on angiogenic mimicry, addition of KBP106 to KBB106 prevented the inhibition of angiogenic mimicry by KBB106, suggesting that KBP106, by binding to sortilin, prevents KBB106 from interacting with the receptor.

[0216] Fig.51 Depicts images of ES-2 ovarian cancer cells exposed to sortilin ligand, neurotensin, and progranulin at 0 and 12 hours of exposure to each ligand. This figure demonstrates that sortilin ligand, neurotensin, and progranulin do not affect vasculogenic mimicry.

[0217] Fig.52are images of panels showing ES-2 ovarian cancer cells exposed to KBB106 conjugate and either neurotensin ligand or progranulin ligand at 0 and 12 hours of exposure. These images demonstrate that the addition of sortilin ligand, neurotensin, and progranulin reverses the angiogenic mimetic inhibition of KBB106 conjugate.

[0218] Fig.53A , Fig.53B , Fig.53C , Fig.53D and Fig.53E Consists of images of tissue sections of ES-2 xenograft tumors in nude mice. They are examples of individual markers at 40X. Fig.53A Explain the labeling of CASPASE-3; Fig.53B Explain the markings of PAS; Fig.53C Explain the labeling of Ki-67; Fig.53D Describe the marker for mouse CD3 1; and Fig.53E The labeling of CD133 is described.

[0219] Fig.54 An example of vasculogenic mimicry identification by immunohistochemistry analysis is shown. PAS positivity and CD31 positivity indicate normal vasculature of the mouse identified as "vessel" in the image. PAS positivity and CD31 negativity indicate vasculogenic mimicry identified as "VM" in the image.

[0220] Fig.55A , Fig.55B and Fig.55C By depicting mouse CD3 1-PAS ( Fig.55A )、sortilin-PAS( Fig.55B ) and CD133-PAS( Fig.55C ) stained ES-2 tumor tissue. All figures depict four progressively larger images of the stained tissue. Fig.55A In the figure, blood vessels are identified as "vessels" and vasculogenic mimicry is identified by "VM".

[0221] Fig.56A , Fig.56B and Fig.56C As depicted, the expression of proteins targeting mouse CD31-PAS ( Fig.56A )、sortilin-PAS( Fig.56B ) and CD133-PAS( Fig.56C ) stained ES-2 tumor tissue. All figures depict four progressively larger images of the stained tissue. Fig.56A In the figures, blood vessels are identified by the word "Vascular", and vasculogenic mimicry is identified by the word "VM".

[0222] Fig.57A , Fig.57B and Fig.57C By depicting mouse CD3 1-PAS ( Fig.57A )、sortilin-PAS( Fig.57B ) and CD133-PAS( Fig.57C ) stained ES-2 tumor tissue. These images show immunohistochemical detection of sortilin and CD133 in vasculogenic mimicry.

[0223] Fig.58 are images of immunoblot analysis under non-denaturing conditions demonstrating the presence of sortilin in various triple negative breast cancer (TNBC) cell lines (MDA-MB 231, MDA-MB 468, MDA-MB 157, DU4475, HCC70, BT-20) as well as the ES-2 ovarian cell line.

[0224] Fig.59A and Fig.59B Another example of BT-20TNBC cancer cells that can form 3D tubular structures is shown. More specifically, Fig.59A Image of 20,000 BT-20TNBC cancer cells before forming angiogenic mimicry structures. Fig.59B Depicts the same cells after forming an angiogenic mimicry structure. DETAILED DESCRIPTION

[0225] The terms "peptide compound" or "Katana peptide", "Katana biopharmaceutical peptide" or "KBP" as used herein refer to peptides derived, for example, from bacterial proteins or from ligands of receptors that target receptors expressed on cancer cells, including multidrug-resistant cancer cells. For example, the peptide compound can be derived from a bacterial protein involved in cell penetration or from sortilin ligands, such as progranulin and neurotensin. For example, the peptide compound can be cyclic. In certain embodiments, the peptide compound is linked (e.g., by a covalent bond, atom, or linker) to at least one therapeutic agent (such as an anticancer agent or a phytochemical) to form a conjugated compound that can be used, for example, to treat cancer or invasive cancer. In certain other embodiments, the peptide compound can be used on the surface of a liposome. For example, the peptide compound can be used to coat a liposome, graphene, nanotube, or nanoparticle, which can be loaded with at least one therapeutic agent (such as an anticancer agent or a phytochemical, or a gene or siRNA).

[0226] The term "Katana Biopharmaceuticals Peptide Family 1 Peptide Compound" or "KBP Family 1 Peptide Compound" refers to a peptide compound derived from a bacterial cell permeable protein. For example, a KBP Family 1 Peptide Compound may be derived from a protein having an amino acid sequence of IKLSGGVQAKAGVINMDKSESM (SEQ ID NO: 5). Non-limiting examples of KBP Family 1 Peptide Compounds are shown below:

[0227] Amino acid sequence

[0228]

[0229] As used herein, the peptide compound KBP-101 is represented by the amino acid sequence of IKLSGGVQAKAGVINMDKSESM (SEQ ID NO: 5).

[0230] As used herein, the peptide compound KBP-102 is represented by the amino acid sequence of succinyl-IKLSGGVQAKAGVINMFKSESY, which comprises the peptide sequence of SEQ ID NO: 6, wherein a succinyl group is attached thereto at the N-terminus.

[0231] As used herein, the peptide compound KBP-103 is represented by the amino acid sequence of IKLSGGVQAKAGVINMFKSESYK (biotin), which comprises the peptide sequence of SEQ ID NO: 7, wherein a biotin molecule is linked thereto at the C-terminus.

[0232] As used herein, the peptide compound KBP-104 is represented by the amino acid sequence of GVQAKAGVINMFKSESY (SEQ ID NO: 8).

[0233] As used herein, the peptide compound KBP-105 is represented by the amino acid sequence of acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14).

[0234] As used herein, the peptide compound KBP-106 is represented by the amino acid sequence of acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15).

[0235] The term "Katana Biopharmaceuticals Peptide Family 2 Peptide Compound" or "KBP Family 2 Peptide Compound" refers to a peptide derived from sortilin ligand, progranulin, and neurotensin. For example, the peptide can be derived from progranulin of human, rat, or mouse. For example, a KBP Family 2 Peptide Compound can be derived from human progranulin, such as having the amino acid sequence KCLRREAPRWDAPLRDPALRQLL (SEQ ID NO: 19), from rat progranulin, such as having the amino acid sequence KCLRKKTPRWDILLRDPAPRPLL (SEQ ID NO: 20), from mouse progranulin, such as having the amino acid sequence KCLRKKIPRWDMFLRDPVPRPLL (SEQ ID NO: 21), or from neurotensin, such as having the amino acid sequence XLYENKPRRPYIL (SEQ ID NO: 22). Non-limiting examples of KBP Family 2 Peptide Compounds are shown below:

[0236] Amino acid sequence

[0237]

[0238] As used herein, the peptide compound KBP-201 is represented by the amino acid sequence of acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16).

[0239] As used herein, the peptide compound KBP-202 is represented by the amino acid sequence of acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17).

[0240] As used herein, the peptide compound KBP-203 is represented by the amino acid sequence of acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 18).

[0241] As used herein, the term "sortilin" or "sortilin receptor" refers to a neuronal type 1 membrane glycoprotein encoded by the SORT1 gene, which belongs to the vacuolar protein sorting 10 protein (Vps10) receptor family. Sortilin (also known as neurotensin receptor 3; accession number NP 002950, ​​incorporated herein by reference) is abundantly expressed in the central nervous system and peripheral nervous system, and is also expressed in other types of tissues. For example, expression of sortilin is upregulated in many cancers, including, for example, ovarian cancer, breast cancer, colon cancer, and prostate cancer. The encoded precursor protein is proteolytically processed by furin to generate a mature receptor with a molecular weight of 100-110 kDa. Truncated and soluble forms of sortilin (95 kDa) have also been described, corresponding to its large luminal domain (i.e., extracellular domain or ectodomain), which have previously been detected in supernatant culture medium from cells overexpressing sortilin (48). The amino acid residues of Sortilin cited herein correspond to the positions of the full-length form (i.e., Accession No. NP 002950). The extracellular domain of Sortilin is located at amino acid residues 78-755 of the full-length form. The peptide compounds, conjugated compounds, antibodies, and conjugated antibodies described herein can have high binding affinity to Sortilin and can therefore specifically target cancer cells that express or overexpress Sortilin.

[0242] The term "compound" as used in this document refers to a compound of formula (I), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), (XIII), (XIV), (XV), (XVI), (XVII), (XIX), (XXIII), (XXVI), (XXVIII), (LI), (LII) or a pharmaceutically acceptable salt, solvate, hydrate and / or prodrug of these compounds, an isomer of these latter compounds or a racemic mixture of these latter compounds, and / or a composition made with such compounds as previously indicated in the present disclosure. The expression "compound" also refers to mixtures of the various compounds disclosed herein.

[0243] The compounds of the present disclosure include prodrugs. In general, such prodrugs will be functional derivatives of these compounds that are easily converted in vivo to the compounds from which they are theoretically derived. Prodrugs of the compounds of the present disclosure can be conventional esters formed with available hydroxyl 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 acyl chloride in pyridine). Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C8-C 24) esters, acyloxymethyl esters, carbamates and amino acid esters. In some cases, prodrugs of the disclosed compounds are those in which one or more hydroxyl groups in the compound are masked as groups that can be converted to hydroxyl groups in vivo. Conventional procedures for selecting and preparing suitable prodrugs are described, for example, in "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985.

[0244] The compounds of the present disclosure include radiolabeled forms, for example, by incorporation into the structure 2 H. 3 H. 14 C. 15 N or radioactive halogens (such as 125 Radiolabeled compounds of the disclosed compounds can be prepared using standard methods known in the art.

[0245] As used herein, the term "analog" includes portions, extensions, substitutions, variants, modifications or chemical equivalents of the amino acids disclosed herein and derivatives thereof, which perform substantially the same function as the peptides or antigens disclosed herein in substantially the same manner. For example, analogs of the peptides and antigens disclosed herein include, but are not limited to, conservative amino acid substitutions. Analogs of the peptides and antigens disclosed herein also include additions and deletions to the peptides and antigens disclosed herein.

[0246] As used herein, a "conservative amino acid substitution" is one in which one amino acid residue is substituted for another amino acid residue without abolishing a desired property of the peptide or antigen.

[0247] The expression "derivatives thereof" as used herein when referring to a compound refers to derivatives of the compound that have similar reactivity and can be used as substitutes for the compound to achieve the same desired result.

[0248] As used herein, the term "cancer" refers to a primary cancer or a secondary cancer, and includes non-metastatic cancer and / or metastatic cancer. Reference to cancer includes reference to cancer tissue or cells. For example, the cancer is 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 lymphocytic leukemia, acute myeloid leukemia, Hodgkin's lymphoma, neuroblastoma, non-Hodgkin's lymphoma, soft tissue cancer, osteosarcoma, thyroid cancer, transitional cell bladder cancer, Wilms tumor, glioma, pancreatic cancer or spleen cancer. As used herein, the term "cancer" also includes any cancer involving the expression of sortin.

[0249] As used herein, the term "invasive cancer" refers to a cancer with cancer cells that divide and grow rapidly. An invasive cancer may be invasive or metastatic, or more likely invasive or metastatic and spread to lymph nodes and / or other body organs. Reference to an invasive cancer includes reference to invasive cancer tissues or cells. An invasive cancer may be any of the cancer types described herein. An invasive cancer may also exhibit features such as angiogenic mimicry.

[0250] The term "angiogenic mimicry" (or VM) as used herein refers to the formation of microvascular channels by cancer cells. Cancer cells that participate in angiogenic mimicry are typically invasive, metastatic, and genetically deregulated. Angiogenic mimicry differs from angiogenesis in that it occurs de novo in the absence of endothelial cells, as cancer cells are arranged on tumor vessels, mimicking real vascular endothelium. There are two main types of angiogenic mimicry: tubular and patterned. Tubular angiogenic mimicry is morphologically similar to normal blood vessels, while patterned angiogenic mimicry is significantly different, but is able to anastomose with blood vessels. Angiogenic mimicry is found in various cancer types, such as melanoma, ovarian cancer, breast cancer (e.g., triple-negative breast cancer), prostate cancer, osteosarcoma, bladder cancer, colorectal cancer, hepatocellular carcinoma, gastric cancer, lung cancer, and other cancer types described herein.

[0251] As used herein, the expression "therapeutic agent" refers to an agent capable of producing a therapeutic effect by inhibiting or reducing angiogenesis or angiogenic mimicry in a subject, cancer tissue, or cell as compared to a control. For example, the therapeutic agent is an anti-angiogenic mimetic anti-sortin antibody described in the present disclosure. The anti-sortin antibody can be conjugated to an anticancer drug, such as docetaxel, doxorubicin, cabazitaxel, maytansinoids, auristatins, calicheamicins, amatoxins, amanita nitinate, and aldoxorubicin, or a phytochemical (curcumin). The anti-angiogenic mimetic can also be a peptide described herein, for example, KBP-101, KBP-1 02, KBP-103, KBP-104, KBP-105, KBP-106, KBP-201, KBP-202, or KBP-203. The peptide can also be conjugated to an anticancer drug, such as docetaxel, doxorubicin, cabazitaxel, maytansinoids, auristatins, calicheamicin, amatoxin, amanitin and aldoxorubicin, or a phytochemical (curcumin). For example, KBC-106, KBC-201, KBP-106-Cys-Aldoxorubicin, docetaxel-Katana peptide conjugate (DoceKA) or doxorubicin-Katana peptide conjugate (DoxKA).

[0252] As used herein, the term "anticancer agent" refers to an agent that is capable of causing toxicity in cancer cells. For example, taxanes derived from the bark of the Pacific yew, Taxus brevifolia, can be used as anticancer agents. Taxanes include, for example, docetaxel and cabazitaxel. Other anticancer agents include, for example, anthracycline compounds that act by intercalating into DNA. For example, anthracyclines include doxorubicin and aldoxorubicin.

[0253] As used herein, the term "docetaxel" or "docetaxel" refers to an anticancer agent having the following structure:

[0254]

[0255] Or a pharmaceutically acceptable salt, solvate or prodrug thereof and a mixture thereof. For example, docetaxel can be conjugated to the peptide compound or isolated antibody of the present disclosure via an oxygen atom attached to the carbon atom at position 2 of its side chain. Docetaxel can be linked to the peptide compound or isolated antibody directly or via a linker.

[0256] As used herein, the term "doxorubicin," "dox," or "doxo" refers to an anticancer agent having the following structure:

[0257]

[0258] Or a pharmaceutically acceptable salt, solvate or prodrug thereof and mixtures thereof. For example, doxorubicin can be conjugated to the peptide compound or isolated antibody of the present disclosure via an oxygen atom attached to the carbon atom at position 14. Doxorubicin can be linked to the peptide compound or isolated antibody directly or via a linker.

[0259] As used herein, the term "cabazitaxel" or "cab" refers to an anticancer agent having the following structure:

[0260]

[0261] or a pharmaceutically acceptable salt, solvate or prodrug thereof and a mixture thereof. For example, cabazitaxel can be conjugated to the peptide compound or isolated antibody of the present disclosure via an oxygen atom attached to the carbon atom at position 2 of its side chain. Cabazitaxel can be linked to the peptide compound or isolated antibody directly or via a linker.

[0262] As used herein, the term "aldoxorubicin" or "aldo" refers to an anticancer agent having the following structure:

[0263]

[0264] Or a pharmaceutically acceptable salt, solvate or prodrug thereof and a mixture thereof. For example, aldoxorubicin can be conjugated to the peptide compound or isolated antibody of the present disclosure via (6-maleimidocaproyl)hydrazone attached to the carbon at position 13 of its side chain. Aldoxorubicin can be linked to the peptide compound or isolated antibody directly or via a linker thereof.

[0265] As used herein, the term "phytochemical" refers to a chemical compound that occurs naturally in plants and can be used to inhibit angiogenic mimicry. Examples of phytochemicals include, for example, curcumin. Curcumin (diferuloylmethane) is a yellow pigment found in the spice turmeric root (curcuma longa) that is associated with anti-inflammatory properties. Other phytochemicals with anti-inflammatory properties include, for example, omega-3, white willow bark, green tea, catechins, pycnogenol, Boswellia serrata resin, resveratrol, Uncaria tomentosa, capsaicin, anthocyanins / anthocyanins, flavonoids, olive oil compounds, chlorogenic acid, and sulfopharaphane.

[0266] As used herein, the term "curcumin" or "cur" refers to a phytochemical having the following structure:

[0267]

[0268] Or a pharmaceutically acceptable salt, solvate or prodrug thereof and a mixture thereof. For example, curcumin can be conjugated with the peptide compound or isolated antibody of the present disclosure through the oxygen atom of its phenolic group. Curcumin can be connected to the peptide compound or isolated antibody directly or through a linker.

[0269] The expression "conjugate compound", "peptide-drug conjugate" or "peptide conjugate" as used herein refers to a compound comprising a peptide compound disclosed herein, optionally linked to at least one therapeutic agent via a linker. The conjugate compound may comprise, for example, 1, 2, 3 or 4 molecules of a therapeutic agent linked thereto. These 1-4 molecules of the therapeutic agent may be identical or different, i.e., up to four different therapeutic agents may be linked to the 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 may be used to inhibit angiogenic mimicry. Examples of conjugate compounds include, but are not limited to, the conjugate compounds shown below:

[0270]

[0271] The term "antibody" as used herein refers to monoclonal antibodies, including chimeric and humanized monoclonal antibodies, polyclonal antibodies, humanized antibodies, human antibodies and chimeric antibodies. Antibodies can be produced from recombinant sources and / or in transgenic animals. The term "antibody fragment" as used herein is intended to include Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, dimers, minibodies, diabodies and multimers and bispecific antibody fragments thereof. Antibodies can be fragmented using conventional techniques. For example, F(ab')2 fragments can be produced by treating antibodies with pepsin. The resulting F(ab')2 fragments can be treated to reduce disulfide bridges, thereby producing Fab' fragments. Papain digestion can lead to the formation of Fab fragments. Fab, Fab' and F(ab')2, scFv, dsFv, ds-scFv, dimers, minibodies, diabodies, bispecific antibody fragments and other fragments can also be synthesized by recombinant technology. The antibodies are optionally of any useful isotype, including, in one embodiment, IgM for diagnostic applications, and in one embodiment, IgG, such as IgGl, IgG2, IgG3, and IgG4, for therapeutic applications.

[0272] The term "isolated antibody" refers to an in vitro or in vivo produced antibody that has been removed from a source, such as an animal, hybridoma or other cell line, including recombinant cells that produce the antibody. The isolated antibody is optionally "purified," which means at least: 80%, 85%, 90%, 95%, 98% or 99% pure and optionally pharmaceutical grade pure.

[0273] The term "anti-sortilin mAb #1" or "anti-SORT1 mAb #1" refers to a monoclonal antibody (clone F11; Cat # MABN1792) obtained from EMB Millipore. The immunogen of this antibody is located in the extracellular domain of sortilin, i.e., amino acid residues 78-755 of sortilin.

[0274] The term "anti-sortilin mAb #2" or "anti-SORT2 mAb #2" refers to a monoclonal antibody obtained from BD Biosciences (clone 48; Cat # 612100). The immunogen of this antibody is amino acid residues 300-422 of sortilin, corresponding to part of the extracellular domain of this protein.

[0275] Specific antibodies or antibody fragments reactive to specific antigens or molecules accessible in Sortilin can also be produced by screening expression libraries encoding immunoglobulin genes or portions thereof expressed in bacteria with cell surface components, including amino acid residues 300-422 of Sortilin (SEQ ID NO: 25). For example, complete Fab fragments, VH regions, and FV regions can be expressed in bacteria using phage expression libraries (see, e.g., ref. 33). Examples of antigenic Sortilin residues include, but are not limited to, the amino acid sequence shown below:

[0276]

[0277]

[0278] In some embodiments, an isolated antibody that specifically binds to a polypeptide having or comprising an amino acid sequence as set forth in any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof is used to inhibit angiogenic mimicry. In some embodiments, the isolated antibody targets the sortilin receptor. In other embodiments, the isolated antibody binds to at least 2, optionally at least 4, consecutive amino acid residues as set forth in any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof.

[0279] As used herein, the term "humanized antibody" refers to an antibody or fragment that contains human conserved framework regions (otherwise known as constant regions) and hypervariable regions (otherwise known as antigen binding domains) of non-human origin. For example, the hypervariable regions may be from mouse, rat, or other species. Humanization of antibodies from non-human species has been well described in the literature. See, e.g., Carter & Merchant 1997 (34). Humanized antibodies are also readily available commercially.

[0280] Humanized forms of rodent antibodies are readily produced by CDR grafting (35). In this approach, the six CDR loops that comprise the antigen binding site of a rodent monoclonal antibody are linked to corresponding human framework regions. CDR grafting typically produces antibodies with reduced affinity because amino acids in the framework regions may affect antigen recognition (36). In order to maintain the affinity of the antibody, it is often necessary to replace certain framework residues by directed mutagenesis or other recombinant techniques, and this may be assisted by computer modeling of the antigen binding site (37). Humanized forms of antibodies are optionally obtained by resurfacing (38). In this approach, only the surface residues of the rodent antibody are humanized.

[0281] Humanized antibodies are selected from any class of immunoglobulins, including: IgM, IgG, IgD, IgA or IgE and any isotype, including: IgG1, IgG2, IgG3 and IgG4. Humanized antibodies or human antibodies may include sequences from one or more isotypes or classes. In addition, these antibodies are usually produced as antigen-binding fragments, such as Fab, Fab'F(ab')2, Fd, Fv and single domain antibody fragments, or produced as single chain antibodies in which heavy and light chains are connected by spacers. In addition, humanized antibodies can exist in monomeric or polymeric forms. Humanized antibodies optionally include a non-human chain and a humanized chain (i.e., a humanized heavy chain or light chain).

[0282] In addition, antibodies specific for a polypeptide having or comprising the amino acid sequence set forth in any one of SEQ ID NOs: 25-50, such as amino acid residues 300-422 of sortilin (Accession No. NP 002950) are readily isolated by screening an antibody phage display library. For example, an antibody phage library is optionally screened using portions of the antigens of the present disclosure to identify antibody fragments specific for sortilin. The identified antibody fragments are optionally used to generate a variety of recombinant antibodies useful in various embodiments of the present disclosure. Antibody phage display libraries are commercially available, for example, from Xoma (Berkeley, California). Methods for screening antibody phage libraries are well known in the art.

[0283] Other methods of producing antibodies are known in the art. For example, an antigenic polypeptide having or comprising the amino acid sequence of any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof can be conjugated to KLH and used, for example, in immunization of BALB / c mice to generate B cells reactive to an epitope on the polypeptide. Alternatively, a portion of a polypeptide having or comprising the amino acid sequence of any one of SEQ ID NOs: 25-50 peptides (comprising one or more antigenic determinants) is conjugated to KLH, minimally comprising 3 or 5 consecutive amino acids of any peptide sequence that is immunogenic when alone or coupled to KLH.

[0284] After immunizing an animal with an antigenic preparation of a Sortilin polypeptide (e.g., an amino acid sequence as shown in SEQ ID NO: 25-50, or an analog thereof, or a fragment thereof), antiserum can be obtained, and polyclonal antibodies can be isolated from the serum. To produce monoclonal antibodies, antibody-producing cells (i.e., B-lymphocytes) can be harvested from the immunized animal and fused with immortalized cells such as myeloma cells by somatic cell fusion procedures well known in the art to produce hybridoma cells. Such techniques include, for example, the hybridoma technique (39), the human B cell hybridoma technique (40), and the EBV-hybridoma technique for producing human monoclonal antibodies (41). Hybridoma cells can be screened by immunochemical methods to produce antibodies that specifically bind to a Sortilin polypeptide and monoclonal antibodies isolated from cultures containing such hybridoma cells.

[0285] The term "specific binding" or its derivatives as used herein in reference to an antibody is intended to mean that the antibody has sufficient selectivity between an antigen of interest (e.g., a sortilin polypeptide) and other antigens of no interest, as is generally understood in the art, for use in detecting the presence of the antigen of interest in a particular type of biological sample. Without wishing to be bound by theory, in certain methods employing the antibody, for example, in therapeutic applications, a higher degree of specificity in binding may be desired. Monoclonal antibodies are generally more effective than polyclonal antibodies in distinguishing between a desired antigen and cross-reactive polypeptides. The affinity of an antibody for an antigen, which is often expressed as a dissociation constant, is a characteristic that influences the specificity of the antibody: antigen interaction. The desired specificity can be achieved with a range of different affinities, and generally preferred antibodies will have a specificity of about 10 -6 , 10 -7 , 10 -8 , 10 -9 In another example, the antibody can bind its antigen of interest 3-5, 5-7, 7-10, 10-15, 5-15, or 5-30 times more efficiently than another molecule.

[0286] In addition, the properties of the antibodies obtained are affected by the techniques used to screen the antibodies. For example, if the antibody is used to bind the antigen in the solution, solution binding can be performed. Different techniques can be used to test the interaction between the antibody and the antigen to determine a particularly desirable antibody. Such techniques include immunoblotting, immunoprecipitation assays, immunohistochemistry, ELISA, surface plasmon resonance binding assays (such as Biacore binding assays (Bia-core AB, Uppsala, Sweden)) and sandwich assays (such as paramagnetic bead systems).

[0287] In one aspect, the present disclosure provides antibodies that bind to a soluble Sortilin polypeptide. Such antibodies can be generated as described herein using a soluble Sortilin polypeptide sequence as set forth in any one of SEQ ID NOs: 25-50, an analog or fragment thereof as an antigen. Antibodies of this type can be used, for example, to detect Sortilin polypeptides in biological samples and / or to monitor soluble Sortilin polypeptide levels in a subject. In another aspect, antibodies that specifically bind to a soluble Sortilin polypeptide can be used to modulate the activity of Sortilin polypeptides and related pathways, thereby inhibiting angiogenic mimicry.

[0288] As used herein, the expression "antibody-drug conjugate", "antibody conjugate" or "conjugated antibody" refers to an antibody disclosed herein, optionally linked to at least one therapeutic agent via a linker. The antibody-drug conjugate may comprise, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 therapeutic agent molecules linked thereto. These 1-12 therapeutic agent molecules may be the same or different, i.e., up to four different therapeutic agents may be linked to the antibody. The therapeutic agent is linked to the antibody via at least one covalent bond, at least one atom or at least one linker. The antibody-drug conjugate may be used to inhibit angiogenic mimicry. Examples of antibody-drug conjugates include, but are not limited to, an anti-sortin antibody conjugated to an anti-cancer drug, such as docetaxel, doxorubicin, cabazitaxel, maytansinoids, auristatins, calicheamicins, amatoxins, amanitine and aldoxorubicin, and / or a phytochemical, such as curcumin. The following table summarizes anti-cancer drugs that can be conjugated to the anti-sortin antibody:

[0289]

[0290]

[0291] The term "conjugation" as used herein refers to the preparation of a conjugate, for example as defined above. Such conjugation comprises linking the peptide compound or antibody to at least one therapeutic agent, optionally via a linker.

[0292] As used herein, the term "CD133 positive cell or CD133 positive cells" refers to one or more cells that express the CD133 cell surface marker.

[0293] For example, the following are general formulas for some of the peptide-conjugate compounds disclosed herein.

[0294] Curcumin-Katana Conjugate:

[0295]

[0296] For example, below are the chemical structures of some conjugated compounds disclosed herein.

[0297] Docetaxel-Katana peptide conjugate (DoceKA):

[0298]

[0299] Doxorubicin-Katana peptide conjugate (DoxKA):

[0300]

[0301] KBC-106:

[0302]

[0303] Curcumin-Katana Peptide Conjugate:

[0304] KBC-201:

[0305]

[0306] KBP-1 06-Cys-Aldoxorubicin:

[0307]

[0308] The term "linker" as used herein refers to a chemical structure that connects the peptide compound or antibody disclosed herein to at least one therapeutic agent. The linker can be connected to the peptide compound or isolated antibody at different functional groups on the peptide compound or antibody. For example, the linker can be connected to the peptide compound or isolated antibody at a primary amine (amine (-NH2): this group is present at the N-terminus of each polypeptide chain (called α-amine) and in the side chain of lysine (Lys, K) residues (called ε-amine). For example, the linker can be connected to the peptide compound or isolated antibody at a carboxyl group (-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, the linker can be connected to the peptide compound or isolated antibody at a sulfhydryl group (-SH): 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, the linker can be connected to the peptide compound or isolated antibody at a sulfhydryl group (-SH): 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). In the side chain of cysteine ​​(Cys, C). Typically, as part of the secondary or tertiary structure of a protein, cysteines are linked together by disulfide bonds (-SS-) between their side chains. It must be reduced to a sulfhydryl group so that it can be used for cross-linking through most types of reactive groups. For example, a linker can be linked to a peptide compound or an isolated antibody at the carbonyl (-CHO) position: post-translational modification (glycosylation) of polysaccharides by oxidation with sodium metaperiodate can produce ketone or aldehyde groups in glycoproteins. For example, a linker can be a cleavable linker. For example, a linker can be a non-cleavable linker.

[0309] The following table summarizes the reactivity classes and chemical groups of some of the main linkers for standard conjugation chemistries:

[0310]

[0311] For example, homobifunctional and heterobifunctional crosslinkers can be used. For example, disuccinimidyl suberate (DSS) is a homobifunctional crosslinker with the same amine-reactive NHS ester group at either end 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. Commercially available homobifunctional cross-linkers are: BSOCOES (bis(2-[succinimidyloxycarbonyloxy]ethyl)sulfone; DDPPB (1,4-bis-(3'-[2-pyridyldithio]-propionamido)butane; DSS (disuccinimidyl suberate); DST (disuccinimidyl tartrate); sulfoDST (sulfodisuccinimidyl tartrate); DSP (dithiobis(succinimidyl propionate); DTSSP (3,3'-dithiobis(sulfosuccinimidyl propionate); EGS (ethylene glycol bis(succinimidyl succinate)); and BASED (iodinated bis(β-[4-azidosalicylicylamino]-ethyl) disulfide).

[0312] The peptide compound or antibody can be conjugated through various linkers, such as sulfhydryl, amino (amine) or any suitable reactive group. The linker can be a covalent bond. The linker group can contain a flexible arm, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 or 15 carbon atoms.

[0313] Exemplary linkers include, but are not limited to, pyridyl disulfide, thiosulfonate, vinyl sulfonate, isocyanate, imidoester, diazines, hydrazines, thiols, carboxylic acids, polypeptide linkers, and acetylene. Alternatively, other linkers that may be used include BS 3 [Bis(sulfosuccinimidyl) suberate] (which is a homobifunctional N-hydroxysuccinimide ester that targets accessible primary amines), NHS / EDC (N-hydroxysuccinimide and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (NHS / EDC allows conjugation of primary amine groups with carboxyl groups), Sulfo-EMCS ([N-ε-maleimidopropionic acid] hydrazide (Sulfo-EMCS is a heterobifunctional reactive group reactive toward sulfhydryl and amino groups), hydrazides (most proteins contain exposed carbohydrates, and hydrazides are useful reagents for linking carboxyl and primary amines).

[0314] To form a covalent bond, various active carboxyl groups (e.g., esters) can be used as chemically reactive groups, wherein the hydroxyl moiety is physiologically acceptable at the level required for modifying the peptide compound or antibody. Specific reagents include, for example, N-hydroxysuccinimide (NHS), N-hydroxy-sulfosuccinimide (sulfo-NHS), maleimido-benzoyl-succinimide (MBS), γ-maleimido-butyryloxysuccinimide ester (GMBS), maleimidopropionic acid (MPA), maleimidohexanoic acid (MHA) and maleimidoundecanoic acid (MUA).

[0315] Primary amines are the main targets of NHS esters; NHS esters react with primary amines to form covalent amide bonds. The accessible α-amine groups present at the N-terminus of proteins and the ε-amine of lysine react with NHS esters. Therefore, the conjugated compounds disclosed herein may include a linker having an NHS ester conjugated to the N-terminal amino group of a peptide compound or antibody or the ε-amine of lysine. When the NHS ester reacts with the primary amine to release N-hydroxysuccinimide, an amide bond is formed. Succinimidyl containing reactive groups may be more simply referred to as succinimidyl groups. In some embodiments, the functional group on the peptide compound or antibody will be a thiol group, and the chemically reactive group will be a maleimide-containing group, such as γ-maleimide-butylamide (GMBA or MPA). Such maleimide-containing groups may be referred to as maleyl groups herein.

[0316] Amine to amine linkers include NHS esters, imido esters, and the like, examples of which are listed below.

[0317]

[0318]

[0319] The linker can also be a thiol-to-thiol linker, such as maleimide and pyridyldithiol listed below.

[0320]

[0321] The linker can be an amine to thiol linker, which includes NHS ester / maleimide compounds. Examples of these compounds are provided below.

[0322]

[0323]

[0324] The linker can react with an amino group and a non-selective entity. Such linkers include NHS ester / aryl azide and NHS ester / bis(aziridine) linkers, examples of which are listed below.

[0325]

[0326] Exemplary amine to carboxyl linkers include carbodiimide compounds (e.g., DCC (N,N-dicyclohexylcarbodiimide) and EDC (1-ethyl-3-[3-dimethylaminopropyl]carbodiimide). Exemplary thiol to non-selective linkers include pyridyl dithiol / aryl azide compounds (e.g., APDP ((N-[4-(p-azido salicylamino)butyl]-3'-(2'-pyridyldithio)propionamide)). Exemplary thiol to carbohydrate linkers include maleimide / hydrazide compounds (e.g., BMPH (N-[β-maleimidopropionic acid] hydrazide), EMCH ([N-ε-maleimidocaproic acid] hydrazide), MPBH Exemplary carbohydrate to non-selective linkers include hydrazide / arylazide compounds (e.g., ABH (p-azidobenzoyl hydrazide)). Exemplary hydroxyl to sulfhydryl linkers include isocyanate / maleimide compounds (e.g., (N-[p-maleimidophenyl]isocyanate)). Exemplary amine to DNA linkers include NHS ester / psoralen compounds (e.g., SPB (succinimidyl-[4-(psoralen-8-yloxy)]-butyrate)).

[0327] To create branch points of varying complexity in conjugated peptide compounds or antibodies, linkers are able to connect 3-7 entities.

[0328]

[0329] TMEA and TSAT are accessible to sulfhydryl groups through their maleimide groups. The hydroxyl and carboxyl groups of THPP can react with primary or secondary amines. Other useful linkers conform to the formula Y=C=NQAC(O)-Z, where Q is a homoaromatic or heteroaromatic ring system; A is a single bond or an unsubstituted or substituted divalent C 1-30 A bridging group, Y is O or S; and Z is Cl, Br, I, N3, N-succinimidyloxy, imidazolyl, 1-benzotriazolyloxy, OAr (wherein Ar is an electron-deficient activated aromatic group) or OC(O)R (wherein R is -AQN=C=Y or a C4-20 tertiary alkyl group) (see U.S. Pat. No. 4,680,338).

[0330] Other useful connectors have the following formula Where R1 is H, C 1-6 Alkyl, C 2-6 Alkenyl, C 6-12Aryl or aralkyl or with divalent organic -O-, -S- or The coupling of these, wherein R' is C 1-6 Alkyl, linking part; R2 is H, C 1-12 Alkyl, C 6-12 Aryl or C 6-12 Arylalkyl, R3 is 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, antibody or reagent (see, e.g., U.S. Pat. No. 5,306,809).

[0331] The joint can include at least one amino acid residue, and can be a peptide with at least or about 2, 3, 4, 5, 6, 7, 10, 15, 20, 25, 30, 40 or 50 amino acid residues. When the joint is a single amino acid residue, it can be any natural or non-natural amino acid (e.g., Gly or Cys). When the joint is a short peptide, it can be a peptide rich in glycine (which tends to be flexible), such as a peptide with a sequence [Gly-Gly-Gly-Gly-Ser]n, wherein n is an integer of 1 to 6 (including end values) (see U.S. Patent No. 7,271,149) or a peptide joint rich in serine (see U.S. Patent No. 5,525,491). The peptide joint rich in serine includes those of formula [XXXX-Gly]y, wherein at most two X are Thr, and the remaining X are Ser, and y is an integer of 1 to 5 (including end values) (e.g., Ser-Ser-Ser-Ser-Gly, wherein y is greater than 1). Other connectors include rigid connectors (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, wherein n is 1, 2, 3, 4 or 5).

[0332] The linker can be an aliphatic linker (e.g., having an amide bond to the polypeptide and an ester bond to the therapeutic agent). Where an aliphatic linker is used, it can be in length (e.g., C1-C 20 ) and the chemical moieties they contain (e.g., amino or carbamate).

[0333] Examples of suitable amino acid linkers are succinic acid, Lys, Glu and Asp, or dipeptides such as Gly-Lys. When the linker is succinic acid, one of its carboxyl groups can form an amide bond with the amino group of the amino acid residue, and the other carboxyl group can, for example, form an amide bond with the amino group of a peptide or a substituent. When the linker is Lys, Glu or Asp, its carboxyl group can form an amide bond with the amino group of the amino acid residue, and its amino group can, for example, form an amide bond with the carboxyl group of the substituent. When Lys is used as a linker, another linker can be inserted between the ε-amino group of Lys and the substituent. Another linker can 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, another linker is Glu or Asp (for example, it forms an amide bond with the ε-amino group of Lys, and forms another amide bond with the carboxyl group present in the substituent), that is, the substituent is N ε -acylated lysine residues.

[0334] The linker can also be a branched polypeptide. Exemplary branched peptide linkers are described in U.S. Pat. No. 6,759,509, which is incorporated herein by reference.

[0335] 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 bound to a linker that reacts with a modified free amine that is present at a lysine residue in a polypeptide and at the amino terminus of a polypeptide. Therefore, the linker that can be used for the present conjugated compound can include a group that reacts with a primary amine on a polypeptide that is partially conjugated to a therapeutic agent or a modified polypeptide. More specifically, the linker can be selected from a group consisting of monofluorocyclooctyne (MFCO), bicyclo[6.1.0]nonyne (BCN), N-succinimidyl-S-acetylthioacetate (SATA), N-succinimidyl-S-acetylthiopropionate (SATP), maleimide and dibenzocyclooctyne esters (DBCO esters). In a given linker, useful cyclooctynes ​​include OCT, ALO, MOFO, DIFO, DIBO, BARAC, DIBAC and DIMAC.

[0336] The linker can include a flexible arm, such as a short arm (<2 carbon chains), a medium sized arm (2-5 carbon chains), or a long arm (3-6 carbon chains).

[0337] Click chemistry can also be used for the conjugation of peptides (DBCO, TCO, tetrazine, azide, and alkyne linkers). These linker families can be reactive toward amines, carboxyls, and sulfhydryls. In addition, these linkers can also be biotinylated, PEGylated, modified with fluorescent imaging dyes, or phosphorylated for incorporation into oligonucleotide sequences.

[0338] The term "intermediate" as used herein refers to a therapeutic agent that has been reacted with a linker to form an activated form of the intermediate or therapeutic agent. The intermediate can be reacted with a peptide compound or antibody disclosed herein to form a conjugated compound disclosed herein that can be used to treat cancer or invasive cancer.

[0339] The expression "amino acid" refers to common natural (genetically encoded) or synthetic amino acids and common derivatives thereof known to those skilled in the art. When applied to amino acids, "standard" or "proteinogenic" refers to the 20 amino acids genetically encoded in their natural configuration. Similarly, when applied to amino acids, "non-standard", "non-natural" or "unusual" refers to a wide selection of non-natural, rare or synthetic amino acids, such as those described in Hunt, S. in "Chemistry and Biochemistry of the Amino Acids", Barrett, GC, ed., Chapman and Hall: New York, 1985. Some examples of non-standard amino acids include non-alpha amino acids, D-amino acids.

[0340] The abbreviations used for amino acid and peptide nomenclature follow the following conventions: 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, followed by p 84; "Journal of Biochemistry", 1985, 260, 14-42; "Pure Appl. Chem.", 1984, 56, 595-624; "Amino Acids and Peptides", 1985, 16, 387-410; and "Biochemical Nomenclature and Related Documents", 2nd edition, Portland Press, 1992, pp An extension of these rules was published in the JCBN / NC-IUB Newsletter 1985, 1986, 1989; see "Biochemical Nomenclature and Related Documents", 2nd ed., Portland Press, 1992, pp 68-69.

[0341] The term "antagonist" refers to a compound that reduces at least some of the effects of a protein's endogenous ligand, receptor, enzyme, interaction, etc.

[0342] The term "inhibitor" refers to a compound that decreases the normal activity of a protein, receptor, enzyme, interaction, or the like.

[0343] The expression "inverse agonist" refers to a compound that reduces the activity of a constitutively active receptor below its basal level.

[0344] 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, antibodies, peptide-conjugates and / or antibody-conjugates disclosed herein.

[0345] The term "mixture" as used herein refers to a composition comprising two or more peptide-compounds or antibodies. In an embodiment, the mixture is a mixture of two or more different peptide-compounds or antibodies. In another embodiment, when a peptide-compound or antibody is referred to as a "mixture", this means that it can contain two or more "forms" of peptide-compounds or antibodies in any ratio, such as a salt, solvate, prodrug or (when applicable) stereoisomer of a peptide-compound. It will be appreciated by those skilled in the art that the peptide-compound or antibody in the mixture can also exist in a mixture of multiple forms. For example, a peptide-compound or antibody can exist in the form of a hydrate of a salt of a peptide-compound or antibody or a hydrate of a salt of a prodrug. All forms of peptide compounds and antibodies disclosed herein are within the scope of the present application.

[0346] The term "modulator" refers to a peptide-compound or antibody that has an effect on a biological or chemical process or mechanism. For example, a modulator can increase, promote, up-regulate, activate, inhibit, reduce, block, prevent, delay, desensitize, deactivate, down-regulate, etc. biological or chemical processes or mechanisms. Thus, a modulator can be an "agonist" or an "antagonist". Exemplary biological processes or mechanisms affected by modulators include, but are not limited to, enzyme binding, receptor binding, and hormone release or secretion. Exemplary chemical processes or mechanisms affected by modulators include, but are not limited to, catalysis and hydrolysis.

[0347] The term "peptide" refers to a chemical compound comprising at least two amino acids covalently bonded together using an amide bond.

[0348] The term "prodrug" as used herein refers to a derivative of an active form of a known compound or composition that, when administered to a subject, is gradually converted to an active form to produce a better therapeutic response and / or a reduced level of toxicity. In general, a prodrug will be a functional derivative of a compound disclosed herein that is easily converted in vivo to a compound from which it is theoretically derived. Prodrugs include, but are not limited to, acyl esters, carbonates, phosphates, and carbamates. These groups are exemplary rather than exhaustive, and those skilled in the art can prepare prodrugs of other known species. Prodrugs can be formed, for example, with available hydroxyl, thiol, amino, or carboxyl groups. For example, available OH and / or NH2 in the disclosed compounds can be acylated using an activated acid in the presence of a base and optionally in an inert solvent (e.g., an acyl chloride in pyridine). Some common esters that have been used as prodrugs are phenyl esters, aliphatic (C1-C 24 ) esters, acyloxymethyl esters, carbamates and amino acid esters. In some cases, prodrugs of the disclosed compounds are those in which the hydroxyl and / or amino groups in the compound are masked as groups that can be converted to hydroxyl and / or amino groups in vivo. Conventional procedures for selecting and preparing suitable prodrugs are described, for example, in "Prodrug Design" edited by H. Bundgaard, Elsevier, 1985.

[0349] Expression " blocking group " refers to any chemical compound that can be used to prevent the potential reactive functional groups on the molecule such as amine, hydroxyl or carboxyl from chemically reacting and chemical changes occur elsewhere in the molecule. Many such blocking groups are well known to those skilled in the art, and examples can be found in " blocking groups in organic synthesis (Protective Groups in Organic Synthesis)", TWGreene and PG Wuts edited, John Wiley (John Wiley & Sons), New York, the 4th edition, 2006, 1082pp, in ISBN 9780471697541. The example of amino blocking group includes but is not limited to phthalimido, trichloroacetyl, benzyloxycarbonyl, tert-butyloxycarbonyl and adamantyl-oxycarbonyl. In certain embodiments, amino blocking group is carbamate amino blocking group, which is defined as the amino blocking group that forms carbamate when combined with amino. In other embodiments, the carbamate protecting group is allyloxycarbonyl (Alloc), benzyloxycarbonyl (Cbz), 9-fluorenylmethyloxycarbonyl (Fmoc), tert-butyloxycarbonyl (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 hydroxy 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 esters, tert-butyl esters, benzyl esters, trimethylsilylethyl esters and 2,2,2-trichloroethyl esters.

[0350] The expression "sequence identity" as used herein refers to the percentage of sequence identity between two polypeptide sequences or two nucleic acid sequences. In order to determine the percentage of identity of two amino acid sequences or two nucleic acid sequences, the sequences are aligned for optimal comparison purposes (for example, a gap can be introduced in the sequence of the first amino acid or nucleic acid sequence to optimally align with the second amino acid or nucleic acid sequence). The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions are then compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, the molecules at that position are identical. The percentage of identity between the 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 multiplied by 1 00%). In one embodiment, the two sequences are of the same length. A mathematical algorithm can also be used to determine the percentage of identity between two sequences. A preferred non-limiting example of a mathematical algorithm for comparing two sequences is the algorithm of ref.52 as modified in ref.53. Such algorithms are incorporated into the NBLAST and XBLAST programs of ref.49. BLAST nucleotide searches can be performed using the NBLAST nucleotide program parameter set, e.g., for score=100, wordlength=12, to obtain nucleotide sequences homologous to the nucleic acid molecules of the present application. BLAST protein searches can be performed using the XBLAST program parameter set, e.g., for score-50, wordlength=3, to obtain amino acid sequences homologous to the protein molecules of the present disclosure. To obtain gapped alignments for comparison purposes, Gap BLAST can be utilized as described in ref. 47. Alternatively, PSI-BLAST can be used to perform an iterated search to detect distance relationships (Id.) between molecules. When utilizing BLAST, Gap BLAST, and PSI-Blast programs, the default parameters of the corresponding programs (e.g., XBLAST and NBLAST) can be used (see, e.g., the NCBI website). Another preferred, non-limiting example of a mathematical algorithm for comparing sequences is the algorithm of Myers and Miller, 1988, CABIOS 4: 11-17. Such an algorithm is incorporated into the alignment program (version 2.0) that is part of the GCG sequence alignment software package. When comparing amino acid sequences using an alignment program, a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4 can be used. The percent identity between the 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.

[0351] As used herein, the expression “consisting essentially of” is intended to specify the presence of stated features, elements, components, groups, integers and / or steps, as well as those that do not materially affect the basic and novel characteristics of the features, elements, components, groups, integers and / or steps.

[0352] The expression "solid phase chemistry" refers to the performance of chemical reactions in which one of the components of the reaction is covalently bonded to a polymeric material (a solid support as defined below). Outside the traditional fields of peptide and oligonucleotide chemistry, reaction methods for performing chemical reactions on a solid phase have become more widely known and established (Solid-Phase Synthesis: A Practical Guide, F. Albericio, ed., CRC Press, 2000, 848 pp, ISBN: 978-0824703592; Organic Synthesis on Solid Phase, 2nd ed., Florencio Zaragoza et al., 2001, pp. 117-126, ISBN: 978-0824703592; Organic Synthesis on Solid Phase, 2nd ed., Florencio Zaragoza et al., 2001, pp. 117-126, ISBN: 978-0824703592; 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).

[0353] The terms "solid support", "solid phase" or "resin" refer to a mechanically and chemically stable polymer matrix used to perform solid phase chemistry. This is referred to by "resin", "P-" or the following symbols: To express.

[0354] Examples of suitable polymeric materials include, but are not limited to, polystyrene, polyethylene, polyethylene glycol (PEG, including but not limited to (Matrix Innovation, Quebec, Quebec, Canada; J. Comb. Chem. 2006, 8, 213-220), polyethylene glycol grafted or covalently bonded to polystyrene (also known as PEG-polystyrene, TentaGel TM , Rapp, W.; Zhang, L.; Bayer, E. In Innovations and Perspectives in Solid Phase Synthesis, Peptides, Polypeptides and Oligonucleotides; Epton, R., ed.; SPCC Ltd.: Birmingham, UK; p 205), polyacrylates (CLEARTM ), polyacrylamide, polyurethane, PEGA [polyethylene glycol poly (N, N dimethyl-acrylamide) copolymer, Tetrahedron Lett. 1 992, 33, 3077-3080], cellulose, etc. These materials may optionally contain additional chemical agents to form cross-linked bonds to mechanically stabilize the structure, such as polystyrene cross-linked with divinylbenzene (DVB, usually 0.1%-5%, preferably 0.5%-2%). As non-limiting examples, this solid support may include aminomethyl polystyrene, hydroxymethyl polystyrene, benzhydrylamine polystyrene (BHA), methylbenzhydrylamine (MBHA) polystyrene, and other polymer backbones containing free chemical functional groups, most typically NH2 or -OH, for further derivatization or reaction. The term is also meant to include "Ultraresins" having a high proportion ("loading") of these functional groups, such as those prepared from polyethyleneimine and cross-linked molecules (Journal of Combinatorial Chemistry 2004, 6, 340-349). At the end of the synthesis, the resins are usually discarded, although they have been shown to be able to be recycled (Tetrahedron Letters 1975, 16, 3055).

[0355] Typically, the material used as a resin is an insoluble polymer, but some polymers have different solubilities depending on the solvent and can also be used in solid phase chemistry. For example, polyethylene glycol can be used in this way because it is soluble in many organic solvents that can be chemically reacted, but it is insoluble in other solvents, such as diethyl ether. Therefore, the reaction can be carried out uniformly in solution, and then the product on the polymer is precipitated by adding diethyl ether and processed into a solid. This is called "liquid phase" chemistry.

[0356] The expression "pharmaceutically acceptable" means compatible with the treatment of subjects such as animals or humans.

[0357] The expression "pharmaceutically acceptable salt" refers to acid addition salts or base addition salts that are suitable for use or compatible with the treatment of subjects such as animals or humans.

[0358] As used herein, the expression "pharmaceutically acceptable acid addition salt" refers to any non-toxic organic or inorganic salt of any compound or antibody of the present disclosure or any intermediate thereof. Exemplary inorganic acids that form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Exemplary organic acids that form suitable salts include monocarboxylic acids, dicarboxylic acids and tricarboxylic acids, such as glycolic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid and salicylic acid, and sulfonic acids such as p-toluenesulfonic acid and methanesulfonic acid. Monoacid or diacid salts can be formed, and such salts can exist in hydrated, solvated or substantially anhydrous forms. In general, the acid addition salts of the compounds or antibodies of the present disclosure are more soluble in water and various hydrophilic organic solvents, and generally exhibit higher melting points than their free base forms. The selection of suitable salts will be known to those skilled in the art. Other non-pharmaceutically acceptable salts, such as oxalates, may be useful, for example, in isolating compounds or antibodies of the disclosure, for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0359] As used herein, the expression "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 intermediate thereof. Acidic compounds of the present disclosure that can form base addition salts include, for example, wherein CO2H is a functional group. Exemplary inorganic bases that form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides. 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 suitable salts will be known to those skilled in the art. Other non-pharmaceutically acceptable base addition salts can be used, for example, to isolate compounds, antibodies or conjugated compounds of the present disclosure, for laboratory use, or for subsequent conversion to pharmaceutically acceptable acid addition salts.

[0360] The formation of salts of the desired compounds is achieved using standard techniques, for example, by treating the neutral compound with an acid or base in a suitable solvent and isolating the formed salt by filtration, extraction or any other suitable method.

[0361] The term "solvate" as used herein refers to a compound or antibody or a pharmaceutically acceptable salt thereof, wherein molecules of a suitable solvent are incorporated into the crystal lattice. Suitable solvents are physiologically tolerable at the dosage administered. Examples of suitable solvents are ethanol, water, etc. When water is the solvent, the molecule is referred to as a "hydrate". The formation of the solvate will vary depending on the compound and the solvate. In general, the solvate is formed by dissolving the compound or antibody in a suitable solvent and separating the solvate by cooling or using an antisolvent. The solvate is typically dried or azeotroped at ambient conditions.

[0362] As used herein, the term "subject" includes all members of the animal kingdom, including mammals such as mice, rats, dogs, and humans.

[0363] The terms "suitable" and "appropriate" mean that the selection of particular groups or conditions will depend on the particular synthetic operation to be performed and the characteristics of the molecule, but the selection will be well within the skill of those well-trained in the art. All process steps described herein are carried out under conditions suitable for providing the products shown. Those skilled in the art will appreciate that all reaction conditions, including, for example, reaction solvents, reaction times, reaction temperatures, reaction pressures, ratios of reactants, and whether the reaction should be carried out under an anhydrous or inert atmosphere, may be varied to optimize the yield of the desired product and are within their skill.

[0364] The expression "therapeutically effective amount", "effective amount" or "sufficient amount" of a compound or composition of the present disclosure is an amount sufficient to produce a beneficial or desired result (including a clinical result) when administered to a subject (including a mammal, such as a human), and thus, a "therapeutically effective amount" or "effective amount" depends on the context in which it is used. For example, in the case of treating cancer, it is an amount of the compound, peptide compound-conjugate, antibody, antibody-conjugate or composition sufficient to achieve such treatment of cancer as compared to the response obtained without administration of the compound, peptide compound-conjugate, antibody, antibody-conjugate or composition. The amount of a given compound, peptide compound-conjugate, antibody, antibody-conjugate or composition of the present disclosure that will correspond to an effective amount will vary depending on various factors, such as a given drug, peptide compound-conjugate, antibody, antibody-conjugate, drug formulation, route of administration, type of disease or disorder, identity of the subject or host being treated, etc., but can still be routinely determined by those skilled in the art. Furthermore, as used herein, a "therapeutically effective amount" or "effective amount" of a compound, peptide compound-conjugate, antibody, antibody-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 cancer cells) as compared to a control.

[0365] As used herein and as known in the art, "treatment" or "treating" is a method for obtaining a beneficial or desired result, including a clinical result. A beneficial or desired clinical result may include, but is not limited to, inhibiting angiogenic mimicry. For example, the reduction in the length of angiogenic mimicry tubes in a subject, cancer tissue, and / or cell is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% greater than an untreated control subject, cancer tissue, and / or cell. For example, the reduction in the number of angiogenic mimicry rings in a subject, cancer tissue, and / or cell is at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% greater than an untreated control subject, cancer tissue, and / or cell. "Treat" also refers to alleviating or ameliorating one or more symptoms or symptoms, lessening the extent of a disease, stabilizing (i.e., not worsening) the disease state, preventing the spread of a disease, delaying or slowing the progression of a disease, improving or palliating the disease state, and remission (partial or total), whether detectable or undetectable.

[0366] As used herein, the term "tolerance" or "tolerable" refers to the degree to which a subject treated with a therapeutic agent can tolerate or accept the therapeutic agent. For example, tolerance can be assessed by measuring different parameters such as (i) maintenance or absence of weight loss, (ii) tolerated duration of treatment, and (iii) reduction or absence of side effects. For example, it is well known that a subject is tolerant to a therapeutic agent when no weight loss is observed during treatment with such agent. For example, the conjugates of the present disclosure (comprising at least one therapeutic agent) can increase the tolerance of a given therapeutic agent because the conjugates are more selective for receptors than the therapeutic agent taken alone. Unconjugated toxins may be too toxic to be administered or used alone in a subject. Therefore, high potency toxins can be used in antibody-drug conjugates to increase tolerance. For example, the conjugates of the present disclosure are antibody conjugates as described herein. In some embodiments, the conjugate is a conjugated antibody comprising at least one therapeutic agent as described herein, used to increase the tolerance of the at least one therapeutic agent. In some embodiments, the therapeutic agent is a toxin selected from the group consisting of maytansinoids, auristatins, calicheamicins, amatoxins, and amanitins.

[0367] As used herein, the term "administered" or "administering" refers to administering a therapeutically effective amount of a compound, peptide compound-conjugate, antibody, antibody-conjugate or composition of the present application to a cell in vitro (e.g., cell culture) or in vivo (e.g., in a subject).

[0368] In understanding the scope of the present disclosure, the term "comprising" and its derivatives as used herein are intended to be open terms, which specify the presence of the features, elements, components, groups, integers and / or steps, but do not exclude the presence of other unstated features, elements, components, groups, integers and / or steps. The foregoing also applies to words with similar meanings, such as the terms "including", "having" and their derivatives. Finally, as used herein, degree terms such as "substantially", "about" and "approximately" refer to reasonable deviation amounts of the modified terms so that the final result will not change significantly. If such deviation will not negate the meaning of the word it modifies, these degree terms should be interpreted as including at least ± 5% deviation of the modified term.

[0369] As used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. Thus, for example, a composition containing "a compound" includes a mixture of two or more compounds. It should also be noted that the term "or" is generally used in its sense including "and / or" unless the context clearly dictates otherwise.

[0370] In compositions comprising an "additional" or "second" component, the second component as used herein is chemically different from the other components or the first component. The "third" component is different from the other components, the first component and the second component, and further listed or "additional" components are similarly different.

[0371] The definitions and embodiments described in certain sections are intended to apply to other embodiments described herein as those skilled in the art understand that they apply to these other embodiments.

[0372] The recitation of numerical ranges by endpoints herein 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 should be understood that all numbers and fractions thereof are considered to be modified by the term "about."

[0373] Previously, a platform was developed that allows for the delivery of therapeutic agents into cancer cells for new therapies against primary and secondary tumors. This approach utilizes peptide compounds derived from bacterial proteins or ligands of receptors expressed in cancer cells (e.g., sortilin / syndecan). In the present disclosure, conjugation of a therapeutic agent for inhibiting angiogenic mimicry with one of these peptide compounds is described. For example, a phytochemical such as curcumin can be conjugated to a peptide compound.

[0374] Disclosed herein are peptide compounds and conjugated compounds comprising at least one therapeutic agent linked to the peptide compounds for use in inhibiting angiogenic mimicry.

[0375] Thus, a first aspect is a peptide compound having at least 60% sequence identity with a compound selected from the group consisting of compounds of formula (A)-(C), (II), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII) and (XIII):

[0376] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO: 1)

[0377] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II) (SEQ ID NO: 2)

[0378] YKX 13 LRRX 14 APRW 15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3)

[0379] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4)

[0380] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO: 5)

[0381] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO: 6)

[0382] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0383] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO: 8)

[0384] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0385] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO: 1 0)

[0386] YKSLRRKAPRWDAPLRDPALRQLL(XI)(SEQ ID NO: 11)

[0387] YKSLRRKAPRWDAYLRDPALRQLL(XII)(SEQ ID NO: 1 2)

[0388] YKSLRRKAPRWDAYLRDPALRPLL(XIII)(SEQ ID NO: 1 3)

[0389] in

[0390] 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 independently selected from any amino acids;

[0391] X 16 , X 17 , X 20 and X 21 independently selected from Q, P, Y, I and L;

[0392] n is 0, 1, 2, 3, 4, or 5;

[0393] When X9 is present more than once, each of said X9 is independently selected from any amino acid;

[0394] When X 19 When present more than once, each of said X9 is independently selected from any amino acid

[0395] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide at the N- and / or C-terminus,

[0396] Used to inhibit vasculogenic mimicry.

[0397] In another aspect is a peptide compound having at least 61%, at least 62%, at least 63%, at least 64%, at least 65%, at least 66%, at least 67%, at least 68%, at least 69%, at least 70%, at least 71%, at least 72%, at least 73%, at least 74%, at least 75%, at least 76%, at least 77%, at least 78%, at least 79%, or at least 80% sequence identity to a compound selected from the group consisting of:

[0398] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO: 1)

[0399] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II) (SEQ ID NO: 2)

[0400] YKX 13 LRRX 14 APRW 15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3)

[0401] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4)

[0402] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO: 5)

[0403] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO: 6)

[0404] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0405] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO: 8)

[0406] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0407] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO: 1 0)

[0408] YKSLRRKAPRWDAPLRDPALRQLL(XI)(SEQ ID NO: 11)

[0409] YKSLRRKAPRWDAYLRDPALRQLL(XII)(SEQ ID NO: 1 2)

[0410] YKSLRRKAPRWDAYLRDPALRPLL(XIII)(SEQ ID NO: 1 3)

[0411] in

[0412] 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 independently selected from any amino acids;

[0413] X 16 , X 17 , X 20 and X 21 independently selected from Q, P, Y, I and L;

[0414] n is 0, 1, 2, 3, 4, or 5;

[0415] When X9 is present more than once, each of said X9 is independently selected from any amino acid;

[0416] When X 19 When present more than once, each of said X9 is independently selected from any amino acid

[0417] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide at the N- and / or C-terminus,

[0418] Used to inhibit vasculogenic mimicry.

[0419] Yet another aspect is a peptide compound having at least 80% sequence identity with a compound selected from the group consisting of compounds of Formula (A)-(C), (IA), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), and (XIII):

[0420] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO:1)

[0421] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II)(SEQ ID NO:2)

[0422] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L(III)(SEQ ID NO:3)

[0423] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV)(SEQ ID NO:4)

[0424] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO:5)

[0425] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO:6)

[0426] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0427] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO:8)

[0428] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0429] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO:1 0)

[0430] YKSLRRKAPRWDAPLRDPALRQLL(XI)(SEQ ID NO:11)

[0431] YKSLRRKAPRWDAYLRDPALRQLL(XII)(SEQ ID NO:1 2)

[0432] YKSLRRKAPRWDAYLRDPALRPLL(XIII)(SEQ ID NO: 1 3)

[0433] in

[0434] 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 independently selected from any amino acids;

[0435] X 16 , X 17 , X 20 and X 21 independently selected from Q, P, Y, I and L;

[0436] n is 0, 1, 2, 3, 4, or 5;

[0437] When X9 is present more than once, each of said X9 is independently selected from any amino acid;

[0438] When X 19 When present more than once, each of said X9 is independently selected from any amino acid

[0439] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide at the N- and / or C-terminus,

[0440] Used to inhibit vasculogenic mimicry.

[0441] In some embodiments, the peptide compound targets the Sortilin receptor. In some embodiments, the peptide compound is used to target the Sortilin receptor.

[0442] For example, the peptide compound is a peptide compound comprising:

[0443] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO: 1)

[0444] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II) (SEQ ID NO: 2)

[0445] YKX 13 LRRX 14 APRW15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3)

[0446] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4)

[0447] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO: 5)

[0448] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO: 6)

[0449] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0450] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO: 8)

[0451] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0452] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO: 1 0)

[0453] YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11) YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 1 2) or YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 1 3).

[0454] For example, the peptide compound is a peptide compound consisting essentially of:

[0455] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO: 1)

[0456] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II) (SEQ ID NO: 2)

[0457] YKX 13 LRRX 14 APRW 15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3)

[0458] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4)

[0459] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO: 5)

[0460] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO: 6)

[0461] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0462] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO: 8)

[0463] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0464] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO: 1 0)

[0465] YKSLRRKAPRWDAPLRDPALRQLL (XI) (SEQ ID NO: 11) YKSLRRKAPRWDAYLRDPALRQLL (XII) (SEQ ID NO: 1 2) or YKSLRRKAPRWDAYLRDPALRPLL (XIII) (SEQ ID NO: 1 3).

[0466] For example, the peptide compound is a peptide compound consisting of:

[0467] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO: 1)

[0468] (X9) n GVX 10 AKAGVX 11 NX 12FKSESY(II) (SEQ ID NO: 2)

[0469] YKX 13 LRRX 14 APRWDX 15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3)

[0470] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4)

[0471] IKLSGGVQAKAGVINMDKSESM(V) (SEQ ID NO: 5)

[0472] IKLSGGVQAKAGVINMFKSESY(VI) (SEQ ID NO: 6)

[0473] IKLSGGVQAKAGVINMFKSESYK(VII) (SEQ ID NO: 7)

[0474] GVQAKAGVINMFKSESY(VIII) (SEQ ID NO: 8)

[0475] GVRAKAGVRNMFKSESY(IX) (SEQ ID NO: 9)

[0476] GVRAKAGVRN(Nle)FKSESY(X) (SEQ ID NO: 10)

[0477] YKSLRRKAPRWDAPLRDPALRQLL(XI) (SEQ ID NO: 11)

[0478] YKSLRRKAPRWDAYLRDPALRQLL(XII) (SEQ ID NO: 12) or

[0479] YKSLRRKAPRWDAYLRDPALRPLL(XIII) (SEQ ID NO: 13).

[0480] According to another aspect, a peptide compound is provided, comprising a compound selected from the group consisting of compounds of Formula (A)-(I), (IA), (III), (IV), (V), (VI), (VII), (VIII), (IX), (X), (XI), (XII), and (XIII):

[0481] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(I)(SEQ ID NO: 1)

[0482] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY(II) (SEQ ID NO: 2)

[0483] YKX 13 LRRX 14 APRW 15 PLRDPALRX 16 X 17 L(III) (SEQ ID NO: 3)

[0484] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4)

[0485] IKLSGGVQAKAGVINMDKSESM(V)(SEQ ID NO: 5)

[0486] IKLSGGVQAKAGVINMFKSESY(VI)(SEQ ID NO: 6)

[0487] IKLSGGVQAKAGVINMFKSESYK(VII)(SEQ ID NO:7)

[0488] GVQAKAGVINMFKSESY(VIII)(SEQ ID NO: 8)

[0489] GVRAKAGVRNMFKSESY(IX)(SEQ ID NO:9)

[0490] GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO: 1 0)

[0491] YKSLRRKAPRWDAPLRDPALRQLL(XI)(SEQ ID NO: 11)

[0492] YKSLRRKAPRWDAYLRDPALRQLL(XII)(SEQ ID NO: 1 2)

[0493] YKSLRRKAPRWDAYLRDPALRPLL(XIII)(SEQ ID NO: 1 3)

[0494] in

[0495] 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 independently selected from any amino acids;

[0496] X 16 , X 17 , X 20 and X 21 independently selected from Q, P, Y, I and L;

[0497] n is 0, 1, 2, 3, 4, or 5;

[0498] When X9 is present more than once, each of said X9 is independently selected from any amino acid;

[0499] When X 19 When present more than once, each of said X9 is independently selected from any amino acid

[0500] and wherein at least one protecting group and / or at least one labeling agent is optionally attached to the peptide at the N- and / or C-terminus,

[0501] Used to inhibit vasculogenic mimicry.

[0502] 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%, at least 99%, at least 100%, at least 101%, at least 102%, at least 103%, at least 104%, at least 105%, at least 106%, at least 107%, at least 108%, at least 109%, at least 110%, at least 111%, at least 112%, at least 113%, at least 114%, at least 115%, at least 116%, at least 117%, at least 118%, at least 119%, %, 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.

[0503] 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 with the peptide compound represented by Formula (I) or SEQ ID NO: 1.

[0504] 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 with the peptide compound represented by Formula (II) or SEQ ID NO: 2.

[0505] 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 with the peptide compound represented by Formula (III) or SEQ ID NO: 3.

[0506] 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 with the peptide compound represented by Formula (IV) or SEQ ID NO:4.

[0507] 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 with the peptide compound represented by Formula (V) or SEQ ID NO:5.

[0508] 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 with the peptide compound represented by Formula (VI) or SEQ ID NO:6.

[0509] 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 with the peptide compound represented by Formula (VII) or SEQ ID NO:7.

[0510] 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 with the peptide compound represented by Formula (VIII) or SEQ ID NO:8.

[0511] 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 with the peptide compound represented by Formula (IX) or SEQ ID NO:9.

[0512] 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 with the peptide compound represented by Formula (X) or SEQ ID NO: 10.

[0513] 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 with the peptide compound represented by Formula (XI) or SEQ ID NO: 11.

[0514] 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 with the peptide compound represented by Formula (XII) or SEQ ID NO: 12.

[0515] 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 with the peptide compound represented by Formula (XIII) or SEQ ID NO: 13.

[0516] 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 with the peptide compound represented by Formula (LI) or SEQ ID NO: 23.

[0517] 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.

[0518] In an 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 an 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).

[0519] 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.

[0520] In one embodiment, at least one protecting group is attached to the peptide at the N- and / or C-terminus.

[0521] In one embodiment, the succinyl group is linked to the peptide compound. For example, the peptide compound has a succinyl-IKLSGGVQAKAGVINMFKSESY sequence, which corresponds to SEQ ID NO: 6, and has a succinyl group attached to it at the N-terminus.

[0522] In one embodiment, the acetyl group is linked to the peptide compound. For example, the peptide compound has the sequence of acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14). For example, the peptide compound has the sequence of acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 15). For example, the peptide compound has the sequence of acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16). For example, the peptide compound has the sequence of acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17). For example, the peptide compound has the sequence of acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 18).

[0523] In one embodiment, at least one labeling agent is attached to the peptide at the N- and / or C-terminus.

[0524] Those skilled in the art will appreciate 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 imaging agent.

[0525] In one embodiment, the peptide compound is biotinylated. For example, the peptide compound has the sequence IKLSGGVQAKAGVINMFKSESYK(biotin), which corresponds to SEQ ID NO: 7, and has a biotin molecule attached to it at the C-terminus.

[0526] For example, the peptide compound is represented by formula (XXXVI):

[0527] Succinyl-IKLSGGVQAKAGVINMFKSESY(XXXVI)

[0528] It comprises the peptide compound having SEQ ID NO: 6, wherein a succinyl group is attached at the N-terminus.

[0529] In one embodiment, X 16 Independently selected from Q, P, Y, I and L.

[0530] For example, X 16 is Q. For example, X 16 is P. For example, X 16 is Y. For example, X 16 It's I.

[0531] In one embodiment, X 17 Independently selected from Q, P, Y, I and L.

[0532] For example, X 17 is Q. For example, X 17 is P. For example, X 17 is Y. For example, X 17 It's I.

[0533] In one embodiment, X 20 Independently selected from Q, P, Y, I and L.

[0534] For example, X 20 is Q. For example, X 20 is P. For example, X 20 is Y. For example, X 20 It's I.

[0535] In one embodiment, X 21 Independently selected from Q, P, Y, I and L.

[0536] For example, X 21 is Q. For example, X 21 is P. For example, X 21 is Y. For example, X 21 It's I.

[0537] In one embodiment, the peptide compound is selected from:

[0538] X1X2X3X4X5GVX6AKAGVX7NX8FKSESY(SEQ ID NO: 1);

[0539] (X9) n GVX 10 AKAGVX 11 NX 12 FKSESY (SEQ ID NO: 2);

[0540] YKX 13 LRRX 14 APRW 15 PLRDPALRX 16 X 17 L (SEQ ID NO: 3);

[0541] YKX 18 LRR(X 19 ) N PLRDPALRX 20 X 21 L(IV) (SEQ ID NO: 4);

[0542] IKLSGGVQAKAGVINMDKSESM (SEQ ID NO: 5);

[0543] Succinyl-IKLSGGVQAKAGVINMFKSESY (comprising SEQ ID NO: 6, wherein a succinyl group is attached thereto at the N-terminus);

[0544] IKLSGGVQAKAGVINMFKSESYK (biotin) (comprising SEQ ID NO: 7, wherein a biotin molecule is attached thereto at the C-terminus);

[0545] GVQAKAGVINMFKSESY(SEQ ID NO: 8);

[0546] Acetyl-GVRAKAGVRNMFKSESY (SEQ ID NO: 14);

[0547] Acetyl-GVRAKAGVRN(Nle)FKSESY (SEQ ID NO: 1 5);

[0548] Acetyl-YKSLRRKAPRWDAPLRDPALRQLL (SEQ ID NO: 16);

[0549] Acetyl-YKSLRRKAPRWDAYLRDPALRQLL (SEQ ID NO: 17);

[0550] Acetyl-YKSLRRKAPRWDAYLRDPALRPLL (SEQ ID NO: 1 8);

[0551] GVRAKAGVRN(Nle)FKSESYC (SEQ ID NO: 23); and

[0552] Acetyl-GVRAKAGVRN(Nle)FKSESYC (SEQ ID NO: 24).

[0553] In one embodiment, the peptide compound can be modified at the C and / or N terminus by adding one or more amino acid residues to obtain or increase the preferential binding site at the end of the peptide. 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 cysteine ​​to the C-terminus. In a specific embodiment, the peptide compound has an acetyl-GVRAKAGVRN(Nle)FKSESY sequence corresponding to SEQ ID NO: 1 5, which is modified by adding cysteine ​​to the C-terminus.

[0554] In one aspect, the peptide compound or its derivative described herein specifically binds to a polypeptide having an amino acid sequence as shown in any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof, for inhibiting angiogenic mimicry. In another aspect, the peptide compound or its derivative described herein targets the Sortilin receptor. In another aspect, the peptide compound or its derivative described herein is used to target the Sortilin receptor. In another aspect, the peptide compound or its derivative described herein binds to at least 2, 3, 4 or 5 consecutive amino acid residues as shown in any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof. For example, the peptide compound or its derivative binds to at least 2 consecutive amino acid residues as shown in SEQ ID NO: 25. For example, the peptide compound or its derivative binds to at least 3 consecutive amino acid residues as shown in SEQ ID NO: 25. For example, the peptide compound or its derivative binds to at least 4 consecutive amino acid residues as shown in SEQ ID NO: 25. For example, the peptide compound or its derivative binds to at least 5 consecutive amino acid residues as shown in SEQ ID NO: 25.

[0555] Peptide compounds as described herein can be connected, linked, mixed or conjugated with small molecules, peptides, proteins, oligonucleotides, diagnostic agents, imaging agents or radionuclide agents, macromolecules such as monoclonal antibodies, therapeutic agents such as phytochemicals or drug delivery systems, including nanoparticles, liposomes, nanotubes, graphene particles loaded with therapeutic agents, imaging agents, genes, siRNA. The resulting conjugated compounds can be used as single or combined therapies, for example, for inhibiting angiogenesis mimicry.

[0556] Therefore, another aspect disclosed herein is a compound having the formula A-(B) n The conjugated compound

[0557] in

[0558] n is 1, 2, 3, or 4;

[0559] A is a peptide compound as defined herein, wherein the peptide is optionally protected by a protecting group; and

[0560] B is at least one therapeutic agent, wherein B is linked to A,

[0561] Optionally, the peptide compound is cyclic,

[0562] Used to inhibit vasculogenic mimicry.

[0563] Another aspect disclosed herein is a compound having the formula A-(B): n The conjugated compound

[0564] in

[0565] n is 1, 2, 3, or 4;

[0566] A is a peptide compound as defined in the present disclosure, wherein the peptide compound is optionally protected by a protecting group; and

[0567] B is at least one therapeutic agent, wherein B is optionally linked to A at a free amine of the peptide compound, at the N-terminal position of the peptide compound, at a free -SH of the peptide compound, or at a free carboxyl group of the peptide compound,

[0568] Optionally, the peptide compound is cyclic,

[0569] Used to inhibit vasculogenic mimicry.

[0570] In some embodiments, the conjugated peptides described herein target the Sortilin receptor. In some embodiments, the conjugated peptides described herein are used to target the Sortilin receptor.

[0571] Another aspect disclosed herein is a compound having the formula A-(B): nThe conjugated compound

[0572] in

[0573] n is 1, 2, 3, or 4;

[0574] A is a peptide compound as defined herein; and

[0575] B is at least one therapeutic agent, wherein 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,

[0576] Optionally, the peptide compound is cyclic,

[0577] Used to treat cancer or aggressive cancer.

[0578] In embodiments, B is linked to A via a linker, optionally a cleavable linker.

[0579] For example, the at least one therapeutic agent is a phytochemical selected from curcumin, omega-3, white willow bark, green tea, catechins, pycnogenol, Boswellia serrata resin, resveratrol, Uncaria tomentosa, capsaicin, anthocyanins, flavonoids, olive oil compounds, chlorogenic acid, and sulfopharaphane.

[0580] In embodiments, the therapeutic agent is a phytochemical or an anticancer agent.

[0581] In an embodiment, the phytochemical is curcumin.

[0582] In an embodiment, the conjugated compound is selected from:

[0583] GVRAK(Curcumin)AGVRN(Nle)FK(Curcumin)SESY-Formula (XIV)

[0584] It comprises the peptide compound having SEQ ID NO: 10, wherein each lysine residue has a curcumin molecule attached thereto; and

[0585] YK(Curcumin)SLRRK(Curcumin)APRWDAPLRDPALRQLL-Formula (XV)

[0586] It comprises the peptide compound having SEQ ID NO: 11, wherein each lysine residue has a curcumin molecule attached thereto.

[0587] For example, the conjugated compound is represented by formula (XIV).

[0588] For example, the conjugated compound is represented by formula (XV).

[0589] In an embodiment, the conjugated compound is selected from:

[0590] Acetyl-GVRAK(Curcumin)AGVRN(Nle)FK(Curcumin)SESY-Formula (XVI)

[0591] It comprises the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a curcumin molecule attached thereto, and

[0592] Acetyl-YK(Curcumin)SLRRK(Curcumin)APRWDAPLRDPALRQLL-Formula (XVII)

[0593] It comprises the peptide compound having SEQ ID NO: 16, wherein each lysine residue has a curcumin molecule attached thereto.

[0594] For example, the conjugated compound is represented by formula (XVI).

[0595] For example, the conjugated compound is represented by formula (XVII).

[0596] In embodiments, the therapeutic agent is an anti-cancer agent.

[0597] In embodiments, the anticancer agent is docetaxel.

[0598] In an embodiment, the conjugated compound is represented by formula (XIX):

[0599] GVRAK (docetaxel) AGVRN (Nle) FK (docetaxel) SESY-formula (XIX)

[0600] It comprises the peptide compound having SEQ ID NO: 10, wherein each lysine residue has a docetaxel molecule attached thereto.

[0601] In another embodiment, the conjugated compound is represented by formula (XXIII):

[0602] Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY-Formula (XXIII)

[0603] It comprises the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a docetaxel molecule attached thereto.

[0604] In embodiments, the anticancer agent is doxorubicin.

[0605] In an embodiment, the conjugated compound is represented by formula (XXVI):

[0606] GVRAK(Adriamycin)AGVRN(Nle)FK(Adriamycin)SESY-Formula (XXVI)

[0607] It comprises the peptide compound having SEQ ID NO: 10, wherein each lysine residue has a doxorubicin molecule attached thereto.

[0608] In another embodiment, the conjugated compound is represented by formula (XXVIII):

[0609] Acetyl-GVRAK(Adriamycin)AGVRN(Nle)FK(Adriamycin)SESY-Formula (XXVIII)

[0610] It comprises the peptide compound having SEQ ID NO: 15, wherein each lysine residue has a doxorubicin molecule attached thereto.

[0611] In embodiments, the anticancer agent is cabazitaxel.

[0612] In embodiments, the anticancer agent is aldoxorubicin.

[0613] In an embodiment, the conjugated compound is represented by formula (LI):

[0614] GVRAKAGVRN(Nle)FKSESYC(aldoxorubicin)-Formula (LI)

[0615] It comprises the peptide compound having SEQ ID NO: 23, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto, or

[0616] It comprises the peptide compound having SEQ ID NO: 10, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, and wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto.

[0617] In an embodiment, the conjugated compound is represented by formula (LII):

[0618] Acetyl-GVRAKAGVRN(Nle)FKSESYC(aldoxorubicin)-Formula (LII)

[0619] It comprises the peptide compound having SEQ ID NO: 24, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto, or

[0620] It comprises the peptide compound having SEQ ID NO: 15, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, and wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto.

[0621] In an embodiment, said at least one therapeutic agent B is linked to said peptide compound A at said free amine of said lysine residue of said peptide compound via a linker.

[0622] In an embodiment, said at least one therapeutic agent B is linked to said peptide compound A at said N-terminal position of said peptide compound via a linker.

[0623] In embodiments, the linker is selected from a succinate and a dimethylglutarate linker.

[0624] For example, the linker is a cleavable linker. For example, the linker is a non-cleavable linker.

[0625] For example, the conjugate compound may comprise a cleavable linker that connects the at least one therapeutic agent to the peptide compound or antibody. For example, the at least one therapeutic agent may be released from the peptide compound or antibody by the action of an esterase on the ester bond.

[0626] For example, the therapeutic agent can be conjugated to the peptide compound or antibody by forming a bond, such as a peptide bond, at a lysine or the amino terminus, at an available free amine on the peptide or antibody.

[0627] In embodiments, the isolated antibody binds to at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 2 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 3 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 4 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 5 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 6 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 7 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 8 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 9 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 10 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 11 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 12 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 13 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 14 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 15 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 16 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 17 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 18 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 19 consecutive residues of any one of SEQ ID NOs: 25-50. In embodiments, the isolated antibody binds to at least 20 consecutive residues of any one of SEQ ID NOs: 25-50.

[0628] In embodiments, the isolated antibody is monoclonal, polyclonal, chimeric or humanized. In embodiments, the isolated antibody is an antibody fragment. In embodiments, the antibody fragment is a Fab, Fab', F(ab')2, scFv, dsFv, ds-scFv, dimer, minibody, diabody or multimer thereof or a bispecific antibody fragment. In embodiments, the isolated antibody is a monoclonal antibody. In embodiments, the mAb is anti-sortin mAb#1 or anti-sortin mAb#2. In embodiments, the mAb is anti-sortin mAb#1. In embodiments, the mAb is anti-sortin mAb#2.

[0629] Those skilled in the art will appreciate that other known antibodies or binding fragments thereof that specifically bind to sortilin can be used. For example, anti-sortilin antibody ab6640 (manufactured by Abcam) that binds amino acid residue 800 to the C-terminus of sortilin can be used.

[0630] Non-limiting examples of antibodies or fragments thereof that bind to Sortilin that can be used include: Cat#PA5-77535, Cat#OSS00052W, Cat#MA5-31438, Cat#OSS00011W, Cat#PA1-18312, Cat#PA5-29195, Cat#PA5-96865, Cat#703207, Cat#PA5-47462, Cat#PA5-19481, Cat# t#OSS00010W, Cat#MA5-31437, Cat#OSS00041G (manufactured by Invitrogen); Cat#ab16640, Cat#ab188586 (manufactured by Abcam); Cat#AF3154, Cat#AF2934, Cat#MAB3154, Cat#BAF3154, Cat#BAF2934, Cat#FAB3154 ​​(manufactured by R&D Systems); clone W16078A (manufactured by BioLegend); Cat#A56294, Cat#A56295, Cat#A56296 (manufactured by E p=Manufactured by igentek); clone CL6526, clone CL6528, HPA006889 (manufactured by Atlas Antibodies); Cat#12369-1-AP (manufactured by Proteintech); sc-376561, sc-376576, sc-376561 HRP, sc-376561 AC (manufactured by Santa Cruz Biotechnology); Cat#N2177-52A, Cat#N2177-51A, Cat#N2177-52, Cat#133710, Cat#133710-HRP, Cat#133710-biotin, Cat#133710-FITC (manufactured by United States Biological); Cat#A01666 (manufactured by Boster Biological Technology); Cat#LS-C198140, Cat#LS-C672508, Cat#LS-C672507, Cat#LS-C672506, Cat#LS-C672509, Cat#LS-C37627, Ca t#LS-C37628, Cat#LS-C73437, Cat#LS-C94842, Cat#LS-C94818, Cat#LS-C94912, Cat#LS-C94806, Cat#LS-C668404 (by Lifespan biosciences); Cat#A7926, Cat#A4101 (manufactured by AB clonal Technology); Cat#NBP2-76498, Cat#NBP2-76501, Cat#NBP2-89745, Cat#H00006172-M01 (manufactured by Novus Biologicals); Cat#orb525096, Cat#orb525097, Cat#orb331290, Cat#orb243645, Cat#orb24364 4. Cat#orb243646, Cat#orb243643, Cat#orb255650, Cat#orb412666, Cat#orb416271, Cat#orb416270, Cat#orb416272, Cat#o rb416269, Cat#orb446447, Cat#orb468236, Cat#orb101927, Cat#orb373861, Cat#orb103522, Cat#orb484107 (manufactured by Biorbyt);Cat#H00006272-M01, Cat#H00006272-A01 (manufactured by Abnova); Cat#DPAB-DC2767, Cat#CABT-B1343 (manufactured by Creative Diagnostics Incorporation); Cat#OAGA03665, Cat#OAAN03744, Cat#ARP64630_P050, Cat#ARP87664_P050, Cat#ARP81139_P050, Cat#OACD07428, Cat#OACA03712 (manufactured by Aviva Systems Biology); Cat#TA351744, Cat#TA 813064, Cat#CF813064, Cat#TA328904 (manufactured by OriGene); Cat#R-150-100 (manufactured by Biosensis); Cat#AB9712 (manufactured by Millipore); Cat#67531 (manufactured by NovaTeinBio) and Cat#612100, Cat#612101 (manufactured by BD Biosciences), all of which are currently incorporated herein in their entirety. ;

[0631] In one aspect, a method for making the isolated antibody described herein is also provided, wherein the isolated antibody specifically binds to an isolated polypeptide comprising a sequence as shown in any one of SEQ ID NOs: 25-50, an analog thereof, or a fragment thereof, by the following steps: i) immunizing an animal with an immunogenic form of the isolated polypeptide; ii) screening an expression library; or iii) using phage display.

[0632] In one aspect, a conjugated antibody having the formula A'-(B)n is also provided,

[0633] in

[0634] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0635] A' is an isolated antibody as defined herein, wherein the isolated antibody is optionally protected by a protecting group; and

[0636] B is at least one therapeutic agent, wherein B is optionally linked to A' at a free amine of the isolated antibody, at the N-terminal position of the isolated antibody, at a free -SH of the isolated antibody, or at a free carboxyl group of the isolated antibody,

[0637] For inhibiting vasculogenic mimicry and / or treating cancer.

[0638] In another aspect, a conjugated antibody having the formula A'-(B)n is also provided,

[0639] in

[0640] n is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

[0641] A' is an isolated antibody as defined herein, wherein the isolated antibody is optionally protected by a protecting group; and

[0642] B is at least one therapeutic agent, wherein B is linked to A' at a free amine of a lysine residue of said isolated antibody, optionally through a linker, or at the N-terminal position of said isolated antibody, optionally through a linker,

[0643] For inhibiting vasculogenic mimicry and / or treating cancer.

[0644] In embodiments, the conjugated antibody targets the Sortilin receptor. In embodiments, the conjugated antibody is used to target the Sortilin receptor.

[0645] In an embodiment, wherein B is linked to A' via a linker, optionally a cleavable linker or a non-cleavable linker. In an embodiment, the at least one therapeutic agent is an anticancer agent. In an embodiment, the anticancer agents docetaxel, doxorubicin, cabazitaxel, aldoxorubicin, maytansinoids, auristatins, calicheamicin, amatoxin, amanita ani, and oligopeptide mimetics (e.g., tobreathesen). In an embodiment, the at least one therapeutic agent is a phytochemical, optionally curcumin. In an embodiment, the anticancer agent is docetaxel. In an embodiment, the anticancer agent is doxorubicin. In an embodiment, the anticancer agent is cabazitaxel. In an embodiment, the anticancer agent is aldoxorubicin.

[0646] The number of therapeutic agents in the antibody conjugate can be heterogeneous. For example, for trastuzumab emtansine, it varies between 0 and 8 maytansine molecules per antibody molecule, with an average of 3.5 to 4 maytansine molecules per antibody.

[0647] In embodiments, the conjugate compound or antibody conjugate comprises 1 therapeutic agent molecule linked to the peptide compound or isolated antibody. In embodiments, the conjugate compound or antibody conjugate comprises at least 1 therapeutic agent molecule linked to the peptide compound or isolated antibody. In embodiments, the conjugate compound or antibody conjugate comprises up to 8 therapeutic agent molecules linked to the peptide compound or isolated antibody. In embodiments, the antibody conjugate comprises up to 10 therapeutic agent molecules linked to the isolated antibody. In embodiments, the antibody conjugate comprises up to 12 therapeutic agent molecules linked to the isolated antibody.

[0648] In an embodiment, the conjugate compound or antibody conjugate comprises 2 therapeutic agent molecules connected to the peptide compound or the isolated antibody. In an embodiment, the conjugate compound or antibody conjugate comprises 3 therapeutic agent molecules connected to the peptide compound or the isolated antibody. In an embodiment, the conjugate compound or antibody conjugate comprises 4 therapeutic agent molecules connected to the peptide compound or the isolated antibody. In an embodiment, the conjugate compound or antibody conjugate comprises 1 to 8 therapeutic agent molecules connected to the peptide compound or the isolated antibody. In an embodiment, the antibody conjugate comprises 0 to 12, optionally 0 to 10, optionally 0 to 8 therapeutic agent molecules connected to the isolated antibody. In another embodiment, the antibody conjugate comprises more than zero and at most 12, optionally 10, optionally 8 therapeutic agent molecules connected to the isolated antibody. In another embodiment, the antibody conjugate comprises 1 to 12, optionally 1 to 10, optionally 1 to 8 therapeutic agent molecules connected to the isolated antibody.

[0649] In embodiments, the conjugated antibody comprises a therapeutic agent selected from the group consisting of a cytotoxic agent, a toxin, an anti-cancer peptide, a targeted drug, an immunotherapy, a phytochemical, and / or an oligopeptide mimetic.In another embodiment, the therapeutic agent is an alkylating agent; a platinum coordinator selected from the group consisting of cisplatin, carboplatin and oxaliplatin; an antimetabolite; a microtubule damaging agent selected from the group consisting of vincristine, vinblastine, vinorelbine, paclitaxel and docetaxel; a topoisomerase-2 inhibitor, such as etoposide; a topoisomerase-1 inhibitor selected from the group consisting of topotecan and irinotecan; an antibiotic selected from the group consisting of actinomycin D, doxorubicin, daunomycin, Epirubicin, bleomycin, and mitomycin C group; hydroxyurea; L-asparaginase; retinoic acid; maytansinoids; auristatins; calicheamicin; amatoxin; amanitin; D-peptide A; D-peptide B; D-peptide C; D-peptide D; D-K6l9; NRC-03; NRC-07; Gomesin; hepatocidin Th2-3; dermatoseptin B2; PTP7; MGA2; HNP-1; taprotin; temporin-1 Cea; NK-2; bactericidal peptide Cb1; tyrosine protein kinase inhibitors selected from the group consisting of imatinib and dasatinib; EFG receptor inhibitors selected from the group consisting of gefitinib and erlotinib; angiogenesis inhibitors selected from the group consisting of bevacizumab, thalidomide, endostatin, angiostatin, angiopoietin and cannabinoids; proteasome inhibitors selected from the group consisting of bortezomib, carfilzomib, isazomib, marizomib and epoxomicin; mAbs selected from the group consisting of rituximab and trastuzumab; checkpoint inhibitors; CAR-T cell therapy; antibodies; antibody drug conjugates; bispecific T cell engagers and bispecific antibodies; genetically engineered T cell-mediated cell killing; oncolytic viruses; T cell-mediated cytolysis; alkaloids selected from the group consisting of chlorogenic acid, theobromine and theophylline; anthocyanins selected from the group consisting of anthocyanidins and dimethoate; carotenoids selected from the group consisting of β-carotene, lutein and tomato The present invention relates to a group consisting of erythrin; coumaranes; flavan-3-ols; flavonoids selected from the group consisting of epicatechin, hesperidin, isorhamnetin, kaempferol, myricetin, naringin, nobiletin, proanthocyanidins, quercetin, rutin and hesperidin; hydroxycinnamic acids selected from the group consisting of chicoric acid, coumarin, ferulic acid and scopoletin; isoflavones selected from the group consisting of daidzein and genistein; lignans such as silymarin; monoterpenes selected from the group consisting of geraniol and limonene; organic sulfur compounds selected from the group consisting of allicin, glutathione, indole-3-carbinol, isothiocyanates and sulforaphane; spathulin; digoxin; phytic acid; phenolic acid selected from the group consisting of capsaicin, ellagic acid, gallic acid, rosmarinic acid and tannic acid; phytosterols such as β-sitosterol; saponins; stilbenes selected from the group consisting of pterostilbene and resveratrol; triterpenoids such as ursolic acid; xanthophylls selected from the group consisting of astaxanthin and β-cryptoxanthin; monophenols such as hydroxytyrosol; or toblysen.

[0650] For example, treating cancer or aggressive cancer comprises inhibiting vasculogenic mimicry in cells expressing Sortilin.

[0651] In one aspect, the compounds, isolated antibodies or antibody conjugates described herein are used to inhibit angiogenic mimicry. In one aspect, the compounds, isolated antibodies or antibody conjugates described herein target the Sortilin receptor. In one aspect, the compounds, isolated antibodies or antibody conjugates described herein are used to target the Sortilin receptor.

[0652] In another aspect, the compounds, isolated antibodies or antibody conjugates described herein are used to inhibit angiogenic mimicry in CD133-positive cells and / or to treat cancer.

[0653] In embodiments, the compound, isolated antibody or antibody conjugate reduces the length of angiogenic mimetic tubes in cancer tissue or cells expressing Sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45%, or about 30% to about 40% greater than untreated cancer tissue or cells expressing Sortilin.

[0654] In embodiments, the compound, isolated antibody or antibody conjugate reduces the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45%, or about 30% to about 40% as compared to untreated cancer tissue or cells expressing Sortilin.

[0655] In embodiments, the compound, isolated antibody or antibody conjugate reduces the length of angiogenic mimetic tubes in cancer tissue or cells expressing Sortilin by at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times, or about 1.2 to about 2.0 times greater than cancer tissue or cells expressing Sortilin treated with said at least one therapeutic agent.

[0656] In embodiments, the compound, isolated antibody or antibody conjugate reduces the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin by at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times, or about 1.2 to about 2.0 times greater than cancer tissue or cells expressing Sortilin treated with said at least one therapeutic agent.

[0657] In one aspect, the compounds, isolated antibodies or antibody conjugates described herein are used to treat cancer or aggressive cancer.

[0658] For example, treating cancer or invasive cancer comprises reducing the length of angiogenic mimetic tubes in a subject, cancer tissue, and / or cell expressing Sortilin by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% greater than an untreated control subject, cancer tissue, and / or cell expressing Sortilin.

[0659] For example, treating cancer or invasive cancer comprises reducing the number of angiogenic mimetic rings in a subject, cancer tissue, and / or cell expressing Sortilin by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90% greater than an untreated control subject, cancer tissue, and / or cell expressing Sortilin.

[0660] For example, treating cancer or invasive cancer comprises reducing the length of angiogenic mimetic tubes in the subject, cancer tissue, and / or cells expressing Sortilin by at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, or at least 2.4 times greater than in cells expressing Sortilin treated with the at least one therapeutic agent.

[0661] For example, treating cancer or invasive cancer comprises causing a reduction in angiogenic mimetic rings in the subject, cancer tissue, and / or cells expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, or at least 2.4 times greater than in cells expressing Sortilin treated with the at least one therapeutic agent.

[0662] For example, the cell expressing sortilin is an immune cell, optionally a macrophage, CD4+, CD8+, B220+, a bone marrow-derived cell, a basophil, an eosinophil, and a cytotoxic T lymphocyte, a natural killer (NK) cell, a T helper type 1 (Th1) cell.

[0663] For example, the cell expressing Sortilin 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 urothelial cancer cell, a benign tumor 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.

[0664] For example, the cell displaying vasculogenic mimicry is a cancer cell, optionally a breast cancer cell (e.g., a triple-negative breast cancer cell), a glioma cell, a hepatocellular carcinoma cell, a colorectal cancer cell, a medulloblastoma cell, a bi-differentiated malignant tumor cell, a gastric cancer cell, a prostate cancer cell, a sarcoma cell, a gallbladder cancer cell, an oral / laryngeal squamous cell carcinoma cell, a melanoma cell, a non-small cell lung cancer cell, or an ovarian cancer cell.

[0665] For example, the triple-negative breast cancer cells are HCC1599, HCC1937, HCC1143, MDA-MB468, HCC38, HCC70, HCC1806, HCC1187, DU4475, BT-549, Hs578T, MDA-MB231, MDA-MB436, MDA-MB157, MDA-MB453, BT-20 or HCC1395 cells.

[0666] For example, the cells are CD133 positive cells.

[0667] The conjugate compounds or antibody conjugates 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 transporter pump that pumps other therapeutic agents out of multidrug resistant cells.

[0668] In one aspect, there is provided a method of obtaining a peptide compound, the method comprising i) providing a library of binding peptides; and ii) selecting a sortilin binding peptide from the library by affinity selection using a target;

[0669] wherein the target is immobilized on a solid support;

[0670] wherein the target comprises an amino acid sequence shown in any one of SEQ ID NOs: 25-50, an analogue thereof, or a fragment thereof; and

[0671] wherein said target interacts with said sortilin binding peptide.

[0672] In another aspect, a process for preparing a conjugate compound or antibody conjugate disclosed herein is provided, the process comprising:

[0673] reacting a linker and the therapeutic agent together to obtain an intermediate;

[0674] optionally purifying the intermediate;

[0675] reacting the intermediate with a peptide compound to obtain the conjugate compound, or reacting the intermediate with an isolated antibody to obtain the antibody conjugate; and

[0676] optionally purifying the conjugate or antibody conjugate;

[0677] wherein the therapeutic agent is linked to the peptide compound or the isolated antibody at the free amine or N-terminus of a lysine residue; and wherein the peptide compound comprises 1, 2, 3 or 4 therapeutic agent molecules linked thereto, wherein the isolated antibody comprises 1-12, optionally 1-10, optionally 1-8 therapeutic agent molecules linked thereto.

[0678] For example, the peptide compound or the separated antibody comprises 1 therapeutic agent molecule connected thereto. For example, the peptide compound or the separated antibody comprises 2 therapeutic agent molecules connected thereto. For example, the peptide compound or the separated antibody comprises 3 therapeutic agent molecules connected thereto. For example, the peptide compound or the separated antibody comprises 4 therapeutic agent molecules connected thereto.

[0679] For example, the linker is succinic acid. For example, the linker is a dimethylglutaric acid linker.

[0680] In embodiments, the peptide compound or isolated antibody is protected at the N-terminus prior to reacting with the intermediate.

[0681] For example, before merging with a linker, a blocking group such as FMOC can be added as a blocking group to a free amine on the therapeutic agent. After its synthesis, the conjugate compound or antibody conjugate can undergo deprotection from the blocking group. For example, a conjugate compound or antibody conjugate comprising the protecting agent FMOC can be deprotected using piperidine. It will be readily appreciated by those skilled in the art that other known chemical reagents can be used for the deprotection of the conjugate compound or antibody conjugate.

[0682] For example, the N-terminus of a therapeutic agent, peptide compound, and / or antibody may be blocked by acetylation thereof, thereby providing an irreversible protecting group at the N-terminus.

[0683] In embodiments, the intermediate is activated prior to reacting with said peptide compound or said antibody.

[0684] For example, the intermediate is activated with a coupling agent prior to reacting with the compound, the coupling agent being optionally selected from N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)urea 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).

[0685] For example, an intermediate comprising a therapeutic agent attached to a linker can be activated with TBTU peptide coupling reagent prior to conjugation to a peptide compound or antibody.

[0686] In one embodiment, the conjugate or antibody conjugate is purified after its synthesis.

[0687] The peptide compounds and antibodies disclosed herein can be used in the context of fusion proteins. For example, the peptide compounds disclosed herein or antibodies (e.g., peptide compounds) can be engineered fusion proteins by fusing one or more proteins or parts thereof (such as functional domains). Fusion proteins can be engineered, for example, by recombinant DNA technology, and expressed using protein expression systems such as bacteria or mammalian protein expression systems. In certain embodiments, peptide linkers are added between proteins. In other embodiments, the fusion protein does not include a linker connecting the protein.

[0688] 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 thermophila.

[0689] Aspects disclosed herein are a liposome, graphene, nanotube or nanoparticle comprising at least one peptide compound or antibody disclosed herein for inhibiting angiogenic mimicry.

[0690] Aspects disclosed herein are a liposome, graphene, nanotube or nanoparticle comprising at least one peptide compound or antibody targeting a Sortilin receptor disclosed herein.

[0691] Aspects disclosed herein are a liposome, graphene, nanotube or nanoparticle comprising at least one peptide compound or antibody disclosed herein for targeting a sortilin receptor.

[0692] Another aspect is a liposome, graphene, nanotube or nanoparticle coated with at least one compound, isolated antibody or antibody conjugate disclosed herein for inhibiting angiogenic mimicry.

[0693] Another aspect is a liposome, graphene, nanotube or nanoparticle coated with at least one compound, isolated antibody or antibody conjugate targeting a Sortilin receptor disclosed herein.

[0694] Another aspect is a liposome, graphene, nanotube or nanoparticle coated with at least one compound, isolated antibody or antibody conjugate disclosed herein for targeting a sortilin receptor.

[0695] Another aspect is a liposome, graphene, nanotube or nanoparticle loaded with at least one therapeutic agent, gene or siRNA; and the liposome or nanoparticle is coated with at least one compound, isolated antibody or antibody conjugate for inhibiting angiogenic mimicry as defined herein. For example, the at least one compound, conjugated compound, isolated antibody or antibody conjugate can be attached to the surface of the liposome or nanoparticle.

[0696] Those skilled in the art can envision different embodiments of liposomes, nanotubes, graphene or nanoparticles. For example, liposomes or nanoparticles can include at least one compound disclosed herein coated on the surface of liposomes or nanoparticles, an isolated antibody or antibody conjugate, and a therapeutic agent, such as an anticancer agent, in the liposomes or nanoparticles. For example, liposomes or nanoparticles can include at least one compound disclosed herein coated on the surface of liposomes or nanoparticles and a therapeutic agent, such as an anticancer agent, in the liposomes or nanoparticles. For example, liposomes or nanoparticles can include at least one peptide compound disclosed herein coated on the surface of liposomes or nanoparticles and a therapeutic agent, such as an anticancer agent, in the liposomes or nanoparticles. For example, liposomes or nanoparticles can include at least one conjugated compound disclosed herein coated on the surface of liposomes or nanoparticles and a therapeutic agent, such as an anticancer agent, in the liposomes or nanoparticles. For example, liposomes or nanoparticles can include at least one isolated antibody disclosed herein coated on the surface of liposomes or nanoparticles and a therapeutic agent, such as an anticancer agent, in the liposomes or nanoparticles. For example, liposomes or nanoparticles may include at least one antibody conjugate coated on the surface of liposomes or nanoparticles disclosed herein and a therapeutic agent in the liposomes or nanoparticles, such as an anticancer agent. In addition, in some embodiments, compounds described herein, peptide compounds, conjugated compounds, separated antibodies or antibody conjugates may be connected, connected (link or connect) with one or more other compounds to form polymers such as dimers, trimers or tetramers, and branched peptides, and optionally, the peptide compounds are cyclic. Such compounds, separated antibodies or antibody conjugates can be connected together, for example, by covalent bonds, atoms or joints. For example, a polymer includes more than one compound, separated antibodies or antibody conjugates. The method for making peptide compounds or antibodies in the form of polymers (e.g., dimers, trimers) is described in U.S. Patent No. 9,161,988, the entire contents of which are incorporated herein by reference.

[0697] Other aspects of the present disclosure generally include methods of inhibiting angiogenic mimicry, the methods comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound, isolated antibody, or antibody conjugate disclosed herein and / or contacting a cell expressing sortilin with at least one compound, isolated antibody, and / or antibody conjugate disclosed herein. Other aspects include the use of the peptide compounds, conjugated compounds, antibodies, and / or antibody conjugates described herein for inhibiting angiogenic mimicry and in the manufacture of a medicament for inhibiting angiogenic mimicry.

[0698] In one aspect, there is provided a method of inhibiting angiogenic mimicry, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound, isolated antibody and / or antibody conjugate as defined herein.

[0699] In another aspect, a method of inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin is provided, the method comprising contacting the cancer tissue or cell with at least one compound, isolated antibody and / or antibody conjugate as defined herein.

[0700] In another aspect, a method of inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin is provided, the method comprising contacting the cancer tissue or cell with at least one compound, isolated antibody and / or antibody conjugate as defined herein, wherein the reduction in the length of angiogenic mimicry tubes or the number of angiogenic mimicry rings is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% greater than that of untreated cancer tissue or cell expressing Sortilin.

[0701] In another aspect, a method of inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin is provided, the method comprising contacting the cancer tissue or cell with at least one compound, isolated antibody and / or antibody conjugate as defined herein, wherein the reduction in angiogenic mimicry tube length or angiogenic mimicry ring is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2 or at least 2.4 times greater than in a cancer tissue or a cell expressing Sortilin treated with the at least one therapeutic agent.

[0702] In another aspect, a method of inhibiting angiogenic mimicry in cancer tissue or CD133-positive cells is provided, the method comprising contacting the cancer tissue or CD133-positive cells with at least one compound, isolated antibody and / or antibody conjugate as defined herein.

[0703] In one aspect, there is provided a method of treating cancer or aggressive cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of at least one compound, isolated antibody and / or antibody conjugate as defined herein.

[0704] In another aspect, a method of treating cancer or invasive cancer in a subject having cancerous tissue or cells expressing Sortilin is provided, the method comprising contacting the cancerous tissue or cells with at least one compound, isolated antibody and / or antibody conjugate as defined herein.

[0705] In another aspect, a method of treating cancer or invasive cancer in a subject having cancer tissue or cells expressing Sortilin is provided, the method comprising contacting the cancer tissue or cells with at least one compound, isolated antibody and / or antibody conjugate as defined herein, wherein the reduction in the length of angiogenic mimetic tubes or the number of angiogenic mimetic rings is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% greater than that of untreated cancer tissue or cells expressing Sortilin.

[0706] In another aspect, a method of treating cancer or invasive cancer in a subject having cancer tissue or cells expressing Sortilin is provided, the method comprising contacting the cancer tissue or cells with at least one compound, isolated antibody or antibody conjugate as defined herein, wherein the reduction in angiogenic mimetic tube length or angiogenic mimetic ring length is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2 or at least 2.4 times greater than in cancer tissue or cells expressing Sortilin treated with the at least one therapeutic agent.

[0707] In another aspect, a method of increasing the stability and / or bioavailability of a therapeutic agent is provided, the method comprising:

[0708] obtaining the conjugate compound or antibody conjugate disclosed herein, wherein the conjugate compound or antibody conjugate comprises the therapeutic agent, and

[0709] A therapeutically effective amount of the conjugate compound or antibody conjugate is administered to a subject in need thereof.

[0710] In another aspect, a method of increasing the stability and / or bioavailability of a therapeutic agent is provided, the method comprising:

[0711] conjugating the therapeutic agent to a peptide compound or an antibody as defined herein to obtain a conjugated compound or an antibody conjugate, and

[0712] A therapeutically effective amount of the conjugate compound or antibody conjugate is administered to a subject in need thereof.

[0713] Compared to non-conjugated therapeutic agents, the conjugate compounds or antibody conjugates disclosed herein may also provide greater tolerability. For example, in an international application filed on November 24, 2016, disclosed as WO 2017 / 088058 and entitled "PEPTIDE COMPOUNDS AND CONJUGATE COMPOUNDS FOR THE TREATMENT OF CANCER THROUGH RECEPTOR-MEDIATED CHEMOTHERAPY", which is incorporated herein by reference in its entirety, it has been shown that Katana-drug conjugates have better tolerability than equivalent doses of non-conjugated therapeutic agents due to specific receptor targeting. In particular, in vivo studies have shown that treatment with the conjugate compound had little effect on the body weight of the test mice, thereby demonstrating the tolerability of the conjugate compound.

[0714] For example, provided herein is a method of increasing the tolerability of a therapeutic agent, the method comprising:

[0715] conjugating the therapeutic agent to the peptide compound or isolated antibody disclosed herein to obtain a conjugate compound or antibody conjugate, and

[0716] A therapeutically effective amount of the conjugate compound or the antibody conjugate is administered to a subject in need thereof.

[0717] For example, provided herein is a method of increasing the tolerability of a therapeutic agent, the method comprising:

[0718] obtaining a conjugate compound or antibody conjugate disclosed herein, wherein the conjugate compound or antibody conjugate comprises a therapeutic agent, and

[0719] A therapeutically effective amount of the conjugate compound or the antibody conjugate is administered to a subject in need thereof.

[0720] For example, provided is a use of a peptide compound, conjugated compound, antibody and / or antibody conjugate disclosed herein for increasing the tolerability of a therapeutic agent.

[0721] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for inhibiting vasculogenic mimicry.

[0722] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for targeting a Sortilin receptor.

[0723] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for inhibiting angiogenic mimicry involving sortilin expression.

[0724] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for inhibiting angiogenic mimicry in cancer tissue or cells expressing Sortilin.

[0725] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for treating cancer or an aggressive cancer.

[0726] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for treating a cancer involving sortilin expression or an aggressive cancer.

[0727] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for treating cancer or invasive cancer in cancer tissue or cells expressing Sortilin.

[0728] In another aspect, a use of at least one compound, isolated antibody or antibody conjugate is provided for reducing the length of angiogenic mimetic tubes in cancer tissue or cells expressing sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45%, or about 30% to about 40% greater than untreated cancer tissue or cells expressing sortilin.

[0729] In another aspect, a use of at least one compound, isolated antibody or antibody conjugate is provided for reducing the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, about 5% to about 50%, about 10% to about 50%, about 15% to about 45%, about 20% to about 45%, or about 30% to about 40% as compared to untreated cancer tissue or cells expressing Sortilin.

[0730] In another aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for causing a reduction in the length of angiogenic mimetic tubes in cancer tissue or cells expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times or about 1.2 to about 2.0 times greater than in cancer tissue or cells expressing Sortilin treated with the at least one therapeutic agent.

[0731] In another aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for causing a reduction in the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, at least 2.4 times, about 1.2 to about 2.4 times or about 1.2 to about 2.0 times greater than in cancer tissue or cells expressing Sortilin treated with the at least one therapeutic agent.

[0732] In another aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for inhibiting angiogenic mimicry in cancer tissue or cells expressing Sortilin, comprising contacting the cancer tissue or cells with at least one compound, isolated antibody and / or antibody conjugate as defined herein, wherein the reduction in the length of angiogenic mimicry tubes or the number of angiogenic mimicry rings is at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% greater than in untreated cancer tissue or cells expressing Sortilin.

[0733] In another aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for inhibiting angiogenic mimicry in a cancer tissue or a cell expressing Sortilin, comprising contacting the cancer tissue or the cell with at least one compound, isolated antibody or antibody conjugate as defined herein, wherein the reduction in angiogenic mimicry tube length or angiogenic mimicry ring is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2, or at least 2.4 times greater than in a cancer tissue or a cell expressing Sortilin treated with said at least one therapeutic agent.

[0734] In another aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein for reducing the length of angiogenic mimetic tubes or the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin by at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80% or at least about 90% greater than in untreated cancer tissue or cells expressing Sortilin.

[0735] In another aspect, there is provided a use of at least one compound, isolated antibody or antibody conjugate as defined herein, for causing a reduction in the length of angiogenic mimetic tubes or the number of angiogenic mimetic rings in cancer tissue or cells expressing Sortilin that is at least 1.2, at least 1.4, at least 1.6, at least 1.8, at least 2.0, at least 2.2 or at least 2.4 times greater than in cancer tissue or cells expressing Sortilin treated with said at least one therapeutic agent.

[0736] In another aspect, there is provided the use of at least one compound, isolated antibody and / or antibody conjugate as defined herein for treating cancer or aggressive cancer in CD133 positive cells.

[0737] In another aspect, there is provided a use of a conjugated compound or an antibody conjugate as defined herein for increasing the stability and / or bioavailability of at least one therapeutic agent.

[0738] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for inhibiting angiogenic mimicry.

[0739] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for targeting angiogenic mimicry.

[0740] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for inhibiting angiogenic mimicry involving sortilin expression.

[0741] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for inhibiting angiogenic mimicry in cancer tissue or cells expressing sortilin.

[0742] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for inhibiting angiogenic mimicry in CD133-positive cells.

[0743] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for treating cancer or aggressive cancer.

[0744] In another aspect, there is provided the use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for treating a cancer or an aggressive cancer involving expression of sortilin.

[0745] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for treating cancer or invasive cancer in cancer tissue or cells expressing Sortilin.

[0746] In another aspect, there is provided use of a compound, isolated antibody and / or antibody conjugate as defined herein in the manufacture of a medicament for treating cancer or aggressive cancer in CD133 positive cells.

[0747] For example, the at least one therapeutic compound contained in the conjugate compound or antibody conjugate and / or used in the manufacture of a medicament for inhibiting angiogenic mimicry is an anticancer agent. For example, the anticancer agent is selected from docetaxel, cabazitaxel, aldoxorubicin, maytansinoids, auristatins, calicheamicin, amatoxin, amanitin and doxorubicin.

[0748] For example, the at least one therapeutic compound contained in the conjugate compound or antibody conjugate and / or used in the manufacture of a medicament for inhibiting angiogenic mimicry is a phytochemical. For example, the phytochemical is curcumin.

[0749] For example, the phytochemicals are selected from curcumin, omega-3, white willow bark, green tea, catechins, pycnogenol, Boswellia serrata resin, resveratrol, Uncaria tomentosa, capsaicin, anthocyanidins / anthocyanins, flavonoids, olive oil compounds, chlorogenic acid, and sulfopharaphane.

[0750] In another aspect, provided is a use of at least one compound disclosed herein, at least one isolated antibody disclosed herein, or at least one conjugated antibody disclosed herein in combination with a therapeutic agent (such as a cytotoxic agent, a toxin, and an anti-cancer peptide), an immunomodulatory agent (such as anti-PD1 and anti-PDL1), an anti-cancer delivery system, an anti-angiogenic agent, and / or radiation therapy for inhibiting vasculogenic mimicry.

[0751] In another aspect, provided is a use of at least one compound disclosed herein, at least one isolated antibody disclosed herein, or at least one conjugated antibody disclosed herein in combination with a therapeutic agent (such as a cytotoxic agent, a toxin, and an anti-cancer peptide), an immunomodulatory agent (such as anti-PD1 and anti-PDL1), an anti-cancer delivery system, an anti-angiogenic agent, and / or radiation therapy for targeting a sortilin receptor.

[0752] Other embodiments of the present disclosure will now be described with reference to the following examples. It should be understood that these examples are for illustrating embodiments of the present disclosure and do not limit the scope of the present disclosure.

[0753] Examples

[0754] Example 1: Composition

[0755] Peptides targeting sortilin

[0756] The first family of Katana peptides targeting sortilin was derived from bacterial cell permeabilizer proteins, while the second family was based on optimized primary sequences derived from sortilin ligand, progranulin, and neurotensin (Table 1). These peptides have been described in PCT / CA2016 / 051379: PEPTIDE COMPOUNDS AND CONJUGATE COMPOUNDS FOR THE TREATMENT OF CANCERTHROUGH RECEPTOR-MEDIATED CHEMOTHERAPY and U.S. Patent Application Serial No. 62 / 510,381: CONJUGATES AND USES THEREOF FOR TREATING INFLAMMATORY DISEASES, which are incorporated herein by reference.

[0757] Table 1 Amino acid sequences of the Katana peptide family.

[0758]

[0759]

[0760] method

[0761] Generation of Katana-peptide drug conjugates

[0762] Docetaxel and doxorubicin were first chosen as proof of principle for the cytotoxic drugs, while curcumin was chosen among the phytochemicals. Docetaxel is a semisynthetic analog of paclitaxel, which is extracted from the bark of the rare Pacific yew, Taxus brevifolia. This drug has been approved by the FDA (National Cancer Institute) for the treatment of locally advanced or metastatic cancers, including breast cancer, ovarian cancer, head and neck cancer, gastric cancer, hormone-refractory prostate cancer, and non-small cell lung cancer. Docetaxel can be used as a single agent or in combination with other chemotherapeutic drugs depending on the specific cancer type and stage. Doxorubicin is an anthracycline antitumor antibiotic (note: in this context, this does not mean that it is used to treat bacterial infections), closely related to the natural product daunomycin, and like all anthracyclines, acts by intercalating into DNA, with the most serious adverse effect being life-threatening heart damage (National Cancer Institute). It is approved for use alone or in combination with other drugs to treat: acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), breast cancer, gastric (stomach) cancer, Hodgkin lymphoma, neuroblastoma, non-Hodgkin lymphoma, ovarian cancer, small cell lung cancer, soft tissue and bone sarcomas, thyroid cancer, transitional cell bladder cancer, and Wilm's tumor. Curcumin (diferuloylmethane) is a yellow pigment found in the spice turmeric root (Curcuma longa) that has been associated with antioxidant, anti-inflammatory, anticancer, antiviral, and antimicrobial activities (23).

[0763] Cytotoxic drugs (docetaxel, cabazitaxel, doxorubicin) or phytochemicals (curcumin) can be conjugated to peptides using amine conjugation strategies. In short, docetaxel can be conjugated to Katana peptides on available free amines (lysine or amino terminus) on peptides by forming a peptide bond (amide bond) with activated docetaxel. Various conjugation strategies for these peptides have been described in PCT / CA2016 / 051379 and US62 / 510,381, which are incorporated herein by reference.

[0764] Antibody labeling

[0765] Anti-sortilin antibody labeling was performed using the Invitrogen Alexa Fluor 488 protein labeling kit according to the manufacturer's instructions.

[0766] Cell surface binding assay

[0767] Human ES-2 ovarian cancer cells were incubated with anti-sortilin-Alexa 488 antibody (1 μg / ml) at 4°C for 30 min and then trypsinized or not to assess cell surface bound antibody.

[0768] Vascular mimicry

[0769] Malignant solid tumors require a blood supply to promote growth and metastasis. In the past, angiogenesis (a type of new blood vessel formation during embryonic development) was considered the only form of blood supply to support tumors (24). Antiangiogenic therapy targeting endothelial cells has received extensive attention and research as a potential and promising therapeutic target. Many antiangiogenic drugs have been used to prevent tumor growth and metastasis. However, the effects of these drugs on cancer progression are limited and unsatisfactory, suggesting that other forms of blood supply may exist in tumor tissues in addition to angiogenesis. In 1999, highly patterned vessel-like channel structures were observed in highly invasive and metastatic human melanomas in which red blood cells were detected (28). No endothelial cells were detected in these channels by light microscopy, transmission electron microscopy, or immunohistochemistry of endothelial cell markers (such as CD34, CD31). Subsequently, they reported that, unlike angiogenesis, this structure was composed of basement membranes and was mainly lined by tumor cells. Other studies have also confirmed that vasculogenic mimicry provides important perfusion pathways for malignant tumors through adequate blood and nutrient supply (24-27). It is now well accepted that vasculogenic mimicry plays an important role in tumor growth.

[0770] Vasculogenic mimicry has been implicated in tumor malignancy, including invasion and metastasis (24-27). In tumor tissue, there is a junction between tumor-lined vascular channels and endothelial-lined blood vessels. Through this structure, tumor cells lining the surface of the internal network of channels are directly exposed to the blood, which significantly increases the chance of metastasis. Vasculogenic mimicry describes the process by which cancer cells establish alternative perfusion pathways in an endothelial-free manner. Angiogenic tumor cells adopt the embryonic angiogenic approach and directly form primitive, immature blood vessels composed of a variety of capillary-like structures, tubes, and networks. Vasculogenic mimicry has been reported to exist in various malignancies and is known to play a role in cancer progression and metastasis. Vasculogenic mimicry may be present in a variety of malignancies (24, 28, 29), including melanoma, ovarian cancer, breast cancer, prostate cancer, osteosarcoma, bladder cancer, colorectal cancer, hepatocellular carcinoma, gastric cancer, and lung cancer. In breast cancer, vasculogenic mimicry has been reported to be highest in triple-negative breast cancer (TNBC) samples (30). In the latter study, CD133+ cells with cancer stem cell characteristics were associated with vasculogenic mimicry in TNBC. A meta-analysis evaluating the impact of vasculogenic mimicry on 5-year survival in 3062 cancer cases involving 15 malignancies showed that vasculogenic mimicry was associated with a more aggressive tumor phenotype and a poorer 5-year overall survival of cancer patients (24). Without wishing to be bound by theory, vasculogenic mimicry provides growing tumors with a new blood perfusion mechanism and a potential pathway for spread. In addition, sortilin receptors may be involved in cancer cell proliferation, cancer growth, and cancer cell migration and invasion.

[0771] In the present disclosure, the potential role of Sortilin in angiogenic mimicry was investigated. Sortilin disclosed herein is essential in the formation of angiogenic mimicry tubular structures. More importantly, conjugates between anticancer drugs (Adriamycin, Cabazitaxel, Aldoxorubicin, Docetaxel) or phytochemicals (Curcumin) and peptides targeting Sortilin strongly inhibit the formation of angiogenic mimicry. In addition, the results described herein show that the formation of 3D-tubular structures associated with angiogenic mimicry is inhibited by mAbs against Sortilin.

[0772] result

[0773] Figures 1 and 2 show the extent of vasculogenic mimicry in different human cancers and breast cancer, respectively (24, 30). Ovarian cancer and triple-negative (TN) breast cancer have the highest levels of vasculogenic mimicry.

[0774] Figures 3 and 4 depict the formation of vasculogenic mimicry in ovarian cancer cells observed in vitro (31). A 3D reconstruction of an X-ray microtomography of a 4-day 3D culture landscape of ovarian cancer cells on an artificial matrigel (Figure 3A) shows a reconstructed view of an elevated structure with a tubular appearance. In addition, the structure within the white rectangle is shown at a higher magnification in Figures 3B and 3C, where arrows indicate tubular-looking structures protruding above the flat cell aggregates. A cross-section of this structure reveals an air-filled space with an estimated diameter of 50 μm (Figure 3C). Figure 4 shows confocal microscopy of angiogenic mimicry tubular structures using SKOV3 expressing green fluorescent protein (GFP). Overall, the Z-stack reconstructed images in Figure 4A demonstrate the presence of cells containing tubular structures with a continuous upper monolayer [1], a central wall structure, a hollow center [2], and a continuous lower monolayer [3]. The computer-generated cross-section in Figure 4B clearly shows a tubular structure containing a lumen.

[0775] Figure 5 Shown are microscopic images demonstrating that ES-2 ovarian cancer cells are developing vasculogenic mimicry. Within 4 hours after seeding on artificial Matrigel, 3D tubular structures were rapidly formed and observed in ES-2 cells.

[0776] Figure 6 shows the detection of sortilin in 3D tubular structures of ES2 ovarian cancer cells. ES-2 ovarian cancer cells were seeded on Matrigel. Fig. 6A After 12 hours of display, Sortilin (SORT1) was detected in 3D tubular structures by confocal microscopy using rabbit anti-sortilin antibody. Figure 6B A control experiment performed using only the secondary anti-rabbit antibody is shown. The overall results indicate that the Sortilin detection is specific. Figure 6C and Fig.6DDAPI staining of ES-2 cancer cell nuclei is shown, which was used as a control to demonstrate that the nuclei of ES-2 cancer cells were stained with anti-sortilin ( Fig. 6A ) and secondary antibody ( Figure 6B ) under the conditions detected.

[0777] FIG7 shows the effect of sortilin gene silencing on the formation of angiogenic mimicry in ES-2 ovarian cancer cells. When sortilin expression was specifically inhibited, the 3D-tubular structures observed during the formation of angiogenic mimicry were strongly inhibited compared to scrambled siRNA ( Fig. 7A The images were sent to Onimagin Technologies for quantitative analysis of total ring number and total tube length using Wimasis image analysis software ( Figure 7B ). The results showed that after silencing the Sortilin gene using siRNA, both the number of rings and the total tube length were inhibited by more than 90%. These results clearly indicate that Sortilin plays a key role in the formation of 3D tubular structures in vasculogenic mimicry.

[0778] Figure 8 Fig. 9 , Figure 10 and Fig.11 Examples of inhibition of angiogenic mimicry by novel conjugates between anticancer drugs (Doxorubicin, Cabazitaxel, Aldoxorubicin, Docetaxel) or phytochemicals (Curcumin) and peptides targeting Sortilin are shown. In Figure 8, angiogenic mimicry of ES-2 ovarian cancer cells grown on Matrigel was performed in the presence of unconjugated Doxorubicin or a Doxorubicin conjugate (DoxKA). Fig. 8A showed that after 24 h, increasing DoxKA concentrations strongly inhibited the formation of vasculogenic mimicry. Figure 8B The 3D tubular structures analyzed using Wimasis image analysis software are shown. The results are plotted as a function of drug concentration. The IC50 values ​​of DoxKA obtained for total tube length and number of rings were in the low nM range (5-10 nM), as shown in Figure 8B A second example of an Aldoxorubicin-drug conjugate is presented in Fig. 9 The conjugation of Aldoxorubicin to the peptide is different from that to Doxorubicin. In the case of Aldoxorubicin, the drug is conjugated on a cysteine ​​amino acid residue added to the C-terminus of the peptide. The linker used is sensitive to acidic pH and not to esterases as in the case of Doxorubicin. The incorporation ratio of AldoxKA is also different, as only one Aldoxorubicin molecule is conjugated to the peptide compared to 2 Doxorubicin molecules in the DoxKA conjugate. This demonstrates the flexibility of the platform starting with two different Doxorubicin molecules. A third example of an anticancer-drug conjugate is presented in Fig. 10A and Fig. 10B Compared with docetaxel, docetaxel-conjugate (DoceKA) has a stronger inhibitory effect on the formation of angiogenic mimicry. For this conjugate, the IC50 value for the number of rings is about 30pM. Another example is shown in Fig.11 For this class of molecules, curcumin was conjugated with a sortilin targeting peptide (CurKA). Curcumin has been suggested to inhibit tube formation in SK-Hep-1 hepatocellular carcinoma cells (32). Curcumin inhibited tube formation in a dose-dependent manner in the range of 3-30 μM, with 18%-92% inhibition observed. Fig.11 It was clearly shown that at nM concentrations, CurKA conjugates affected the formation of vasculogenic mimicry in ES-2 ovarian cells. CurKA had a stronger effect on 3D tube formation in ES-2 ovarian cancer cells compared to unconjugated curcumin.

[0779] Fig.12 Anti-sortilin mAb inhibits angiogenic mimicry. ES-2 ovarian cancer cells were seeded onto Matrigel in the presence of nonspecific mouse IgG or anti-sortilin mAb at a concentration of 12 nM. Images taken 12 hours later showed that anti-sortilin mAb prevented ES-2 ovarian cancer cells from forming 3D tubular structures compared to controls, while mouse IgG had no effect. This inhibition of angiogenic mimicry by anti-sortilin mAb is very similar to that observed when sortilin gene silencing was performed using siRNA (Figure 6).

[0780] Fig.13A Binding and internalization of anti-SORT1 mAb are shown. Fig.13A showed that anti-sortilin antibodies labeled with the fluorescent dye Alexa488 bind to the receptor sortilin on the cell surface of ovarian cancer cells. Anti-sortilin antibodies were labeled with Alexa Fluor 488 to generate anti-sortilin-Alexa488 antibodies. Human ES-2 ovarian cancer cells were incubated with anti-sortilin-Alexa488 antibodies (1 μg / ml) for 30 minutes and then trypsinized or not to assess binding on the cell surface. The results clearly showed that the major part of the fluorescent signal was caused by binding to the sortilin receptor on the cell surface, as trypsinization reduced the fluorescence level by more than 90%. Fig. 13BIn the present study, the binding of anti-sortilin-Alexa488 antibody (1 μg / ml, 30 minutes) to the cell surface of human ES-ovarian cancer cells was inhibited by sortilin ligands (neurotensin (NT) and progranulin (PGRN)). In addition, incubation in the presence of Katana peptides (KBP106 and KBP201), which are also recognized by sortilin, greatly reduced the binding of the fluorescent antibody. Overall, these results indicate that the interaction of sortilin ligands and Katana peptides prevents labeling and recognition of the receptor by the fluorescent anti-sortilin antibody.

[0781] Fig. 13C The results in show that anti-sortilin antibodies can internalize fluorescent dye conjugates into cancer cells. In this experiment, binding of anti-sortilin-Alexa488 antibodies (1 μg / ml, 30 minutes) to human ES-2 ovarian cancer cells was first performed at 4°C, the cells were then washed to remove unbound fluorescent antibodies, and the cells were incubated at 37°C for 1 or 2 hours and then trypsinized. This allowed the anti-sortilin-Alexa488 conjugate to be internalized into the cells over time. The fluorescence associated with the internalized fluorescent antibody was then quantified by flow cytometry, and the results showed that approximately 50% of the anti-sortilin-Alexa488 antibodies that were first bound to the cell surface were internalized within 2 hours. The internalization of the anti-sortilin-Alexa488 antibody was measured as the concentration increased ( Fig.13D ). The results showed that the internalization of anti-sortilin-Alexa488 fluorescent conjugate increased with the increase of fluorescent conjugate concentration and was saturable.

[0782] Fig.14 Schematic diagram showing different regions of sortilin and the regions from which anti-sortilin antibodies used in the present disclosure were generated. Anti-sortilin mAb #1 (anti-SORT1 mAb #1) was obtained from EMB Millipore (Cat #MABN1792). The immunogen of this antibody is located in the extracellular domain of sortilin, i.e., amino acid residues 78-755. Anti-sortilin mAb #2 (anti-SORT1 mAb #2) was obtained from BD Biosciences (Cat #612100). The immunogen of this antibody is amino acid residues 300-422 of sortilin, corresponding to a portion of the extracellular domain of this protein.

[0783] Fig.15The inhibitory effect of anti-sortilin antibodies on vasculogenic mimicry in ovarian cancer cells was shown. ES-2 ovarian cancer cells were seeded on artificial Matrigel in the presence of vehicle (control), mouse IgG (4 μg / mL (about 25 nM)), or anti-SORT1 mAb #1 (4 μg / mL (about 25 nM)), or anti-SORT1 mAb #2 (4ug / mL (about 25 nM)). After ES-2 cells were exposed to antibodies for 12 hours, anti-sortilin mAb #1 and anti-sortilin mAb #2 strongly inhibited the formation of 3D-tubular structures, which was reflected by the effects of these mAbs on total rings (Figure 16A) and total tube length (Figure 16B). Fig. 16B )’s impact can be seen.

[0784] discuss

[0785] Without being bound by theory, it is believed that angiogenic mimicry is a phenomenon associated with more aggressive tumor phenotypes and poor prognosis in patients with various cancers. Since overexpression of Sortilin in many types of cancers is associated with their survival, invasion and progression, targeting this receptor with conjugated compounds, antibodies or conjugated antibodies may provide a highly effective way to increase the binding / internalization of cancer drugs in these tumors. The results disclosed herein clearly show that conjugated compounds, mAbs and derivatives thereof that target / interact with Sortilin result in a strong inhibition of angiogenic mimicry.

[0786] Example 2: Sortilin receptor-mediated cancer therapy: Targeted pathways for inhibition of angiogenic mimicry in ovarian and breast cancer

[0787] background

[0788] Angiogenesis mimicry is defined as the formation of microvascular channels by tumor cells that are invasive, metastatic, and genetically deregulated. This microcirculatory system is independent of endothelial cells and provides oxygen and nutrition to tumor cells. Angiogenesis mimicry has appeared in ovarian cancer and triple-negative breast cancer (TNBC) and has been shown to be associated with a decrease in overall survival in cancer patients. This process is partly responsible for current chemoresistance and promotes tumor progression and the spread of cancer metastasis. Therefore, targeting angiogenesis mimicry in ovarian and TNBC tumors may contribute to cancer treatment. Sortilin (a scavenging receptor) is known to play a major function in cancer cells; however, it is reported herein that it further plays a new role in angiogenesis mimicry. Targeting angiogenesis mimicry with peptide-drug conjugates by sortilin has been explored in ovaries and TNBC.

[0789] method

[0790] The in vitro angiogenesis mimicry of cancer cells was evaluated using an artificial basement membrane tube formation assay. In brief, each well of a 96-well plate was pre-coated with an artificial basement membrane. ES-2 ovarian cancer or MDA-MB-231 TNBC cell suspensions were seeded on top of the artificial basement membrane. 3D tubular structures were analyzed and quantified using Wimasis analysis software. Real-time cell migration was evaluated using the xCELLigence system. Sortilin gene silencing was performed using specific siRNA. The doxorubicin-KA-peptide conjugate (DoxKA) KBA-106 represented by the formula acetyl-GVRAK (doxorubicin) AGMRN (Nle) FK (doxorubicin) SESY (formula (XXVIII))) and the docetaxel-KA-peptide conjugate (DoceKA) represented by the formula acetyl-GVRAK (docetaxel) AGMRN (Nle) FK (docetaxel) SESY (formula (XXIII)) targeting sortin were determined to affect angiogenesis mimicry and cell migration.

[0791] result

[0792] Sortilin was found to be expressed in 3D tubular structures on artificial matrigel and was required for angiogenic mimicry in ovarian cancer and TNBC. When sortilin expression was specifically inhibited, the 3D tubular structures observed during angiogenic mimicry were strongly suppressed. Furthermore, anti-sortilin mAb prevented the occurrence of angiogenic mimicry, whereas nonspecific IgG had no effect. Interestingly, peptide-drug conjugates DoxKA or DoceKA targeting sortilin showed a stronger inhibitory effect on angiogenic mimicry than the unconjugated free drug. DoxKA and DoceKA IC for angiogenic mimicry inhibition 50 The values ​​were in the low nM to pM concentration range. Both DoxKA and DoceKA conjugates also inhibited ES-2 and MDA-MB231 cancer cell migration in a sortilin-dependent process.

[0793] in conclusion

[0794] Our results identify the Sortilin receptor as a key player in angiogenic mimicry. More importantly, the design of peptide-drug conjugates targeting Sortilin was shown to strongly inhibit angiogenic mimicry, a phenomenon associated with more aggressive tumor phenotypes and poor prognosis in patients with TNBC and ovarian cancer. Our peptide-drug conjugate platform provides preclinical molecular insights into receptor-mediated chemotherapy and more efficient therapeutic management of Sortilin-positive cancers.

[0795] Example 3: Increasing the efficacy and safety of anticancer drugs through sortilin receptor-mediated cancer therapy: Targeting pathways for the treatment of ovarian cancer

[0796] background

[0797] In the current modern oncology, the development of personalized therapy for ovarian cancer remains extremely challenging. One strategy to achieve higher selectivity and better delivery of anticancer drugs into cancer cells is to conjugate cytotoxic agents with specific peptide ligands that selectively target receptors that are abundantly and / or exclusively expressed on these cells. Increased expression of sortilin, a scavenging receptor, has been observed clinically in invasive ovarian cancer biopsies and correlates with tumor grade. In light of this, we developed a peptide conjugation platform and sortilin receptor-mediated vectorization strategy to increase cell targeting selectivity and cell delivery efficacy of anticancer agents.

[0798] method

[0799] As a proof of concept, doxorubicin was conjugated to a sortilin binding peptide (KA-peptide). In vitro intracellular delivery of doxorubicin-KA-peptide conjugate (DoxKA) KBB-106 represented by the formula Acetyl-GVRAK(Doxorubicin)AGVRN(Nle)FK(Doxorubicin)SESY (Formula (XXVIII)) was evaluated in ES-2 and SKOV-3 ovarian cancer cell line models using flow cytometry and fluorescence microscopy. Sortilin gene silencing was performed using specific siRNA. The efficacy and safety of DoxKA were evaluated in vivo using ES-2 (CD1 nude mice) and SKOV-3 (athymic mice) subcutaneous xenograft models.

[0800] result

[0801] DoxKA uptake was observed in both sortilin-positive ovarian cancer cell lines tested and was reduced when sortilin expression was specifically silenced or competed with the sortilin ligands neurotensin and progranulin. The results suggest that, in contrast to simple diffusion of doxorubicin, DoxKA uptake occurs via sortilin-mediated endocytosis. In MDCK-MDR1 cells overexpressing P-gp, DoxKA was found to bypass the P-glycoprotein (P-gp) efflux pump, as the P-gp inhibitor cyclosporine A did not affect DoxKA uptake. In vivo, DoxKA had lower potential side effects and reduced accumulation in healthy tissues such as the heart and ovaries compared to doxorubicin alone. In mice, DoxKA had a stronger inhibitory effect on the growth of human ovarian tumor xenografts and was better tolerated (no leukopenia and neutropenia) than equivalent doses of unconjugated doxorubicin.

[0802] in conclusion

[0803] These results support the future clinical application of this platform to generate new personalized therapies, with specific targeting of sortilin-positive tumors in the next stage of development in a Phase 1 clinical trial.

[0804] Example 4: Docetaxel-peptide conjugate for the treatment of sortilin-positive triple-negative breast cancer

[0805] background

[0806] Triple-negative breast cancer (TNBC) is a heterogeneous disease that still lacks clear molecular biomarkers. In the past decade, targeting specific gene / protein molecular signatures of tumors has become one of the best anticancer strategies. Recently, increased expression of the sortilin (SORT1) receptor has been reported in TNBC patients. Given the role of SORT1 in protein internalization, sorting, and transport, we developed a peptide-anticancer drug conjugate platform to target SORT1-positive breast cancer by linking docetaxel to a peptide (KA-peptide) that specifically targets SORT1.

[0807] method

[0808] MDA-MB-231 cells were used as a TNBC cell model for in vitro and in vivo xenograft (CD1 nude mice) assays. Cell migration was assessed using the xCELLigence real-time system, while cell proliferation analysis was performed using the MTT assay. Expression of apoptosis biomarkers was assessed by immunoblotting.

[0809] result

[0810] In MDA-MB-231 cells, docetaxel-KA-peptide conjugate (DoceKA) KBA-106 (represented by the formula acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY-formula (XXIII)) exerted potent anti-proliferative and anti-migratory activity in vitro. The experimental results are shown in Figures 17 to 29. Compared with the use of free docetaxel alone, the cell death mechanism triggered by DoceKA is faster and higher. The apoptotic and anti-migratory effects were reversed by SORT1 ligands neurotensin and progranulin and when siRNA-mediated silencing of SORT1. DoceKA altered microtubule polymerization and triggered the downregulation of IL-6, survivin, Bcl-xL and mutant p53 pro-survival biomarkers (see Figure 22 in particular). In vivo, compared with docetaxel, DoceKA showed greater tumor regression ability and prolonged survival in the murine MDA-MB-231 xenograft tumor model.

[0811] The pharmacokinetic (PK) parameters of docetaxel compared to conjugated docetaxel (DoceKA) are shown in Table 2 below.

[0812] Table 2: Comparison of pharmacokinetic parameters between docetaxel and conjugated docetaxel (DoceKA)

[0813]

[0814] The PK data of docetaxel are from refs.50 and 51. PK analysis of DoceKA was performed using PK solution software. The PK of docetaxel in mice is biphasic and linear between 13-62 mg / kg. Compared with docetaxel (20 mg / kg), the Cmax of DoceKA is about 18 times higher. The area under the curve (AUC) (tissue exposure) is about 29 times higher, indicating that the tissue exposure of DoceKA is higher than that of docetaxel. The half-lives of the two are similar. DoceKA has a lower clearance (CL) and distribution volume (Vd). These preliminary data need to be confirmed with more data (shorter and longer time points).

[0815] in conclusion

[0816] In conclusion, our results suggest that DoceKA is specifically internalized via a receptor-mediated mechanism. Such properties allow for the targeting of SORT1-positive breast cancer and make DoceKA a promising new therapy for the treatment of TNBC.

[0817] Example 5: Overexpression of SORT1 in various cancers

[0818] exist Fig.30 In Figure 40, Sortilin is shown to be overexpressed in a variety of cancers, pathological subtypes, and cancer subtypes, including, for example, ovarian cancer (e.g., epithelial ovarian cancer), breast cancer (e.g., invasive ductal carcinoma, invasive lobular carcinoma, luminal A, luminal B, HER2+, TNBC), brain cancer, melanoma, uterine cancer (e.g., endometrial cancer and cervical cancer), and lung cancer. An association between SORT1 expression and clinical pathological parameters in breast cancer has been shown. This is shown in Table 3 below.

[0819] Table 3: Correlation between SORT1 expression and clinicopathological parameters in breast cancer

[0820]

[0821]

[0822] Sortilin is expressed in normal tissues such as the gastrointestinal tract, pancreas, bone marrow, brain, and kidney. HER2 is expressed in normal tissues such as the liver, gastrointestinal tract, pancreas, bone marrow, and breast. All ovarian cancers (100%) overexpress Sortilin compared to 7% for HER2. SORT1 is overexpressed in 66% of breast cancers, while for HER2 expression is 10%-15%. Both Sortilin and HER2 targets are conserved between species, as shown in Table 4 below:

[0823] Table 4: Sequence homology compared to human

[0824]

[0825] Example 6: Role of Sortilin in vasculogenic mimicry in ovarian and breast cancer and inhibition of vasculogenic mimicry in vitro and in vivo

[0826] In Figures 40 and 44, it is shown that the Sortilin receptor is involved in the early events leading to the formation of angiogenic mimicry in ovarian cancer and triple negative breast cancer cells. Sortilin is expressed in 3D tubular structures formed by OVCAR-3 and ES-2 ovarian cancer cells (Figures 40 and 44). These results indicate that Sortilin positive cells contribute to angiogenic mimicry in vitro.

[0827] Inhibition of vasculogenic mimicry by siRNA gene silencing

[0828] When sortilin expression was specifically knocked down by sortilin-specific siRNA, 3D tubular structures were strongly suppressed in MDA-MB231 TNBC cells compared with scrambled siRNA ( FIG. 42A to FIG. 42D ). As described in the previous example, the total ring and total tube length were quantitatively analyzed. The results showed that when the sortilin gene was silenced, the number of rings and the total tube length were suppressed by more than 80% ( Fig.42E and Fig.42F ). These results confirm that sortilin is important for the formation of 3D capillary-like structures.

[0829] Inhibition of angiogenic mimicry by peptide conjugates

[0830] DoceKA at very low pM concentrations inhibited the angiogenic mimicry of ES-2 ovarian cancer cells (Figure 41). DoceKA had a stronger inhibitory effect on angiogenic mimicry than docetaxel alone (Figure 43).

[0831] exist Figures 49 to 50 In the present study, KA-peptide drug conjugates targeting sortilin were shown to exhibit strong anti-angiogenic mimicry effects by suppressing the invasive phenotype of ovarian and breast cancer cells. The angiogenic mimicry of ES-2 ovarian cancer cells was evaluated on Matrigel in the presence of KBP106 peptide or conjugated doxorubicin (KBB106). Fig.49 and Fig.50 Under the same experimental conditions used for the Katana conjugates, the peptide (KBP106) had no significant effect on vasculogenic mimicry up to 50 μM ( Fig.49 Although the peptide alone (KBP106) had no effect on angiogenic mimicry, the addition of the peptide to KBB106 prevented the angiogenic mimicry inhibition of the doxorubicin conjugate (KBB106) ( Fig.50 ). These results suggest that KBP106, by binding to sortilin, prevents the interaction of KBB106 with the receptor.

[0832] exist Figure 51 to Figure 52 showed that in ES-2 ovarian cancer cells, sortilin ligand, neurotensin, and progranulin did not affect vasculogenic mimicry ( Fig.51 ), but did reverse the inhibition of vasculogenic mimicry caused by exposure of cells to KBB106.

[0833] Inhibition of vasculogenic mimicry by anti-sortin mAb

[0834] In Figures 46 to 48, it is shown that angiogenic mimicry formation is primarily abolished by anti-sortilin mAb. ES-2 ovarian cancer cells were seeded on top of an artificial basement membrane in the presence of non-specific mouse IgG, rabbit IgG, anti-sortilin rabbit pAb, or anti-sortilin mAb (Figure 46). The results show that incubation with anti-sortilin mAb prevents the formation of 3D tubular structures in ES-2 ovarian cancer, while the other antibodies tested had no effect (Figure 46). ES-2 ovarian cancer cells were exposed to increasing concentrations of anti-Sortl, which showed that increasing concentrations of anti-Sortl were more effective in preventing the formation of 3D tubular structures than lower concentrations (Figure 46). Fig.47 ). At concentrations that inhibit angiogenic mimicry (12-24 hours), anti-sortin had no effect on ES-2 cancer cell proliferation, indicating that angiogenic mimicry inhibition was not associated with cytotoxic effects (Figure 48). Table 5 below shows the effects of different concentrations of anti-Sort1 on tube length, branching, and number of rings in ES-2 ovarian cancer cells.

[0835] Table 5: Effects of different concentrations of anti-Sort1 on tube length, branching, and number of loops that appear during vasculogenic mimicry

[0836] Table 5 (continued)

[0837]

[0838] Example 7: Expression of Sortilin and CD133 during the formation of vasculogenic mimicry

[0839] In Figures 53 to 57, it is shown that both sortilin and CD133 are present in the angiogenic mimicry structures formed by ES-2 tumor xenografts. Tumor tissue sections were first hybridized with primary antibodies against sortilin, CD31, and CD133 or stained with periodic acid Schiff (PAS) (Figure 53). The sections were then co-stained with PAS-anti-CD31, PAS-anti-sortilin, or PAS-anti-CD133 (Figure 54). Figure 54 to Figure 57). The observed angiogenic mimicry structures were PAS positive and CD31 negative and were denoted by the word "VM", while the blood vessels were denoted by the word "Vascular" and were positive for CD3 1. Both Sortilin and CD1 33 staining were associated with cancer cells and also partially correlated with PAS staining.

[0840] Identification of angiogenic mimicry by immunohistochemistry was performed as follows. Formalin-fixed, paraffin-embedded tumor tissue sections were stained with appropriate primary antibodies to detect CD31, CD133, and sortin. The sections were treated with 0.5% periodic acid solution for 15 minutes. After rinsing with distilled water for 2 minutes, the tissue sections were placed in Schiff's solution, placed in a dark room for 15-30 minutes, and then rinsed with distilled water 3 times. The sections were then counterstained with hematoxylin. 3D tubular structures seen on hematoxylin-eosin stained slides will be formed by CD31-negative tumor cells. Angiogenic mimicry was then verified by CD31 / periodic acid-Schiff (PAS) double staining, and angiogenic mimicry was identified by detecting PAS-positive rings surrounded by tumor cells (but not endothelial cells). For immunohistochemical staining of CD133 and sortin, formalin-fixed and paraffin-embedded slides from cancer tissue sections were routinely dewaxed and rehydrated. Then, the slides were incubated with 3% H2O2 to block endogenous peroxidase, and then incubated with 20% goat serum to reduce nonspecific binding. After washing with phosphate-buffered saline, mouse anti-human CD1 33 monoclonal antibody (clone CD133, Miltenyi Biotec) was added to the slides at a dilution of 1:50. The slides were then incubated overnight at 4°C. The next day, the slides were incubated at 1:200 in peroxidase-conjugated rabbit anti-mouse secondary antibodies (DakoCytomation, Carpinteria, California, USA) for 30 minutes. The reaction was visualized using diaminobenzidine. Finally, the slides were counterstained with hematoxylin.

[0841] In Figures 44 and 45, it is shown that the expression of sortilin and cancer stem cell-like CD133 genes increases during the formation of angiogenic mimicking 3D tubular structures.

[0842] During the formation of 3D tubular structures by ES-2 ovarian cancer cells (Figure 44) and MDA-MB-231 cells (Figure 45), gene expression of sortin, CD133, and MMP9 was evaluated by reverse transcription and quantitative polymerase chain reaction (RT-qPCR). During the formation of these capillary-like structures by ES-2 ovarian cancer cells, sortin gene expression increased rapidly after 2 hours and remained at a high level within 24 hours (Figure 44). During the formation of angiogenic mimicry, CD133 and MMP9 gene expression increased more than 4 times over time. CD133 is one of the most commonly used markers for isolating cancer stem cell (CSC) populations from tumors. CD133+ cancer cells (CSC) are positively correlated with angiogenic mimicry formation, local regional recurrence, and distant metastasis. In the case of angiogenic mimicry in MDA-MB-231 (Figure 45), sortin and CD133 gene expression increased slightly over time, and MMP9 increased by about 2 times. This suggests that the role of CD133 in vasculogenic mimicry may be modest in MDA-MB-231, whereas in contrast to ES-2 cancer cells, a more robust increase in CD133 gene expression was observed.

[0843] Example 8: Screening for additional sortilin-positive TNBC cell line models

[0844] Screening for additional TNBC cell lines expressing sortilin is ongoing. Figure 58 to Figure 5 9, various triple-negative breast cancer (TNBC) cell lines were shown to be sortilin-positive cell lines ( Fig.58 and Table 6), and in particular one cell line has been demonstrated to form 3D tubular angiogenic mimicry structures, the BT-20TNBC cells (Figure 59).

[0845] Table 6: List of TNBC cell line models

[0846]

[0847] The embodiments of paragraphs

[0062] to

[00458] of the present disclosure are presented in the present disclosure in such a way as to demonstrate that every combination of the embodiments can be made when applicable. Therefore, these embodiments have been presented in the specification in a manner equivalent to making dependent claims to all embodiments that depend on any preceding claim (covering the previously presented embodiments), thereby demonstrating that they can be combined together in all possible ways. For example, when applicable, all possible combinations between the embodiments of paragraphs

[0062] to

[00458] and the various aspects presented in paragraphs

[005] to

[0064] are thereby covered by the present disclosure.

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Claims

1. Having the formula A-(B) n Use of a conjugated compound of for the manufacture of a medicament for treating an aggressive cancer expressing sortilin and exhibiting angiogenic mimicry: in, n is 1, 2, 3, or 4; A is a peptide compound of formula (X): GVRAKAGVRN(Nle)FKSESY(X)(SEQ ID NO:10) wherein at least one protecting group is optionally attached to the peptide compound at the N- and / or C-terminus and / or at least one cysteine ​​residue is optionally attached to the peptide compound at the C-terminus, B is at least one anticancer agent, wherein B is linked to the peptide compound, optionally at a free amine of the peptide compound, at the N-terminal position of the peptide compound, at a free -SH of the peptide compound, or at a free carboxyl group of the peptide compound, wherein the cancer is ovarian cancer or breast cancer.

2. The use according to claim 1, wherein the peptide compound comprises at least one protecting group, which is an acetyl group or a succinyl group.

3. The use according to claim 1, wherein the peptide compound comprises at least one cysteine ​​residue, wherein the cysteine ​​residue is linked to the C-terminus, and B is linked to the peptide compound at the free -SH.

4. The use according to claim 1, wherein the peptide compound is represented by formula (XXXIX): Acetyl-GVRAKAGVRN(Nle)FKSESY(XXXIX) (SEQ ID NO: 15).

5. The use according to claim 1, wherein B is linked to the peptide compound via a linker, optionally a cleavable linker.

6. The use according to claim 1, wherein the anticancer agent is docetaxel, paclitaxel, doxorubicin, cabazitaxel, maytansinoid, auristatin, calicheamicin, amatoxin, amanitin or aldoxorubicin.

7. The use according to claim 6, wherein the anticancer agent is docetaxel.

8. The use according to claim 7, wherein the conjugated compound is represented by formula (XIX): GVRAK (docetaxel) AGVRN (Nle) FK (docetaxel) SESY - Formula (XIX) It comprises a peptide compound of SEQ ID NO: 10, wherein each lysine residue has a docetaxel molecule attached thereto.

9. The use according to claim 7, wherein the conjugated compound is represented by formula (XXIII): Acetyl-GVRAK(docetaxel)AGVRN(Nle)FK(docetaxel)SESY – Formula (XXIII) It comprises a peptide compound of SEQ ID NO: 15, wherein each lysine residue has a docetaxel molecule attached thereto.

10. The use according to claim 6, wherein the anticancer agent is doxorubicin.

11. The use according to claim 10, wherein the conjugated compound is represented by formula (XXVI): GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY - formula (XXVI) It comprises a peptide compound of SEQ ID NO: 10, wherein each lysine residue has a doxorubicin molecule attached thereto.

12. The use according to claim 10, wherein the conjugated compound is represented by formula (XXVIII): Acetyl-GVRAK(doxorubicin)AGVRN(Nle)FK(doxorubicin)SESY - Formula (XXVIII) It comprises a peptide compound of SEQ ID NO: 15, wherein each lysine residue has a doxorubicin molecule attached thereto.

13. The use according to claim 6, wherein the anticancer agent is cabazitaxel.

14. The use according to claim 6, wherein the anticancer agent is aldoxorubicin.

15. The use according to claim 1, wherein the B is linked to the peptide compound via a linker at the free amine of the peptide compound, wherein the free amine is a free amine of a lysine residue of the peptide compound.

16. The use according to claim 1, wherein the B is connected to the peptide compound at the N-terminus of the peptide compound via a linker.

17. The use according to claim 15, wherein the linker is selected from succinic acid and dimethylglutaric acid.

18. The use according to claim 16, wherein the linker is selected from succinic acid and dimethylglutaric acid.

19. The use according to claim 14, wherein the conjugated compound is represented by formula (LI): GVRAKAGVRN(Nle)FKSESYC(aldoxorubicin)–Formula (LI) It comprises a peptide compound of SEQ ID NO: 23, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto, or It comprises a peptide compound of SEQ ID NO: 10, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, and wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto.

20. The use according to claim 14, wherein the conjugated compound is represented by formula (LII): Acetyl-GVRAKAGVRN(Nle)FKSESYC(aldoxorubicin) – Formula (LII) It comprises the peptide compound of SEQ ID NO: 24, wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto, or It comprises a peptide compound of SEQ ID NO: 15, wherein a cysteine ​​residue is added to the C-terminus of the peptide compound, and wherein the cysteine ​​residue has an aldoxorubicin molecule linked thereto.

21. The use according to any one of claims 1 to 20, wherein the cancer is ovarian cancer.

22. The use according to any one of claims 1 to 20, wherein the cancer is breast cancer.

23. The use according to claim 22, wherein the breast cancer is triple negative breast cancer (TNBC).

24. The use according to any one of claims 1 to 20, wherein the medicament is used in combination with a therapeutic agent selected from cytotoxins, anti-cancer peptides, immunomodulators and anti-angiogenic agents.

25. The use according to any one of claims 1 to 20, wherein the medicament is used in combination with a therapeutic agent selected from toxins.

26. The use according to any one of claims 1 to 20, wherein the drug is used in combination with anti-PD1 or anti-PDL1.

27. The use according to any one of claims 1 to 20, wherein the medicament is used in combination with radiotherapy.

28. The use according to any one of claims 1 to 20, wherein the cancer comprises CD133 positive cells.

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