Application of CCR5 inhibitors in cancer treatment

Abstract

The present invention provides a method of treating cancer comprising administering a CCR5 inhibitor to a subject.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 677,114, filed on May 28, 2018, and U.S. Provisional Patent Application No. 62 / 792,600, filed on January 15, 2019, which are both incorporated herein by reference in their entireties. Technical Field

[0003] The present application relates to methods of treating cancer. Background Art

[0004] Chemokines and chemokine receptors have been implicated in a variety of diseases. One chemokine can bind to several chemokine receptors and vice versa, thus forming a complex system.

[0005] Among the known chemokine receptors, CC chemokine receptor type 5 (CCR5) has been identified as a co-receptor that mediates HIV entry. CCR5 exists in at least two conformations on the cell surface, and among the possible explanations for their existence, one conformation consists of G protein-coupled CCR5 and the other consists of G protein-uncoupled CCR5. The CC chemokines CCL3, CCL4, and CCL5 are the major endogenous agonists of CCR5. CCL5, also known as RANTES (regulated upon activation, normal T cell expressed and secreted), has been shown to interact with CC chemokine receptor type 1 (CCR1) and CC chemokine receptor type 3 (CCR3) in addition to CCR5.

[0006] The engagement of endogenous CCR5 agonists results in the activation of all intracellular signal transduction pathways, which are broadly defined as G protein-dependent and G protein-independent signal transduction pathways. One manifestation of G protein-dependent signal transduction is the induction of intracellular calcium flow. One manifestation of G protein-independent signal transduction is the induction of receptor internalization, leading to intracellular receptor sequestration.

[0007] CCR5 belongs to the G protein-coupled receptor superfamily. For members of this superfamily, ligands that can preferentially activate G protein-dependent signal transduction pathways or G protein-independent signal transduction pathways have been identified. These ligands, collectively referred to as "biased ligands", have been shown to have interesting pharmacological and pharmaceutical properties, and can selectively activate or inhibit pathways of interest in certain pathologies.

[0008] CCR5 is expressed by certain cancer cells, where its activation is thought to provide survival and metastasis signals. In addition, CCR5 is expressed on immunoregulatory leukocytes (M2 macrophages and regulatory T cells) that infiltrate tumors and suppress anti-tumor immune responses.

[0009] Maraviroc (MVC) It is a CCR5 inhibitor currently approved for the treatment of HIV infection. In addition, maraviroc has also been shown to be active in both in vitro (Pervaiz A. et al. Med Oncol. 2015; 32(5): 158; Zi J. et al. Am J Cancer Res. 2017; 7(4): 869-80) and in vivo cancer models (Ward ST et al. Br J Cancer. 2015; 112(2): 319-28; Tanabe Y. et al. Oncotarget. 2016; 7(30): 48335-45).

[0010] In addition, patients with metastatic colorectal cancer (mCRC) who received oral maraviroc showed evidence of changes in the tumor microenvironment that may inhibit tumor growth or metastasis. In some cases, patients also experienced clinical responses to maraviroc treatment, including regression of metastatic disease (Halama N. et al. Cancer Cell. 2016; 29(4): 587-601). Summary of the invention

[0011] In one aspect, a method of treating cancer is provided, the method comprising administering to a subject a CCR5 inhibitor, wherein the CCR5 inhibitor comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises the signature sequence QGP[P or L], and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO:1.

[0012] In one embodiment of the methods of the invention, the CCR5 inhibitor inhibits HIV entry into cells and is selective for CCR5 compared to CCR1 and CCR3.

[0013] In one embodiment of the methods of the invention, the CCR5 inhibitor inhibits only a subset of the CCR5 intracellular signaling pathway.

[0014] In one embodiment of the methods of the invention, the CCR5 inhibitor inhibits or reduces the inflammatory effects of CCR5, e.g., resulting in a signaling response that is 30% or less of the maximal response (Emax) elicited by PSC-RANTES when tested at a concentration of 300 nM in a calcium signaling assay.

[0015] In one embodiment of the method of the present invention, the signature sequence is QGP[P or L][L or G or S or M][M or D or S or Q or G].

[0016] In one embodiment of the method of the present invention, the signature sequence is QGP[P or L][L or G or S or M][M or D or S or Q or G]XX[Q or G or L or A or T or S]X, wherein X represents any natural or modified amino acid.

[0017] In one embodiment of the method of the present invention, the signature sequence is QGP[P or L]LM or QGPPG[D or S].

[0018] In one embodiment of the method of the present invention, the signature sequence is QGPPLM or QGPPGD.

[0019] In one embodiment of the method of the present invention, the signature sequence is QGP[P or L][L or M][M or Q][A or W or G or Q or N]X[Q or G or L][S or V or T or G], wherein X represents any natural or modified amino acid.

[0020] In one embodiment of the method of the present invention, the signature sequence is QGPPLM[A or W][L or T or M][Q or G][S or V or T or G].

[0021] In one embodiment of the method of the present invention, the signature sequence is QGPP[G or L][M or Q]XX[Q or S][S or V], wherein X represents any natural or modified amino acid.

[0022] In one embodiment of the method of the present invention, the signature sequence is selected from the group consisting of QGPPLMALQS (SEQ ID NO: 2), QGPPLMWMQV (SEQ ID NO: 3), QGPPLMWLQV (SEQ ID NO: 4), QGPPLMWTQS (SEQ ID NO: 5), QGPPLMWLQT (SEQ ID NO: 6), QGPPLMWTQV (SEQ ID NO: 7), QGPPLMWMQS (SEQ ID NO: 8), QGPPLMATQS (SEQ ID NO: 9), QGPPLMWLQS (SEQ ID NO: 10), QGPPLMALQV (SEQ ID NO: 11), QGPPLMWLGG (SEQ ID NO: 12), QGPPLMWRGS (SEQ ID NO: 13), QGPLLMWLQV (SEQ ID NO: 14), QGPPLMQTTP (SEQ ID NO: 15), QGPPLSWLQV (SEQ ID NO: 30), QGPPLSWLQS (SEQ ID NO: 31). NO:31), QGPPGQWSQV (SEQ ID NO:32), QGPPMMAGLS (SEQ ID NO:33), QGPPLSWQQS (SEQ ID NO:34), QGPPGMWSQS (SEQ ID NO:35), QGPPLQWRQS (SEQ ID NO:36), QGPPLMGTQS (SEQ ID NO:37), QGPPLMQLQV (SEQ ID NO:38), QGPPLSWSQV (SEQ ID NO:39), QGPPMSWSQS (SEQ ID NO:40), QGPPLMNLQV (SEQ ID NO:41), QGPPMSAYQV (SEQ ID NO:42) and QGPPMQGGLS (SEQ ID NO:43).

[0023] In one embodiment of the method of the present invention, the signature sequence is selected from the group consisting of QGPPLMALQS (SEQ ID NO: 2), QGPPLMWMQV (SEQ ID NO: 3), QGPPLMWLQV (SEQ ID NO: 4), QGPPLMWTQS (SEQ ID NO: 5), QGPPLMWLQT (SEQ ID NO: 6), QGPPLMWTQV (SEQ ID NO: 7), QGPPLMWMQS (SEQ ID NO: 8), QGPPLMATQS (SEQ ID NO: 9), QGPPLMWLQS (SEQ ID NO: 10), QGPPLMALQV (SEQ ID NO: 11), QGPPLMWLGG (SEQ ID NO: 12), QGPPLMWRGS (SEQ ID NO: 13), QGPLLMWLQV (SEQ ID NO: 14) and QGPPLMQTTP (SEQ ID NO: 15).

[0024] In one embodiment of the method of the present invention, the signature sequence is QGPPLMATQS (SEQ ID NO: 9).

[0025] In one embodiment of the method of the present invention, the signature sequence is located at the extreme N-terminus.

[0026] In one embodiment of the method of the invention, the C-terminal portion is identical to SEQ ID NO:1.

[0027] In one embodiment of the method of the present invention, the CCR5 inhibitor comprises the amino acid sequence of SEQ ID NO:70.

[0028] In one embodiment of the method of the present invention, the cancer is colorectal cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, pancreatic cancer, esophageal cancer, gastric cancer, liver cancer or leukemia.

[0029] In one embodiment of the method of the present invention, wherein the cancer is metastatic.

[0030] In one embodiment of the method of the present invention, wherein the cancer is refractory to chemotherapy or radiotherapy and / or resistant to chemotherapy or radiotherapy.

[0031] Other aspects and features of the present invention will become apparent to those skilled in the art after reading the following description of specific embodiments of the invention in conjunction with the accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0032] Figure 1 shows the potency of 5P12-RANTES in inhibiting signaling through human CCR5 compared to various known CCR5 inhibitors.

[0033] Figure 2 Shown is a comparison of the anti-HIV efficacy of 5P12-RANTES with AZT and MVC.

[0034] FIG. 3 shows that 5P12-RANTES antagonizes neither CCR1 nor CCR3.

[0035] Figure 4 shows the efficacy of 5P12-RANTES in a colorectal cancer animal model."QD" indicates daily dosing, and "Q3D" indicates dosing every three days. DETAILED DESCRIPTION

[0036] The inventors surprisingly discovered that an N-terminally modified RANTES variant, 5P12-RANTES (SEQ ID NO: 70), is more effective than maraviroc (MVC) in inhibiting CCR5 signaling and / or HIV-1 replication. The inventors further demonstrated that, like MVC, 5P12-RANTES is selective for CCR5 over CCR1 and CCR3. Moreover, in preclinical evaluation of 5P12-RANTES, the compound was administered to cynomolgus macaques and rats at a dose of 20 mg / kg as a single dose intravenous infusion without any adverse events. These findings suggest that this N-terminally modified RANTES variant and its structurally related analogs have enhanced efficacy and very few side effects compared to MVC, which is known to be effective in treating several types of cancer. The inventors have demonstrated the efficacy of 5P12-RANTES in animal models of colorectal cancer.

[0037] Therefore, the method of the present invention relates to treating cancer by administering to a subject a CCR5 inhibitor, in particular a polypeptide comprising an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises the characteristic sequence QGP[P or L], i.e., the fourth position of the characteristic sequence is P or L, and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1.

[0038] Without being limited by theory, it is believed that the CCR5 inhibitors provided herein can inhibit cancer cell growth and / or reprogram immunoregulatory leukocytes (e.g., induce a phenotypic shift of "tumor-infiltrating macrophages from an immunosuppressive (M2) phenotype to an immunostimulatory (M1) phenotype"). It is also believed that the CCR5 inhibitors provided herein are insensitive to tumor mutation load.

[0039] CCR5 inhibitors

[0040] The term "CCR5 inhibitor" used in the present invention refers to a molecule or compound that inhibits one or more biological and / or pathological activities induced by CCR5. CCR5 inhibitors can prevent the binding of ligands or pathogens (orthosteric inhibitors) by partially or completely occupying one or more sites required for their interaction on CCR5. Alternatively, CCR5 inhibitors can prevent the binding of ligands or pathogens (allosteric inhibitors) by occupying other sites on CCR5 and inducing CCR5 to take one or more conformations that ligands or pathogens cannot recognize. CCR5 inhibitors can inhibit all or only subgroups of CCR5 intracellular signal transduction pathways. CCR5 inhibitors can also work by inducing long-term intracellular isolation of CCR5, so that it cannot be approached by extracellular ligands or pathogens. CCR5 inhibitors can also work by specifically inhibiting or removing the expression of CCR5 genes. CCR5 inhibitors can also work by combining with one or more ligands or pathogens, so that they cannot be combined with CCR5.

[0041] The CCR5 inhibitors that can be used in the method of the present invention are highly effective inhibitors of HIV entry into cells, that is, they have high anti-HIV efficacy, and compared with the receptors CCR1 and CCR3, the CCR5 inhibitors are CCR5 selective; and may also have the ability to bind to CCR5 in a variety of cell surface conformations, and / or only induce low-level pro-inflammatory signal transduction, and / or only inhibit a subset of all CCR5 intracellular signal transduction pathways, and / or induce CCR5 internalization into cells (receptor concealment, downregulation or downward regulation).

[0042] In the context of the present invention, the expressions "high anti-HIV efficacy", "high potency" or "high efficiency" are used for CCR5 inhibitors having IC50 values ​​as measured by the cell fusion or HIV replication assay described in the Materials and Methods section of U.S. Patent No. 8,686,111, of 1000 pM (1 nM) or less, such as less than 900, 800, 700, 600, 500, 400, 300, 200, 150, 140, 130, 120, 110, 100, 90, 80, 70, 60, 50, 40, 30 or 20 pM. In some embodiments, the CCR5 inhibitors useful in the methods of the invention are more potent than MVC, e.g., at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 11-fold, 12-fold, 13-fold, 14-fold, 15-fold, 16-fold, 17-fold, 18-fold, 19-fold, 20-fold, 21-fold, 22-fold, 23-fold, 24-fold, 25-fold, 26-fold, 27-fold, 28-fold, 29-fold, or 30-fold more potent than MVC, as measured by a CCR5 signaling assay as described in Example 1 or an HIV replication assay as described in Example 2 of the present application.

[0043] In the context of the present invention, a CCR5 inhibitor that binds to CCR1 and / or CCR3 and CCR5 is still considered selective for CCR5 over CCR1 and / or CCR3 if the CCR5 inhibitor does not substantially activate CCR1 and / or CCR3. In some embodiments, a CCR5 inhibitor useful in the methods of the present invention does not substantially bind to or substantially activate CCR1 and CCR3. In the context of the present invention, a CCR5 inhibitor is considered to be substantially non-binding to CCR1 and / or CCR3 if the CCR5 inhibitor has an IC50 value for CCR1 and / or CCR3 binding greater than 50 nM, e.g., greater than 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 nM, as measured using a CCR1 discrimination binding assay and / or a CCR3 discrimination binding assay as described in the Materials and Methods section of U.S. Patent No. 8,686,111. Selective CCR5 activation relative to CCR1 and / or CCR3 activation can be evaluated by a calcium flux assay as described in the Materials and Methods section of U.S. Patent No. 8,686,111. In the context of the present invention, a CCR5 inhibitor is considered to not substantially activate CCR1 and / or CCR3 if its signaling activity is less than 30% of the Emax elicited by native RANTES / CCL5 for that receptor as measured by the calcium flux assay described in the Materials and Methods section of U.S. Pat. No. 8,686,111, e.g., less than 26%, 22%, 20%, 18%, 16%, 14%, 12%, 10%, 8%, 6%, 4%, 2% or 1%.

[0044] In the context of the present invention, a CCR5 inhibitor is considered to bind to CCR5 in both a G protein-coupled and uncoupled conformation if the binding of a CCR5 inhibitor to CCR5 is not affected by the presence or absence of a non-hydrolyzable GTP analogue such as GTPγS (guanosine 5'-O-(γ-thio)-triphosphate) or Gpp(NH)p (guanosine 5'-(β,γ-acylimine)triphosphate). Binding of the CCR5 inhibitor to CCR5 is considered to be unaffected by the presence or absence of a non-hydrolyzable GTP analog if the difference in specifically bound radiolabeled inhibitor in the presence or absence of Gpp(NH)P or in the presence of 100 μM Gpp(NH)P is less than 20%, e.g., less than 18%, 16%, 14%, 12%, 10%, 8%, 6%, 5%, 4%, 3%, 2%, or 1%, as measured by a radioligand binding assay, such as in Figures 3D and 3E of Colin P. et al. Proc Natl Acad Sci USA 2013; 110(23):9475–9480 and described in the Supporting Information.

[0045] In the context of the present invention, CCR5 inhibitors with "low signaling activity" are those whose administration and / or binding to CCR5 induces only low pro-inflammatory signaling in target cells, resulting in a signaling response of 30% or less of the maximum response (Emax) elicited by PSC-RANTES when tested at a concentration of 300 nM in the calcium flux signaling assay described in the Materials and Methods section of U.S. Patent No. 8,686,111. For example, the CCR5 inhibitor used in the methods of the present invention may have a signaling activity of less than 30%, 26%, 22%, 20%, 18%, 16%, 14%, 12%, 10%, 8%, 6%, 4%, 2% or 1% of the maximum response (Emax) elicited by PSC-RANTES as measured in a calcium flux signaling assay. The sequence of PSC-RANTES is R 1 -SSDTTPCCFAYIARPLPRAHIKEYFYTSGKCSNPAVVFVTRKNRQVCANPEKKWVREYINSLEMS, where R 1 =N α -(N-nonanoyl)-des-Ser 1 -[L-thioprolyl 2 ,L-cyclohexylglycyl 3 ].

[0046] [A] In the context of the present invention, CCR5 inhibitors have "high receptor sequestration activity", i.e., their administration and / or binding to CCR5 causes a high degree of receptor sequestration (such sequestration can be receptor internalization, down-regulation or down-modulation), resulting in sequestration of at least 50% of a control level of surface CCR5 molecules when tested in a CCR5 surface down-modulation / receptor sequestration assay as described in the Materials and Methods section of U.S. Patent No. 8,686,111. For example, a CCR5 inhibitor may have a receptor sequestration activity that exceeds 50%, 55%, 60%, 65%, 70%, 80%, 85%, 90% or 95% of a control level of surface CCR5.

[0047] In some embodiments, the CCR5 inhibitors useful in the methods of the present invention are those disclosed in U.S. Pat. No. 8,686,111, i.e., polypeptides comprising an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises the characteristic sequence QGP[P or L], i.e., the fourth position of the characteristic sequence can be P or L, and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1.

[0048] The CCR5 inhibitors disclosed in U.S. Pat. No. 8,686,111 may combine high anti-HIV efficacy with low signaling activity, or high anti-HIV efficacy with high receptor cloaking activity. In some embodiments, the CCR5 inhibitors useful in the methods of the present invention combine high anti-HIV efficacy with low signaling and high receptor cloaking activity. In some embodiments, the CCR5 inhibitors useful in the methods of the present invention combine high anti-HIV efficacy with low signaling activity, but not high receptor cloaking activity.

[0049] In some embodiments, CCR5 inhibitors useful in the methods of the invention are characterized by a high level of anti-HIV potency (IC50 levels, e.g., between 0.02 and 1 nM, or between 0.02 and 0.15 nM, as measured by the cell fusion assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) in combination with a low level of signaling activity (e.g., no more than 15%, no more than 10%, or no more than 5%, as measured by the calcium flux assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) and a low level of receptor crypting activity (e.g., no more than 20% or no more than 10%, as measured by the CCR5 surface downregulation assay described in the Materials and Methods section of U.S. Patent No. 8,686,111).

[0050] In some embodiments, CCR5 inhibitors useful in the methods of the invention are characterized by a combination of a high level of anti-HIV potency (IC50 levels, e.g., between 0.02 and 1 nM, or between 0.02 and 0.15 nM, as measured by the cell fusion assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) with a high level of signaling activity (e.g., at least 60%, or at least 85%, as measured by the calcium flux assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) and a high level of receptor crypting activity (e.g., at least 60%, or at least 70%, as measured by the CCR5 surface downregulation assay described in the Materials and Methods section of U.S. Patent No. 8,686,111).

[0051] In some embodiments, CCR5 inhibitors useful in the methods of the invention are characterized by a combination of a high level of anti-HIV potency (IC50 levels, e.g., between 0.02 and 1 nM, or between 0.02 and 0.15 nM, as measured by the cell fusion assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) with a low level of signaling activity (e.g., no more than 30%, or no more than 20%, no more than 15%, or no more than 10%, as measured by the calcium flux assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) and a moderate level of receptor crypting activity (e.g., between 20% and 50%, or between 30% and 50%, as measured by the CCR5 surface downregulation assay described in the Materials and Methods section of U.S. Patent No. 8,686,111).

[0052] In some embodiments, CCR5 inhibitors useful in the methods of the invention are characterized by a high level of anti-HIV potency (IC50 levels, e.g., between 0.02 and 1 nM, or between 0.02 and 0.15 nM, as measured by the cell fusion assay described in the Materials and Methods section of U.S. Pat. No. 8,686,111) in combination with a low level of signaling activity (e.g., no more than 30%, or no more than 20%, no more than 15%, or no more than 10%, as measured by the calcium flux assay described in the Materials and Methods section of U.S. Pat. No. 8,686,111) and a high level of receptor crypting activity (e.g., at least 50%, as measured by the CCR5 surface downregulation assay described in the Materials and Methods section of U.S. Pat. No. 8,686,111).

[0053] In some embodiments, CCR5 inhibitors useful in the methods of the invention are characterized by a combination of a high level of anti-HIV potency (IC50 levels, e.g., between 0.02 and 1 nM, or between 0.02 and 0.15 nM, as measured by the cell fusion assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) with a moderate level of signaling activity (e.g., between 30% and 50%, or between 30% and 45%, as measured by the calcium flux assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) and a high level of receptor cloaking activity (e.g., at least 50%, as measured by the CCR5 surface downregulation assay described in the Materials and Methods section of U.S. Patent No. 8,686,111).

[0054] In some embodiments, CCR5 inhibitors useful in the methods of the invention are characterized by a combination of moderate levels of anti-HIV potency (IC50 levels, e.g., between 0.02 and 1 nM, or between 0.02 and 0.15 nM, as measured by the cell fusion assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) with moderate levels of signaling activity (e.g., between 30% and 50%, or between 30% and 45%, as measured by the calcium flux assay described in the Materials and Methods section of U.S. Patent No. 8,686,111) and moderate levels of receptor cloaking activity (e.g., between 20% and 50%, or between 30% and 50%, as measured by the CCR5 surface downregulation assay described in the Materials and Methods section of U.S. Patent No. 8,686,111).

[0055] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is: QGP[P or L][L or G or S or M][M or D or S or Q or G]; QGP[P or L][L or G][M or D or S]; QGP[P or L][L or G or S or M][M or D or S or Q or G]XX[Q or G or L or A or T or S]X, wherein X represents any natural or modified amino acid; QGP[P or L][L or G][M or D or S]XX[Q or L]X, wherein X represents any natural or modified amino acid; QGP[P or L]LM; QGPPG[D or S]; QGPPLM; or QGPPGD.

[0056] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is: QGP[P or L][L or M][M or Q][A or W or G or Q or N]X[Q or G or L][S or V or T or G], wherein X represents any natural or modified amino acid; QGP[P or L][L or M][M or Q][A or W or G or Q or N][L or T or M or S or G or Q or R or Y][Q or G or L][S or V or T or G]; QGP[P or L]LM[A or W][L or T or M][Q or G][S or V or T or G]; or QGPPLM[A or W][L or T or M][Q or G][S or V or T or G].

[0057] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is: QGP[P or L][L or G or S][D or S or G or Q]XX[L or A or T or Q][W or A or V], wherein X represents any natural or modified amino acid; QGP[P or L][L or G or S][D or S or G or Q][T or I or S or W or Q][V or L or A or S or G][L or A or T or Q][W or A or V]; QGPPG[D or S][T or I]VL[W or A]; or QGPPGD[T or I]VL[W or A].

[0058] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is: QGPP[G or L][M or Q]XX[Q or S][S or V], wherein X represents any natural or modified amino acid; QGPP[G or L][M or Q][S or G or W or A or T][L or F or T or S or G or Y][Q or S][S or V]; or QGPPLM[S or G][L or F or T]Q[S or V].

[0059] In some embodiments, a CCR5 inhibitor useful in the methods of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is the same as SEQ ID NO: NO: 1 is at least 70% identical, wherein the signature sequence is selected from the group consisting of QGPPLMALQS, QGPPLMWMQV, QGPPLMWLQV, QGPPLMWTQS, QGPPLMWLQT, QGPPLMWTQV, QGPPLMWMQS, QGPPLMATQS, QGPPLMWLQS, QGPPLMALQV, QGPPLMWLGG, QGPPLMWRGS, QGPLLMWLQV, QGPPLMQTTP, QGPPLSWLQV, QGPPLSWLQS, QGPPGQWSQV, QGPPMMAGLS, QGPPLSWQQS, QGPPGMWSQS, QGPPLQWRQS, QGPPLMGTQS, QGPPLMQLQV, QGPPLSWSQV, QGPPMSWSQS, QGPPLMNLQV, QGPPMSAYQV and QGPPMQGGLS.

[0060] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the group consisting of QGPPLMALQS, QGPPLMWMQV, QGPPLMWLQV, QGPPLMWTQS, QGPPLMWLQT, QGPPLMWTQV, QGPPLMWMQS, QGPPLMATQS, QGPPLMWLQS, QGPPLMALQV, QGPPLMWLGG, QGPPLMWRGS, QGPLLMWLQV and QGPPLMQTTP.

[0061] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the group consisting of QGPPGDTVLW, QGPPGDIVLA, QGPPGSYDYS, QGPPGDGGSV, QGPLSGQSTP, QGPPGDWLQV, QGPPLMSLAV, QGPPLMSLTV, QGPLSGWAQV, QGPLSQSSQV, QGPLSSQSQV, and QGPLGQQGQV.

[0062] In some embodiments, a CCR5 inhibitor useful in the methods of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the group consisting of QGPPGDTVLW, QGPPGDIVLA, QGPPGSYDYS, QGPPGDGGSV, QGPLSGQSTP, and QGPPGDWLQV.

[0063] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the group consisting of QGPPLMSFQS, QGPPLMSTQS, QGPPLMSLQV, QGPPLMGLQV, QGPLSGWLQV, QGPPLQWFQV, QGPPLQWTQV, QGPPLMALSV, QGPPLMWSQV, QGPPGQWGQV, QGPPGSWSQV, QGPPLMSSQS, QGPPLMGLSV, QGPPLMTLQV and QGPPGQWYQS.

[0064] In some embodiments, a CCR5 inhibitor useful in the methods of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the group consisting of QGPPLMSFQS, QGPPLMSTQS, QGPPLMSLQV, QGPPLMGLQV and QGPLSGWLQV.

[0065] In some embodiments, a CCR5 inhibitor useful in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the group consisting of QGPPLMSVLA, QGPPGSWSSV, QGPPLGSMGP, QGPPLQWMQA, QGPPLQWMQV, QGPPLMSTQV, QGPPLMSLSV, QGPPLMSLQS, QGPPLMSLQA, QGPPLMSVQS, QGPPLMSAQS, QGPPLMSGQS and QGPPLMSGQV.

[0066] In some embodiments, a CCR5 inhibitor useful in the methods of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the group consisting of QGPPLMSVLA, QGPPGSWSSV and QGPPLGSMGP.

[0067] In some embodiments, a CCR5 inhibitor useful in the methods of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1, wherein the signature sequence is selected from the signature sequences listed in Table 1:

[0068] Table 1

[0069] SEQ ID NO Characteristic sequence

[0070] SEQ ID NO:2QGPPLMALQS

[0071] SEQ ID NO:3QGPPLMWMQV

[0072] SEQ ID NO:4QGPPLMWLQV

[0073] SEQ ID NO:5QGPPLMWTQS

[0074] SEQ ID NO:6QGPPLMWLQT

[0075] SEQ ID NO:7QGPPLMWTQV

[0076] SEQ ID NO:8QGPPLMWMQS

[0077] SEQ ID NO:9QGPPLMATQS

[0078] SEQ ID NO:10QGPPLMWLQS

[0079] SEQ ID NO:11QGPPLMALQV

[0080] SEQ ID NO:12QGPPLMWLGG

[0081] SEQ ID NO:13QGPPLMWRGS

[0082] SEQ ID NO:14QGPLLMWLQV

[0083] SEQ ID NO:15QGPPLMQTTP

[0084] SEQ ID NO:16QGPPGDTVLW

[0085] SEQ ID NO:17QGPPGDIVLA

[0086] SEQ ID NO:18QGPPGSYDYS

[0087] SEQ ID NO:19 QGPPGDGGSV

[0088] SEQ ID NO:20 QGPLSGQSTP

[0089] SEQ ID NO:21 QGPPGDWLQV

[0090] SEQ ID NO:22 QGPPLMSFQS

[0091] SEQ ID NO:23 QGPPLMSTQS

[0092] SEQ ID NO:24 QGPPLMSLQV

[0093] SEQ ID NO:25 QGPPLMGLQV

[0094] SEQ ID NO:26 QGPLSGWLQV

[0095] SEQ ID NO:27 QGPPLMSVLA

[0096] SEQ ID NO:28 QGPPGSWSSV

[0097] SEQ ID NO:29 QGPPLGSMGP

[0098] SEQ ID NO:30 QGPPLSWLQV

[0099] SEQ ID NO:31 QGPPLSWLQS

[0100] SEQ ID NO:32 QGPPGQWSQV

[0101] SEQ ID NO:33 QGPPMMAGLS

[0102] SEQ ID NO:34 QGPPLSWQQS

[0103] SEQ ID NO:35 QGPPGMWSQS

[0104] SEQ ID NO:36 QGPPLQWRQS

[0105] SEQ ID NO:37 QGPPLMGTQS

[0106] SEQ ID NO:38 QGPPLMQLQV

[0107] SEQ ID NO:39 QGPPLSWSQV

[0108] SEQ ID NO:40 QGPPMSWSQS

[0109] SEQ ID NO:41 QGPPLMNLQV

[0110] SEQ ID NO:42 QGPPMSAYQV

[0111] SEQ ID NO:43 QGPPMQGGLS

[0112] SEQ ID NO:44 QGPPLMSLAV

[0113] SEQ ID NO:45 QGPPLMSLTV

[0114] SEQ ID NO:46 QGPLSGWAQV

[0115] SEQ ID NO:47 QGPLSQSSQV

[0116] SEQ ID NO:48 QGPLSSQSQV

[0117] SEQ ID NO:49 QGPLGQQGQV

[0118] SEQ ID NO:50QGPPLQWFQV

[0119] SEQ ID NO:51QGPPLQWTQV

[0120] SEQ ID NO:52QGPPLMALSV

[0121] SEQ ID NO:53QGPPLMWSQV

[0122] SEQ ID NO:54QGPPGQWGQV

[0123] SEQ ID NO:55QGPPGSWSQV

[0124] SEQ ID NO:56QGPPLMSSQS

[0125] SEQ ID NO:57QGPPLMGLSV

[0126] SEQ ID NO:58QGPPLMTLQV

[0127] SEQ ID NO:59QGPPGQWYQS

[0128] SEQ ID NO:60QGPPLQWMQA

[0129] SEQ ID NO:61QGPPLQWMQV

[0130] SEQ ID NO:62QGPPLMSTQV

[0131] SEQ ID NO:63QGPPLMSLSV

[0132] SEQ ID NO:64QGPPLMSLQS

[0133] SEQ ID NO:65QGPPLMSLQA

[0134] SEQ ID NO:66QGPPLMSVQS

[0135] SEQ ID NO:67QGPPLMSAQS

[0136] SEQ ID NO:68QGPPLMSGQS

[0137] SEQ ID NO:69QGPPLMSGQV

[0138] In one embodiment, the CCR5 inhibitor for use in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises the signature sequence QGPPLMATQS and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO:1.

[0139] [B] In one embodiment, the CCR5 inhibitor used in the method of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises the characteristic sequence QGPPGDIVLA and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1.

[0140] In one embodiment, the CCR5 inhibitor for use in the methods of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises the signature sequence QGPPLMSLQV and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO:1.

[0141] In one embodiment, the CCR5 inhibitor used in the method of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion consists of the signature sequence QGPPLMATQS and the amino acid sequence of the C-terminal portion is SEQ ID NO:1.

[0142] In one embodiment, the CCR5 inhibitor used in the method of the invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion consists of the signature sequence QGPPGDIVLA and the amino acid sequence of the C-terminal portion is SEQ ID NO:1.

[0143] In one embodiment, the CCR5 inhibitor used in the method of the present invention comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion consists of the signature sequence QGPPLMSLQV and the amino acid sequence of the C-terminal portion is SEQ ID NO:1.

[0144] In one embodiment, the CCR5 inhibitor for use in the methods of the invention comprises the amino acid sequence of SEQ ID NO:70.

[0145] In one embodiment, the CCR5 inhibitor for use in the methods of the invention comprises the amino acid sequence of SEQ ID NO:71.

[0146] In one embodiment, the CCR5 inhibitor for use in the methods of the invention comprises the amino acid sequence of SEQ ID NO:72.

[0147] The N-terminal portion of the CCR5 inhibitor described in paragraphs [A] to [B] may consist of no more than 15, 14, 13, 12, 11 or 10 amino acids. In one embodiment, the N-terminal portion consists of 10 amino acids.

[0148] In the CCR5 inhibitors described in paragraphs [A] to [B], the N-terminus of the C-terminal portion may be directly adjacent to the C-terminus of the N-terminal portion, ie, the N-terminal portion and the C-terminal portion are directly adjacent.

[0149] The C-terminal portion of the CCR5 inhibitor described in paragraphs [A] to [B] may have greater than 70%, 75%, 80%, 85%, 90%, 95%, 98%, 99%, 99.9% or 100% sequence identity with SEQ ID NO:1.

[0150] The term "sequence identity" as used herein has the standard meaning in the art. As is known in the art, many different programs can be used to identify whether a polynucleotide or polypeptide has sequence identity or similarity to a known sequence. Sequence identity or similarity can be determined using standard techniques known in the art, including but not limited to the local sequence identity algorithm of Smith & Waterman, Adv. Appl. Math. 2:482 (1981), the sequence identity alignment algorithm by Needleman & Wunsch, J. Mol. Biol. 48:443 (1970), by the search similarity method of Pearson & Lipman, Proc. Natl. Acad. Sci. USA 85:2444 (1988), by computer implementations of these algorithms (GAP, BESTFIT, FASTA and TFASTA in the Wisconsin Genetics Software Package, Genetics Computer Group, 575 Science Drive, Madison, WI), the best fit sequence program described by Devereux et al., Nucl. Acid Res. 12:387 (1984), preferably using the default settings, or by inspection.

[0151] The characteristic sequence of the CCR5 inhibitor described in paragraphs [A] to [B] may be located near the N-terminus of the polypeptide. For example, the position of the characteristic sequence may be such that the starting point of the characteristic sequence is located within 15, 12, 10, 8, 6, 5, 4, 3, 2 or 1 residues of the N-terminus of the polypeptide. The "starting point of the characteristic sequence" described herein refers to the N-terminus of the characteristic sequence. The characteristic sequence may also be located at the very N-terminus of the polypeptide, i.e., the N-terminus of the polypeptide as a whole, and the characteristic sequences may be identical.

[0152] In some embodiments, nucleic acids encoding the polypeptides provided herein can be used in the methods of the present invention. Those skilled in the art know how to design or identify nucleic acids encoding the polypeptides according to the genetic code. Such nucleic acids can include one or more sections encoding one or more polypeptides provided herein. Such nucleic acids can be RNA or DNA. Such nucleic acids can be vectors, i.e. nucleic acids encoding the polypeptides provided herein can be incorporated into vectors.

[0153] In some embodiments, the nucleic acid encoding the polypeptides provided herein can be incorporated into a virus. Therefore, a virus containing one or more segments encoding one or more polypeptides provided herein in the viral genome can be used in the method of the present invention.

[0154] As used herein, the terms "protein", "peptide" or "polypeptide" are used interchangeably and refer to amino acid polymers of any length. The polymer may be linear or branched, it may contain modified amino acids, and it may be interrupted by non-amino acids. The term also encompasses amino acid polymers that have been modified naturally or by intervention; for example, disulfide bond formation, glycosylation, lipidation, acetylation, phosphorylation, or any other manipulation or modification, such as conjugation with a labeling component. Also included within the definition are, for example, polypeptides containing one or more amino acid analogs (including, for example, non-natural amino acids, etc.), as well as other modifications known in the art. The polypeptide may exist as a single chain or associated chains. The polypeptides of the invention may be naturally or non-naturally glycosylated (i.e., the polypeptide has a glycosylation pattern that is different from the glycosylation pattern found in the corresponding naturally occurring polypeptide).

[0155] Pharmaceutical compositions and dosage forms

[0156] The present invention provides compositions, such as pharmaceutical compositions, comprising a CCR5 inhibitor as described herein. The terms "pharmaceutical composition" and "composition" as used herein can be used interchangeably as the context requires. The pharmaceutical compositions described herein can be administered to a subject in a therapeutically effective amount. "Therapeutically effective amount" as used herein refers to the amount of a composition or therapeutic agent that effectively provides a therapeutic, preventive or diagnostic benefit to a subject. In some embodiments, the therapeutically effective amount of a composition is an amount that can induce a clinical response in a subject in the treatment of a particular disease or condition. The determination of the therapeutically effective amount of a composition is fully within the capabilities of those skilled in the art, particularly in light of the disclosure provided herein. The therapeutically effective amount can vary according to a variety of factors such as the condition, weight, sex and age of the subject.

[0157] The pharmaceutical compositions provided herein may also include pharmaceutically acceptable carriers, excipients and / or stabilizers (see Remington: The Science and practice of Pharmacy 20th Ed., 2000, Lippincott Williams and Wilkins, Ed. KE Hoover). Acceptable carriers, excipients or stabilizers are non-toxic to recipients at dosages and concentrations, and may include buffers such as phosphates, citrates and other organic acids; antioxidants, including ascorbic acid and methionine; preservatives (e.g., octadecyldimethylbenzylammonium chloride); hexamethonium chloride; benzalkonium chloride, benzethonium chloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methyl or propyl parabens; paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine, or lysine; monosaccharides, disaccharides, and other carbohydrates, including glucose, mannose, or dextran; chelating agents such as EDTA; sugars such as sucrose, mannitol, trehalose, or sorbitol; salt-forming counterions such as sodium; metal complexes (e.g., Zn-protein complexes); and / or nonionic surfactants such as TWEEN®. TM 、PLURONICS TM or polyethylene glycol (PEG).

[0158] In some embodiments, the pharmaceutical compositions provided herein may include more than one CCR5 inhibitor described herein, for example, two or more CCR5 inhibitors. In some embodiments, the pharmaceutical compositions provided herein may include a second therapeutic agent known to have a therapeutic effect against cancer. The term "therapeutic agent" as used herein is any molecule, substance or compound that can provide therapeutic activity, response or effect in the treatment or prevention of a disease, disorder or condition, including diagnostic agents and prophylactic agents.

[0159] Pharmaceutical composition provided herein can be prepared into various pharmaceutical dosage forms, such as instant release, controlled release, sustained release or targeted drug delivery system. Commonly used dosage forms include, for example, solutions and suspensions, (micro) emulsions, ointments, gels, creams, pastes, foams, suppositories, ovules, implants, patches, liposomes, tablets, dragees, lozenges, soft shell or hard shell capsules, amorphous or crystalline powders, effervescent powders or tablets, aerosols and lyophilized preparations. According to the route of administration used, special devices may be needed to apply or apply dosage forms, such as syringes and needles, inhalers, pumps, injection pens, applicators, special bottles or other application devices that can also be implanted in vivo.

[0160] The pharmaceutical dosage forms provided herein can be prepared by any method well known in the art, for example, by conventional mixing, sieving, dissolving, melting, granulating, making dragees, tableting, suspending, extruding, spray drying, hydro-aeration, emulsifying, (nano / micro) encapsulation, embedding or lyophilization methods.

[0161] For the methods of the present invention, the CCR5 inhibitors, pharmaceutical compositions or dosage forms provided herein can be administered to a subject by conventional techniques, such as intravenous (as a bolus or by continuous infusion over a period of time), intramuscularly, transmucosally, intraperitoneally, intracerebrally, subcutaneously, intraarticularly, intrasynovially, intrathecally, nasally, orally, topically or by inhalation. Other suitable routes of administration may include intralesional or perilesional routes.

[0162] For example, for intravenous injection, if necessary, the pharmaceutical composition provided herein can be prepared in an aqueous solution, using a physiologically compatible buffer, including, for example, phosphate, histidine or citrate for adjusting the pH of the formulation, and a tonicity agent, such as sodium chloride or dextrose. For transmucosal or nasal administration, semisolid, liquid preparations or patches may be preferred, and may contain a penetration enhancer. Such permeabilizing agents are generally known in the art. For oral administration, the pharmaceutical composition provided herein can be formulated into a liquid or solid dosage form, and optionally with immediate or controlled release / slow release formulations. Suitable dosage forms for oral ingestion by a subject include tablets, capsules, pills, dragees, hard and soft shell capsules, liquids, gels, syrups, slurries, suspensions, and emulsions.

[0163] Solid oral dosage forms can be obtained using excipients, which may include inert diluents, fillers, disintegrants, binders (dry and wet), dissolution retardants, lubricants, glidants, antiadhesives, cation exchange resins, wetting agents, antioxidants, preservatives, colorants, sweeteners and flavorings. These excipients may be synthetic or natural sources. Examples of these excipients include cellulose derivatives, citric acid, dicalcium phosphate, gelatin, magnesium carbonate, magnesium lauryl sulfate / sodium, mannitol, polyethylene glycol, polyvinyl pyrrolidone, silicates, silicon dioxide, sodium benzoate, sorbitol, starch, stearic acid or its salts, carbohydrates (i.e., dextrose, sucrose, lactose, etc.), talcum, mucilage of tragacanth, vegetable oils (hydrogenated) and waxes. Ethanol and water may be used as granulation aids. In some cases, it may be necessary to coat the tablets with, for example, a film that masks odor, a gastric acid-resistant film or a delayed release film. Tablets are typically coated with natural and synthetic polymers in combination with colorants, sugars, and organic solvents or water to produce dragees. When capsules are preferred over tablets, the drug powder, suspension, or solution thereof may be delivered in compatible hard or soft shell capsules.

[0164] Suitable inert diluents include sodium carbonate and calcium carbonate, sodium phosphate and calcium phosphate and lactose. Corn starch and alginic acid are suitable disintegrants. Binders can include starch and gelatin. If a lubricant is present, it is typically magnesium stearate, stearic acid or talc. If desired, the tablet can be coated with a material such as glyceryl monostearate or glyceryl distearate to delay absorption in the gastrointestinal tract.

[0165] Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent and soft gelatin capsules in which the active ingredient is mixed with water or oil such as peanut oil, liquid paraffin or olive oil.

[0166] In some embodiments, the CCR5 inhibitors provided herein can be administered topically, through the skin or mucosa, for example, through a skin patch, a semisolid or liquid formulation, such as a gel, (micro) emulsion, an ointment, a solution, a (nano / micro) suspension or a foam. The penetration of the active ingredient into the skin or mucosa and subcutaneous tissue of the subject can be regulated, for example, using a penetration enhancer; appropriately selecting and combining lipophilic, hydrophilic and amphiphilic excipients, including water, organic solvents, waxes, oils, synthetic and natural polymers, surfactants, emulsifiers; by pH adjustment; and the use of complexing agents.

[0167] In some embodiments, CCR5 inhibitors provided herein can be administered by inhalation, or applied to the nose in the form of a solution, suspension, emulsion or a semisolid aerosol or atomizer from a pressurized package, usually using a propellant, such as a halocarbon derived from methane and ethane, carbon dioxide or any other suitable gas. For surface aerosols, hydrocarbons such as butane, isobutylene and pentane are useful. In the case of pressurized aerosols, a suitable dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges such as gelatin can be formulated for inhalers or insufflators. These usually contain a powder mixture of active ingredient and a suitable powder base such as lactose or starch.

[0168] Compositions prepared for parenteral administration by injection are usually sterile and can exist in unit dosage form, for example, in ampoule, syringe, injection pen, or in multi-dose container, the latter usually containing preservative. Pharmaceutical compositions suitable for parenteral administration can take the form of suspensions, solutions or emulsions such as in oily or aqueous vehicles, and can contain preparatons, such as buffers, tonicity agents, viscosity enhancers, surfactants, suspensions and dispersants, antioxidants, biocompatible polymers, chelating agents and preservatives. Depending on the injection site, the vehicle can contain water, synthetic or vegetable oils and / or organic cosolvents. In some cases, for example, using lyophilized products or concentrates, parenteral preparations will be reconstructed or diluted before administration. The storage formulations for the controlled release or sustained release of active agents can include injectable suspensions of nanometer / micron particles or nanometer / micron or non-micronized crystals. In addition to other substances well known in the art, polymers such as poly (lactic acid), poly (glycolic acid) or its copolymers can be used as controlled release / slow release matrix. Other depot-delivery systems are available in the form of implants and pumps that require an incision.

[0169] Suitable carriers for intravenous injection of CCR5 inhibitors provided herein are well known in the art, including aqueous solutions containing alkalis such as sodium hydroxide (to form ionized species), sucrose or sodium chloride as tonicity agents. Aqueous solutions can include buffers containing phosphate or histidine. Cosolvents such as polyethylene glycols can be added. These water-based systems are effective in terms of solvents and produce low toxicity when administered systemically. The ratio of the components of the solution system can be varied considerably without destroying solubility and toxicity characteristics. In addition, the components themselves can be changed. For example, low toxicity surfactants such as polysorbates or poloxamer can be used, polyethylene glycol or other cosolvents, biocompatible polymers such as polyvinyl pyrrolidone can also be added, and other sugars and polyols can replace dextrose.

[0170] Treatment Indications

[0171] The CCR5 inhibitors, pharmaceutical compositions and dosage forms provided herein can be applied to any situation in which it is desired to administer a therapeutic agent to a subject to treat or prevent cancer. "Individual" or "subject" as used herein is a mammal, such as a human. Mammals also include, but are not limited to, livestock animals, sports animals, pets, primates and horses.

[0172] As used herein, "treatment" or "treatment..." or "prevention" or "prevention..." refers to an approach for obtaining a beneficial or desired result. Beneficial or desired results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, lessening of the extent of a disease, stabilization of a disease state, prevention of the development of a disease, prevention of the spread of a disease, delay or slowing of the progression of a disease (e.g., inhibition), delay or slowing of the onset of a disease, conferring protective immunity against a pathogen, and amelioration or alleviation of a disease state. "Treatment" or "prevention" may also refer to prolonging a patient's survival beyond that which would be expected without treatment, and may also refer to temporarily inhibiting the progression of a disease or preventing the occurrence of a disease, such as by preventing an infection in a subject.

[0173] "Treatment" can be distinguished from "prevention" in that "treatment" generally occurs in a subject who already has a disease or condition or is known to have been exposed to an infectious agent, while "prevention" generally occurs in a subject who does not already have the disease or condition or is not known to have been exposed to an infectious agent. As will be appreciated, there may be overlap in treatment and prevention. For example, a subject may be "treated" for a disease while at the same time "preventing" the symptoms or progression of the disease.

[0174] As used herein, the term "cancer" refers to a condition in which cells proliferate at an abnormally high and poorly controlled or uncontrolled rate that exceeds and is out of tune with the rate of surrounding normal tissue. Cancer can be primary or metastatic. Cancer can spread from where it started to another part of the body. The original cancer is called a primary tumor. Cancer in another part of the body is called metastatic cancer.

[0175] Cancers that can be treated by the methods of the invention may be refractory or resistant to conventional treatments such as chemotherapy or radiotherapy. The term "refractory or resistant" refers to a situation where the cancer does not respond to treatment. The cancer may be resistant at the beginning of treatment, or may become resistant during treatment.

[0176] Specific examples of cancer include, but are not limited to, skin cancer, such as melanoma and basal cell carcinoma; lymph node cancer; breast cancer; cervical cancer; uterine cancer; gastrointestinal cancer, such as gastric (stomach) and gastrointestinal stromal tumors; lung cancer; ovarian cancer; prostate cancer; colon cancer; rectal cancer; oral cancer; brain cancer; head and neck cancer; pharyngeal cancer; thyroid cancer; testicular cancer; kidney cancer; pancreatic cancer; bone cancer; spleen cancer; liver cancer; bladder cancer; laryngeal cancer; nasal passage cancer; AIDS-related cancers; sarcomas, such as soft tissue sarcomas, liposarcoma, and osteosarcoma; and cancers of the blood and bone marrow, such as multiple myeloma, myeloproliferative disorders, and acute and chronic leukemias, such as lymphoblastic leukemia, myeloid leukemia, lymphocytic leukemia, and myeloid leukemia.

[0177] Other specific cancers include, but are not limited to, advanced malignancies, amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiple brain metastases, glioblastoma multiforme, glioblastoma, brain stem glioma, poor prognosis malignant brain tumors, malignant glioma, recurrent malignant glioma, anaplastic astrocytoma, anaplastic oligodendroglioma, neuroendocrine tumors, rectal adenocarcinoma, Dukes C&D colorectal cancer, unresectable colorectal cancer, metastatic hepatocellular carcinoma, Kaposi's sarcoma, nuclear acute myeloblastic leukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma, non-Hodgkin's lymphoma, peripheral T-cell lymphoma (including anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, and cutaneous T-cell lymphoma), cutaneous B-cell lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, small lymphocytic lymphoma, Castleman's disease, metastatic melanoma (localized melanoma, including but not limited to, ocular melanoma), malignant mesothelioma, malignant pleural effusion mesothelioma tumor syndrome, peritoneal carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneous vasculitis, Langerhans cell histiocytosis, leiomyosarcoma, fibrodysplasia ossificans progressiva, hormone-refractory prostate cancer, resected high-risk soft tissue sarcoma, unrescectabie hepatocellular carcinoma, Waldenstrom macroglobulinemia, smoldering myeloma, indolent myeloma, fallopian tube cancer, androgen-independent prostate cancer, androgen-dependent stage IV non-metastatic prostate cancer, hormone-insensitive prostate cancer, chemotherapy-insensitive prostate cancer, papillary thyroid carcinoma, follicular thyroid cancer, medullary thyroid carcinoma, and leiomyoma.

[0178] Cancers treatable by the methods of the invention may be characterized by tumor cells expressing CCR5 and / or solid tumors infiltrated by leukocytes expressing CCR5.

[0179] In a specific embodiment, the cancer is colorectal cancer. Histological types of colon cancer include the following: adenocarcinoma (most colon cancers), including mucinous (colloid) adenocarcinoma and signet ring adenocarcinoma; scirrhous tumors; and neuroendocrine (tumors with neuroendocrine differentiation generally have a worse prognosis than pure adenocarcinoma variants). The colorectal cancer treated by the methods of the present invention can be metastatic, refractory to chemotherapy or radiotherapy or both, or resistant to chemotherapy or radiotherapy or both.

[0180] In a specific embodiment, the cancer is breast cancer. Among all women with breast cancer, 5%-10% may have germline mutations of the BRCA1 and BRCA2 genes. It is estimated that the lifetime risk of women with BRCA1 and BRCA2 mutations developing breast cancer is 40% to 85%. The application of molecular profiles in breast cancer includes the following: estrogen receptor (ER) and progesterone receptor (PR) status detection; HER2 / neu receptor status detection; and gene profile detection by microarray analysis or reverse transcription-polymerase chain reaction (e.g., MammaPrint, Oncotype DX). Based on ER, PR and HER2 / neu results, breast cancer is classified as one of the following types: hormone receptor positive; HER2 / neu positive; and triple negative (ER, PR and HER2 / neu negative). ER, PR and HER2 status are important in determining prognosis and predicting responses to endocrine and HER2-directed treatments. For example, hormone receptor (ER and / or PR)-positive patients will receive hormone therapy; HER2 overexpression means the use of adjuvant trastuzumab, usually in combination with chemotherapy; and when HER2 overexpression and hormone receptors are absent (i.e., triple-negative breast cancer), adjuvant therapy relies on chemotherapy regimens, which can be combined with investigational targeted methods. Adjuvant therapy options may include the following: tamoxifen; aromatase inhibitor (AI) treatment; ovarian function suppression; and chemotherapy. Breast cancer treated by the methods of the present invention can be metastatic (e.g., breast cancer can metastasize to the lungs, liver, bones, or brain), refractory to chemotherapy or radiotherapy or both, or resistant to chemotherapy or radiotherapy or both.

[0181] In a specific embodiment, the cancer is lung cancer. The two main types of lung cancer are small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC); NSCLC accounts for approximately 85% of all lung cancer cases. SCLC includes small cell carcinoma and combined small cell carcinoma, i.e., SCLC combined with neoplastic squamous and / or glandular components. The most common types of NSCLC are squamous cell carcinoma, large cell carcinoma, and adenocarcinoma. Lung cancer treated by the methods of the present invention may be metastatic, refractory to chemotherapy or radiotherapy or both, or resistant to chemotherapy or radiotherapy or both. Metastatic sites in SCLC include liver, bone, brain, and lung. Metastatic sites in NSCLC include bone, lung, brain, liver, and adrenal glands.

[0182] In a specific embodiment, the cancer is prostate cancer. More than 95% of primary prostate cancers are adenocarcinomas. Prostate adenocarcinomas are usually multifocal and heterogeneous in differentiation patterns. Prostatic intraepithelial neoplasia ([PIN] benign non-invasive atypical epithelial cells within the acinus) is usually present in association with prostate adenocarcinoma. PIN is subdivided into low-grade and high-grade. High-grade forms can be precursors to adenocarcinomas. Studies have also estimated that within five years of diagnosis, 10-20% of men with prostate cancer will develop castration-resistant prostate cancer (CRPC), which further significantly reduces survival rates. Prostate cancer treated by the methods of the present invention can be metastatic, refractory to chemotherapy or radiotherapy or both, or resistant to chemotherapy or radiotherapy or both.

[0183] In a specific embodiment, the cancer is ovarian cancer. Ovarian cancer includes epithelial ovarian cancer, fallopian tube cancer (FTC) and primary peritoneal cancer (PPC). Epithelial ovarian cancer, fallopian tube cancer and primary peritoneal cancer can be histologically divided into serous cystoma, mucinous cystoma, endometrioid tumor (similar to adenocarcinoma in the endometrium) and clear cell (mesonephroid) tumor. Ovarian cancer treated by the method of the present invention can be metastatic, refractory to chemotherapy or radiotherapy or both or resistant to chemotherapy or radiotherapy or both.

[0184] In a specific embodiment, the cancer is pancreatic cancer.The pancreatic cancer treated by the methods of the invention may be metastatic, refractory or resistant to chemotherapy or radiotherapy or both.

[0185] In a specific embodiment, the cancer is esophageal cancer. Two histological types account for the main malignant esophageal neoplasms: adenocarcinoma and squamous cell carcinoma. Adenocarcinoma usually starts in the lower esophagus, and squamous cell carcinoma can develop throughout the esophagus. The esophageal cancer treated by the method of the present invention can be metastatic, refractory to chemotherapy or radiotherapy or both, or resistant to chemotherapy or radiotherapy or both.

[0186] In a specific embodiment, the cancer is gastric cancer. There are two main types of gastric adenocarcinoma, intestinal type and diffuse type. Intestinal type adenocarcinoma is highly differentiated, and cells tend to arrange themselves in tubular or glandular structures. The terms tubular, papillary and mucinous refer to various types of intestinal type adenocarcinoma. Adenosquamous carcinoma rarely occurs. Diffuse type adenocarcinoma is undifferentiated or poorly differentiated, and they lack glandular formation. Clinically, diffuse type adenocarcinoma can cause infiltration of the stomach wall (i.e., leather stomach). Some tumors can have mixed features of intestinal type and diffuse type. Gastric cancer treated by the method of the present invention can be metastatic, refractory to chemotherapy or radiotherapy or both, or resistant to chemotherapy or radiotherapy or both.

[0187] In a specific embodiment, the cancer is leukemia. Leukemia can be divided into acute leukemia or chronic leukemia. Leukemia can also be classified by the type of blood cells affected, i.e., lymphoblastic leukemia or lymphocytic leukemia, or myeloid leukemia or myeloid leukemia. The leukemia treated by the method of the present invention can be acute lymphoblastic leukemia (ALL). ALL is an aggressive leukemia characterized in that there are too many lymphoblasts or lymphocytes in the bone marrow and peripheral blood. The leukemia treated by the method of the present invention can be metastatic, refractory to chemotherapy or radiotherapy or both or resistant to chemotherapy or radiotherapy or both. It can spread to lymph nodes, spleen, liver, central nervous system (CNS) and other organs.

[0188] In a specific embodiment, the cancer is liver cancer. Malignant primary tumors of the liver are composed of two main cell types, which are hepatocellular carcinoma (90% of cases) and cholangiocarcinoma. The histological classification of liver tumors includes hepatocellular carcinoma (HCC), fibrolamellar variant of HCC, cholangiocarcinoma (intrahepatic bile duct carcinoma), mixed hepatocellular cholangiocarcinoma, undifferentiated tumors and hepatoblastoma. The liver cancer treated by the method of the present invention can be metastatic, refractory to chemotherapy or radiotherapy or both, or resistant to chemotherapy or radiotherapy or both. The sites of primary liver cancer metastasis include the lungs, portal vein and portal lymph nodes.

[0189] In some embodiments, treating cancer by the methods of the present invention can result in inhibition of cancer cell growth or proliferation. In some embodiments, treating cancer by the methods of the present invention can result in inhibition of cancer cell migration. In some embodiments, treating cancer by the methods of the present invention can result in inhibition of angiogenesis. In some embodiments, treating cancer by the methods of the present invention can result in reprogramming of immunoregulatory leukocytes.

[0190] According to some embodiments, the CCR5 inhibitor, pharmaceutical composition or dosage form provided herein is administered before the onset of cancer symptoms. According to some embodiments, the subject can be treated for a long time to prevent metastasis and damage caused therefrom. According to some embodiments, cancer is treated in patients who are resistant and / or insensitive to conventional treatments such as chemotherapy or radiotherapy. According to some embodiments, cancer symptoms are treated by the CCR5 inhibitor, pharmaceutical composition or dosage form provided herein.

[0191] The CCR5 inhibitors, pharmaceutical compositions and dosage forms provided herein can be applied by achieving any mode of its intended purpose. For example, the route of administration can be by oral, sublingual, buccal, surface, rectal, via inhalation, percutaneous, subcutaneous, intravenous, intraarterial or intramuscular, via intracardiac administration, intraosseous, intradermal, intraperitoneal, intracerebral, transmucosal, vaginal, intravitreal, epidermal, intraarticular, intravesical, intrathecal, periarticular or local. The dosage will depend on the age, health and weight of the subject, the type of treatment (if any) performed simultaneously, the frequency of treatment and the properties of the desired effect.

[0192] According to some embodiments, the CCR5 inhibitor provided herein can be administered orally, possibly in the form of tablets, capsules, powders, lozenges, soft gelatin capsules, syrups, liquid suspensions or lozenges. According to some embodiments, the CCR5 inhibitor provided herein can be administered in the form of parenteral formulations, such as subcutaneous intramuscular or intravenous administration. According to other embodiments, the CCR5 inhibitor provided herein can be administered by any suitable nasal cavity, pulmonary administration, topical administration or any suitable dermatological administration.

[0193] According to some embodiments, the CCR5 inhibitors provided herein can be administered with any suitable non-toxic pharmaceutical carrier. The carrier can be a gas, a solid or a liquid. According to some embodiments, the carrier is selected from saline solution, water, any suitable emulsion or dispersion or any combination thereof.

[0194] According to some embodiments, the CCR5 inhibitors provided herein can be administered together with any ingredients suitable for modulating the release of the CCR5 inhibitor from a dosage form comprising the CCR5 inhibitor. For example, a time-delaying material, such as an enteric-coated gelatin capsule, can be used.

[0195] According to some embodiments, in the method for treating cancer, the CCR5 inhibitor, pharmaceutical composition or dosage form provided herein can be administered together with any second active agent known to have therapeutic efficacy against cancer. The second active agent can be a macromolecule (e.g., a protein) or a small molecule (e.g., a synthetic inorganic, organometallic or organic molecule).

[0196] Examples of macromolecular active agents include, but are not limited to, hematopoietic growth factors, cytokines, and monoclonal and polyclonal antibodies. Specific examples of active agents are anti-CD40 monoclonal antibodies (e.g., SGN-40); checkpoint inhibitors (e.g., anti-CTLA4 antibodies, such as ipilimumab; anti-PD-1 antibodies, such as nivolumab and pembrolizumab; and anti-PD-L-1 antibodies, such as atezolizumab, avelumab, and durvalumab); histone deacetylase inhibitors (e.g., SAHA and LAQ 824); heat shock protein-90 inhibitors (e.g., 17-AAG); insulin-like growth factor-1 receptor kinase inhibitors; vascular endothelial growth factor receptor kinase inhibitors (e.g., PTK787); insulin growth factor receptor inhibitors; lysophosphatidic acid acyltransferase inhibitors; IkB kinase inhibitors; p38 MAPK inhibitors; EGFR inhibitors (e.g., gefitinib and erlotinib hydrochloride); HCL)) HER-2 antibodies (eg, trastuzumab and pertuzumab (Omnitarg TM )); VEGFR antibodies (such as bevacizumab (Avastin TM )); VEGFR inhibitors (e.g. flk-1 specific kinase inhibitors SU5416 and ptk787 / zk222584); PI3K inhibitors (e.g. wortmannin); C-Met inhibitors (e.g. PHA 665752); monoclonal antibodies (e.g. rituximab) Tositumomab Edratumomab and G250); and anti-TNF-α antibodies. Examples of small molecule active agents include, but are not limited to, anticancer agents and antibiotics (eg, clarithromycin).

[0197] The specific second active compound that can be used in combination with the CCR5 inhibitors provided herein will vary depending upon the specific indication to be treated, prevented or managed.

[0198] For example, the second active agent includes, but is not limited to, semaxanib; cyclosporin; etanercept; doxycycline; bortezomib; lapatinib; acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantron acetate; acetate; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; binafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium sodium; bropirimine; busulfan; cactinomycin; calusterone; caracemide; carbetimer; carboplatin; carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib; chlorambucil; cirolemycin; cisplatin; cladribine; crisnatolmesylate; cyclophosphamide; cytarabine; dacarbazine; dactinomycin;daunorubicin hydrochloride, decitabine, dexormaplatin, dezaguanine, dezaguanine mesylate, diaziquone, docetaxel, doxorubicin, doxorubicin hydrochloride, droloxifene, droloxifene citrate, dromostanolone propionate, duazomycin, edatrexate, eflomithine hydrochloride hydrochloride; elsamitrucin; enloplatin; enpromate; epipropidine; epirubicin hydrochloride; erbulozole; esorubicin hydrochloride; estramustine; estramustine phosphate sodium; etanidazole; etoposide; etoposide phosphate; etoprine; fadrozole hydrochloride; fazarabine; fenretinide; floxuridine; fludarabine phosphate phosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium; gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolide acetate; liarozole hydrochloride; lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol; maytansine; mechlorethamine hydrochloride; megestrol acetate; melengestrol acetate; melphalan; menogaril; mercaptopurine; methotrexate; methotrexate sodium sodium; metoprine; meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin; pentamustine; peplomycin sulfate sulfate; perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine; simtrazene; sparrosate sodium; sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium sodium; taxotere; tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone; testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine; toremifene citrate; trestolone acetate; triciribine phosphate; trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole hydrochloride hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin; vinblastine sulfate; vincristine sulfate; vindesine; vindesine sulfate;vinepidine sulfate; vinglycinate sulfate; vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicin hydrochloride.

[0199] Other second doses include, but are not limited to: 20-epi-1,25-dihydroxyvitamin D3 (20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G G); antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine; atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol; batimastat; BCR / ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitors; bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine; calcipotriol; calphostin C; camptothecin derivatives derivatives; capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRest M3; CARN700; cartilage derived inhibitor; carzelesin; casein kinase inhibitor (ICOS); castanospermine; cecropin B; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine; clomifene analogs; clotrimazole; collismycin A; collismycin B; combretastatin A4; combretastatin analogs; conagenin; crambescidin 816; clotrimazole; cryptophycin 8; cryptophycin A derivatives; curacin A; cyclopentanthraquinones; cycloplatam; cypemycin;cytarabine ocfosfate; cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone; didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine; dihydrotaxol, 9-dihydropaclitaxel; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene; dronabinol; duocarmycin SA SA; ebselen; ecomustine; edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride; estramustine analogues; estrogen agonists; estrogen antagonists; etanidazole; etoposide phosphate phosphate); exemestane; fadrozole; fazarabine; fenretinide; filgrastim; finasteride; flavopiridol; flezlastine; fluasterone; fludarabine; fluorodaunorunicin hydrochloride;forfenimex; formestane; fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene; idramantone; ilmofosine; ilomastat; imatinib; Imiquimod; immunostimulant peptides; insulin-like growth factor-1 receptor inhibitor; interferon agonists; interferons; interleukins; iobenguane; iododoxorubicin; 4-ipomeanol; iroplact; irsogladine; isobengazole; isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinan sulfate sulfate; leptolstatin; letrozole; leukemia inhibitory factor; interferon alpha; leuprolide + estrogen + progesterone; leuprorelin; levamisole; liarozole; linear polyamine analogs; lipophilic disaccharide peptides; lipophilic platinum compounds; lissoclinamide 7; lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone; loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; cleaved peptides; maitansine; mannostatin A; marimastat; masoprocol; maspin; matrix lytic factor (matrilysin) inhibitor; matrix metalloproteinase inhibitor; menogaril; merbarone; meterelin; methionine enzyme; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mitoguazone; mitolactol; mitomycin analog; mitonafide; mitotoxin fibroblast growth factor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, human chorionic gonadotropin; monophosphoryl lipid A+ mycobacterial cell wall sk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterial cell wall extract; myriaporone; N-acetyldinaline; N-substituted benzamide benzamides; nafarelin; nagrestip; naloxone + pentazocine; napavin; naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidants; nitrullyn; oblimersen, ); O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone; ondansetron; oracin; oral cytokine inducers; ormaplatin; osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogs; paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfate sodium sulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillyl alcohol; phenazinomycin; phenylacetate; phosphatase inhibitors; picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetin A; placetin B; plasminogen activator inhibitors; platinum complex; platinum compounds; platinum-triamine complex; porfimer sodium; porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2 J2); proteasome inhibitors; protein A-based immunomodulators; protein kinase C inhibitors; protein kinase C inhibitors; microalgal; protein tyrosine phosphatase inhibitors; purine nucleoside phosphorylase inhibitors; hydroxyrubiin (purpurins); pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonist; raltitrexed; ramosetron; ras farnesyltransferase inhibitor; ras inhibitor; ras-GAP inhibitor; retelliptine demethylated; rhenium-186 etidronate; rhizoxin; ribozyme; R2 retinamide; rohitukine; romurtide; roquinimex; rubiginone Bl; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim; Sdi1 mimetic; semustine; senescence derived inhibitor 1 1); sense oligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane; sodium borocaptate; sodium phenylacetate; solverol; somatomedin binding protein; sonermin; sparrosic acid; spicamycin D; spiromustine; splenopentin; spongistatin 1 1); squalamine; stipiamide; stromelysin inhibitors; sulfmosine; superactive vasoactive intestinal peptide antagonists; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur; tellurapyrylium; telomerase inhibitors; temoporfin; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin; toremifene; translation inhibitor; retinoic acid; triacetyluridine; triciribine; trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenital sinus-derived growth inhibitor; urokinase receptor antagonist; vapreotide; variolin B; velaresol; veramine; verdin; verteporfin; vinorelbine; vinxaltine; vitaminin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer. ;

[0200] Specific second active agents include, but are not limited to, 2-methoxyestradiol, telomestatin, apoptosis inducers in multiple myeloma cells (e.g., TRAIL), statins, semaxanib, cyclosporine, etanercept, doxycycline, bortezomib, oblimexane (Genasense 1Remicade, docetaxel, celecoxib, melphalan, dexamethasone Steroids, gemcitabine, cisplatin, temozolomide, etoposide, cyclophosphamide, temozolomide, carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate, taxol, taxotere, fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alfa, pegylated interferon alfa (e.g., PEG INTRON-A), capecitabine, cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin, cytarabine, doxetaxel, paclitaxel, vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin, busulfan, prednisone, bisphosphonates, arsenic trioxide, vincristine, doxorubicin Paclitaxel, ganciclovir, adriamycin, estramustine sodium phosphate Sulindac and etoposide.

[0201] Specific second active agents used to treat colorectal cancer include, but are not limited to, regorafenib, ziv-aflibercept, and tipiracil / trifluridine; romidepsin for the treatment of peripheral T-cell lymphoma and cutaneous T-cell lymphoma; brentuximab Vedotin is used to treat Hodgkin's lymphoma and anaplastic large cell lymphoma; pixantrone and rituximab are used to treat non-Hodgkin's lymphoma; idelalisib is used to treat chronic lymphocytic leukemia, follicular lymphoma, and small lymphocytic lymphoma; mogamulizumab is used to treat angioimmunoblastic T-cell lymphoma; belinostat is used to treat peripheral T-cell lymphoma; ibrutinib is used to treat mantle cell lymphoma and Waldenstrom's macroglobulinemia; bortezomib is used to treat mantle cell lymphoma; chidamide is used to treat peripheral T-cell lymphoma; nivolumab is used to treat Hodgkin's lymphoma; siltuximab is used to treat uximab for Castleman disease; olaparib, bevacizumab, and rucaparib for ovarian cancer; bevacizumab for cervical cancer; vismodegib and sonidegib for basal cell carcinoma; ruxolitinib for myeloproliferative disorders; ramucirumab for gastric cancer; carfilzomib, pomalidomide, daratumumab, ixazomib, panobinostat, and elotuzumab for multiple myeloma; abiraterone acetate for acetate, enzalutamide, and radium-223dichloride for the treatment of prostate cancer; mifamurtide, trabectedin, eribulin, and olaratumab for the treatment of sarcomas;Crizotinib, afatinib, alectinib, ceritinib, ramucirumab, nivolumab, pembrolizumab, necitumumab, osimertinib, gefitinib, and atezolizumab are used to treat lung cancer; bosutinib, omacetaxine mepesuccinate and radotinib for chronic myeloid leukemia; obinutuzumab for chronic lymphocytic leukemia and follicular lymphoma; ponatinib for chronic myeloid leukemia and acute lymphoblastic leukemia; blinatumomab for acute lymphoblastic leukemia; ibrutinib, ofatumumab, and venetoclax for chronic lymphocytic leukemia. leukemia; regorafenib for gastrointestinal stromal tumors; vandetanib, cabozantinib, and lenvatinib for thyroid cancer; dinutuximab for neuroblastoma; atezolizumab for bladder cancer; nivolumab and pembrolizumab for head and neck cancer; irinotecan liposomal liposome) for pancreatic cancer; axitinib, nivolumab, lenvatinib, and cabozantinib for kidney cancer; pertuzumab, ado-trastuzumab emtansine, and palbociclib for breast cancer; and ipilimumab, vemurafenib, trametinib, dabrafenib, pembrolizumab, nivolumab, cobimetinib, and T-Vec for melanoma.

[0202] As will be appreciated by those skilled in the art, the amount of a CCR5 inhibitor provided herein administered according to the methods of the invention will vary depending upon the route of administration, excipient usage, and the possibility of co-administration with other therapeutic treatments including the use of other therapeutic agents.

[0203] According to some embodiments, the CCR5 inhibitor described herein can be administered in an amount of about 0.1 mg to about 400 mg. According to some embodiments, the CCR5 inhibitor described herein can be administered in an amount of about 1 mg to about 100 mg. According to some embodiments, the CCR5 inhibitor described herein can be administered in an amount of about 4 mg to about 40 mg.

[0204] According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 300 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 200 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 100 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 95 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 90 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 85 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 80 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 75 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 70 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 65 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 60 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 55 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 50 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 45 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 40 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 35 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 30 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 25 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 20 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 15 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 10 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 5 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 0.1 mg to about 1 mg.

[0205] According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 400 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 300 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 200 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 95 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 90 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 85 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 80 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 75 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 70 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 65 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 60 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 55 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 50 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 45 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 40 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 35 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 30 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 25 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 20 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 15 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 10 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 1 mg to about 5 mg.

[0206] According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 400 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 300 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 200 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 100 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 95 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 90 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 85 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 80 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 75 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 70 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 65 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 60 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 55 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 50 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 45 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 40 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 35 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 30 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 25 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 20 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 15 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 5 mg to about 10 mg.

[0207] According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 400 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 300 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 200 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 100 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 95 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 90 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 85 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 80 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 75 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 70 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 65 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 60 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 55 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 50 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 45 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 40 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 35 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 30 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 25 mg. According to some embodiments, the CCR5 inhibitor provided herein can be administered in an amount of about 10 mg to about 20 mg. According to some embodiments, the CCR5 inhibitors provided herein may be administered in an amount of about 10 mg to about 15 mg.

[0208] According to some embodiments, the CCR5 inhibitors provided herein can be administered in an amount of about 400 mg, about 350 mg, about 300 mg, about 250 mg, about 200 mg, about 150 mg, about 100 mg, about 95 mg, about 90 mg, about 85 mg, about 80 mg, about 75 mg, about 70 mg, about 65 mg, about 60 mg, about 55 mg, about 50 mg, about 45 mg, about 40 mg, about 35 mg, about 30 mg, about 25 mg, about 20 mg, about 19 mg, about 18 mg, about 17 mg, about 16 mg, about 15 mg, about 14 mg, about 13 mg, about 12 mg, about 11 mg, about 10 mg, about 9 mg, about 8 mg, about 7 mg, about 6 mg, about 5 mg, about 4 mg, about 3 mg, about 2 mg, about 1 mg, about 0.5 mg or about 0.1 mg.

[0209] According to some embodiments, the CCR5 inhibitors, pharmaceutical compositions or dosage forms provided herein can be administered once a day or in 2, 3, 4, 5 or 6 equal doses per day. According to other embodiments, the CCR5 inhibitors, pharmaceutical compositions or dosage forms provided herein can be administered twice, three times, four times, five times, six times or more per day.

[0210] According to some embodiments, the CCR5 inhibitors, pharmaceutical compositions or dosage forms provided herein can be administered for a long time. According to some embodiments, the CCR5 inhibitors, pharmaceutical compositions or dosage forms provided herein can be administered for one, two, three, four, five, six or seven days; one, two, three or four weeks; one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve months or longer.

[0211] For long-term administration, the CCR5 inhibitors, pharmaceutical compositions or dosage forms provided herein can be administered daily, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months or once every three months.

[0212] In some embodiments, a CCR5 inhibitor, a pharmaceutical composition or a dosage form provided herein is administered or provided, and it is separately, sequentially or simultaneously co-administered with other pharmacologically active compounds. In some embodiments, a CCR5 inhibitor, a pharmaceutical composition or a dosage form provided herein is used in combination with other pharmacologically active compounds. Alternatively, the therapeutic administration of a CCR5 inhibitor, a pharmaceutical composition or a dosage form provided herein may be spaced a few minutes to a few weeks before or after treatment with other pharmacologically active compounds. In the embodiments in which a CCR5 inhibitor, a pharmaceutical composition or a dosage form provided herein and other pharmacologically active compounds are separately administered, those skilled in the art will generally ensure that no significant time has passed between each delivery, so that a CCR5 inhibitor, a pharmaceutical composition or a dosage form provided herein and a pharmacologically active compound will still be able to produce a favorable combination effect on the object. In this case, it can be expected that those skilled in the art can be within about 12-24 hours apart from each other, more preferably, within about 6-12 hours apart from each other, and two forms are administered. In some cases, it may be desirable to extend the time period of administration significantly, with days (2, 3, 4, 5, 6, or 7) to weeks (1, 2, 3, 4, 5, 6, 7, or 8) passing between administrations.

[0213] The CCR5 inhibitors, pharmaceutical compositions or dosage forms described herein can be administered until a subject in need thereof no longer requires treatment, prevention or amelioration of cancer.

[0214] However, it should be understood that the specific dosage and treatment regimen for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination and the judgment of the treating physician and the severity of the specific condition being treated. The amount of the CCR5 inhibitor may also depend on the therapeutic or prophylactic agent (if any) co-administered with the CCR5 inhibitor.

[0215] Implementation

[0216] Specific embodiments of the present invention include but are not limited to the following:

[0217] 1. A method for treating cancer, the method comprising administering to a subject a CCR5 inhibitor, wherein the CCR5 inhibitor comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises a signature sequence QGP[P or L], and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1.

[0218] 2. The method of embodiment 1, wherein the CCR5 inhibitor inhibits HIV entry into cells, and the CCR5 inhibitor is selective for CCR5 compared to CCR1 and CCR3.

[0219] 3. A method as described in embodiment 1 or 2, wherein the CCR5 inhibitor only inhibits a subset of the CCR5 intracellular signaling pathway.

[0220] 4. A method as described in any one of embodiments 1-3, wherein the CCR5 inhibitor inhibits or reduces the inflammatory effects of CCR5, for example, when tested at a concentration of 300 nM in a calcium flux signaling assay, resulting in a signaling response that is 30% or less of the maximum response (Emax) elicited by PSC-RANTES.

[0221] 5. A method as described in any one of embodiments 1-4, wherein the CCR5 inhibitor binds to CCR5 in both G protein-coupled and uncoupled conformations.

[0222] 6. A method as described in any one of embodiments 1-5, wherein the CCR5 inhibitor does not induce CCR5 internalization.

[0223] 7. The method of embodiment 6, wherein the CCR5 inhibitor results in 20% or less receptor cryptic activity as measured by a CCR5 surface downregulation assay.

[0224] 8. A method according to embodiment 1, wherein the characteristic sequence is QGP[P or L][L or G or S or M][M or D or S or Q or G].

[0225] 9. A method according to embodiment 1, wherein the characteristic sequence is QGP[P or L][L or G][M or D or S].

[0226] 10. The method according to embodiment 1, wherein the signature sequence is QGP[P or L][L or G or S or M][M or D or S or Q or G]XX[Q or G or L or A or T or S]X, wherein X represents any natural or modified amino acid.

[0227] 11. The method according to embodiment 1, wherein the signature sequence is QGP[P or L][L or G][M or D or S]XX[Q or G or L]X, wherein X represents any natural or modified amino acid.

[0228] 12. A method according to embodiment 1, wherein the characteristic sequence is QGP[P or L]LM or QGPPG[D or S].

[0229] 13. A method according to embodiment 1, wherein the characteristic sequence is QGPPLM or QGPPGD.

[0230] 14. A method according to embodiment 1, wherein the signature sequence is QGP[P or L][L or M][M or Q][A or W or G or Q or N]X[Q or G or L][S or V or T or G], wherein X represents any natural or modified amino acid.

[0231] 15. A method according to embodiment 1, wherein the characteristic sequence is QGP[P or L][L or M][M or Q][A or W or G or Q or N][L or T or M or S or G or Q or R or Y][Q or G or L][S or V or T or G].

[0232] 16. A method according to embodiment 1, wherein the characteristic sequence is QGP[P or L]LM[A or W][L or T or M][Q or G][S or V or T or G].

[0233] 17. A method according to embodiment 1, wherein the characteristic sequence is QGPPLM[A or W][L or T or M][Q or G][S or V or T or G].

[0234] 18. A method according to embodiment 1, wherein the signature sequence is QGPP[G or L][M or Q]XX[Q or S][S or V], wherein X represents any natural or modified amino acid.

[0235] 19. A method according to embodiment 1, wherein the characteristic sequence is QGPP[G or L][M or Q][S or G or W or A or T][L or F or T or S or G or Y][Q or S][S or V].

[0236] 20. A method according to embodiment 1, wherein the signature sequence is selected from the group consisting of QGPPLMALQS (SEQ ID NO: 2), QGPPLMWMQV (SEQ ID NO: 3), QGPPLMWLQV (SEQ ID NO: 4), QGPPLMWTQS (SEQ ID NO: 5), QGPPLMWLQT (SEQ ID NO: 6), QGPPLMWTQV (SEQ ID NO: 7), QGPPLMWMQS (SEQ ID NO: 8), QGPPLMATQS (SEQ ID NO: 9), QGPPLMWLQS (SEQ ID NO: 10), QGPPLMALQV (SEQ ID NO: 11), QGPPLMWLGG (SEQ ID NO: 12), QGPPLMWRGS (SEQ ID NO: 13), QGPLLMWLQV (SEQ ID NO: 14), QGPPLMQTTP (SEQ ID NO: 15), QGPPLSWLQV (SEQ ID NO: 30), QGPPLSWLQS (SEQ ID NO: 31). NO:31), QGPPGQWSQV (SEQ ID NO:32), QGPPMMAGLS (SEQ ID NO:33), QGPPLSWQQS (SEQ ID NO:34), QGPPGMWSQS (SEQ ID NO:35), QGPPLQWRQS (SEQ ID NO:36), QGPPLMGTQS (SEQ ID NO:37), QGPPLMQLQV (SEQ ID NO:38), QGPPLSWSQV (SEQ ID NO:39), QGPPMSWSQS (SEQ ID NO:40), QGPPLMNLQV (SEQ ID NO:41), QGPPMSAYQV (SEQ ID NO:42) and QGPPMQGGLS (SEQ ID NO:43).

[0237] 21. A method according to embodiment 1, wherein the signature sequence is selected from QGPPLMALQS (SEQ ID NO:2), QGPPLMWMQV (SEQ ID NO:3), QGPPLMWLQV (SEQ ID NO:4), QGPPLMWTQS (SEQ ID NO:5), QGPPLMWLQT (SEQ ID NO:6), QGPPLMWTQV (SEQ ID NO:7), QGPPLMWMQS (SEQ ID NO:8), QGPPLMATQS (SEQ ID NO:9), QGPPLMWLQS (SEQ ID NO:10), QGPPLMALQV (SEQ ID NO:11), QGPPLMWLGG (SEQ ID NO:12), QGPPLMWRGS (SEQ ID NO:13), QGPLLMWLQV (SEQ ID NO:14) and QGPPLMQTTP (SEQ ID NO:15).

[0238] 22. A method according to embodiment 1, wherein the characteristic sequence is QGPPLMATQS (SEQ ID NO: 9).

[0239] 23. The method according to any one of embodiments 1-22, wherein the signature sequence is located at the extreme N-terminus.

[0240] 24. A method according to any one of embodiments 1-23, wherein the C-terminal portion is identical to SEQ ID NO: 1.

[0241] 25. A method according to any one of embodiments 1-24, wherein the cancer is colorectal cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, pancreatic cancer, esophageal cancer, gastric cancer, liver cancer or leukemia.

[0242] 26. The method of any one of embodiments 1-25, wherein the cancer is colorectal cancer.

[0243] 27. The method of any one of embodiments 1-25, wherein the cancer is breast cancer.

[0244] 28. The method of any one of embodiments 1-25, wherein the cancer is lung cancer.

[0245] 29. The method of any one of embodiments 1-25, wherein the cancer is prostate cancer.

[0246] 30. The method of any one of embodiments 1-25, wherein the cancer is ovarian cancer.

[0247] 31. The method of any one of embodiments 1-25, wherein the cancer is pancreatic cancer.

[0248] 32. The method of any one of embodiments 1-25, wherein the cancer is esophageal cancer.

[0249] 33. The method of any one of embodiments 1-25, wherein the cancer is gastric cancer.

[0250] 34. The method of any one of embodiments 1-25, wherein the cancer is liver cancer.

[0251] 35. The method of any one of embodiments 1-25, wherein the cancer is leukemia.

[0252] 36. The method of embodiment 35, wherein the cancer is acute lymphoblastic leukemia (ALL).

[0253] 37. The method of any one of embodiments 1-36, wherein the cancer is metastatic.

[0254] 38. A method according to any one of embodiments 1-36, wherein the cancer is refractory to chemotherapy or radiotherapy and / or resistant to chemotherapy or radiotherapy.

[0255] 39. The method of embodiment 37, wherein the cancer is refractory and resistant to chemotherapy or radiotherapy.

[0256] 40. The method of any one of embodiments 1-39, wherein the CCR5 inhibitor is administered with a second active agent.

[0257] 41. The method of embodiment 40, wherein the second active agent has therapeutic efficacy against cancer.

[0258] 42. The method of any one of embodiments 1-41, wherein the CCR inhibitor is administered before the onset of cancer symptoms.

[0259] 43. The method of any one of embodiments 1-42, wherein the CCR5 inhibitor is administered orally, sublingually, buccally, topically, rectally, via inhalation, transdermally, subcutaneously, intravenously, intraarterially or intramuscularly, via intracardiac administration, intraosseously, intradermally, intraperitoneally, intracerebrally, transmucosally, vaginally, intravitreally, epidermally, intraarticularly, intravesically, intrathecally, periarticularly or locally.

[0260] 44. The method according to any one of embodiments 1-43, wherein the CCR5 inhibitor is administered intravenously, orally or via inhalation.

[0261] 45. The method according to any one of embodiments 1-44, wherein the CCR5 inhibitor is administered intravenously, for example via an injectable controlled release depot device.

[0262] 46. ​​The method according to any one of embodiments 1-45, wherein the CCR5 inhibitor is administered together with a pharmaceutical carrier.

[0263] 47. The method of any one of embodiments 1-46, wherein the CCR5 inhibitor is administered in an amount of about 0.1 mg to about 400 mg.

[0264] 48. The method of embodiment 47, wherein the CCR5 inhibitor is administered in an amount of about 1 mg.

[0265] 49. The method of embodiment 47, wherein the CCR5 inhibitor is administered in an amount of about 2 mg.

[0266] 50. The method of embodiment 47, wherein the CCR5 inhibitor is administered in an amount of about 3 mg.

[0267] 51. The method of embodiment 47, wherein the CCR5 inhibitor is administered in an amount of about 5 mg.

[0268] 52. The method of embodiment 47, wherein the CCR5 inhibitor is administered in an amount of about 10 mg.

[0269] 53. The method of embodiment 47, wherein the CCR5 inhibitor is administered in an amount of about 20 mg.

[0270] 54. The method of embodiment 47, wherein the CCR5 inhibitor is administered in an amount of about 40 mg.

[0271] 55. The method according to any one of embodiments 1-54, wherein the CCR5 inhibitor is administered once a day or divided into 2, 3, 4, 5 or 6 equal doses per day.

[0272] 56. The method according to any one of embodiments 1-55, wherein the CCR5 inhibitor is administered chronically.

[0273] 57. A method according to embodiment 56, wherein the CCR5 inhibitor is administered for one, two, three, four, five, six or seven days; for one, two, three or four weeks; for about one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve months or longer.

[0274] 58. The method of embodiment 57, wherein the CCR5 inhibitor is administered for 24 weeks or longer.

[0275] 59. The method of embodiment 58, wherein the CCR5 inhibitor is administered for 28 weeks or longer.

[0276] 60. The method of any one of embodiments 56-59, wherein the CCR5 inhibitor is administered daily, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months, or once every three months.

[0277] 61. The method of embodiment 60, wherein the CCR5 inhibitor is administered daily.

[0278] 62. The method of embodiment 60, wherein the CCR5 inhibitor is administered once a week.

[0279] 63. The method according to any one of embodiments 1-61, wherein the CCR5 inhibitor is administered or provided separately, sequentially or simultaneously in combination with other pharmacologically active compounds.

[0280] 64. Use of a CCR5 inhibitor for treating cancer, wherein the CCR5 inhibitor comprises an N-terminal portion and a C-terminal portion, wherein the N-terminal portion comprises the characteristic sequence QGP[P or L], and the amino acid sequence of the C-terminal portion is at least 70% identical to SEQ ID NO: 1.

[0281] 65. The use according to embodiment 64, wherein the CCR5 inhibitor inhibits HIV entry into cells, and the CCR5 inhibitor is selective for CCR5 compared to CCR1 and CCR3.

[0282] 66. The use according to embodiment 64 or 65, wherein the CCR5 inhibitor inhibits only a subset of the CCR5 intracellular signaling pathway.

[0283] 67. The use as described in any one of embodiments 64-66, wherein the CCR5 inhibitor inhibits or reduces the inflammatory effects of CCR5, for example, when tested at a concentration of 300 nM in a calcium flux signaling assay, resulting in a signaling response that is 30% or less of the maximum response (Emax) elicited by PSC-RANTES.

[0284] 68. The use according to any one of embodiments 64-67, wherein the CCR5 inhibitor binds to CCR5 in both G protein-coupled and uncoupled conformations.

[0285] 69. The use according to any one of embodiments 64-68, wherein the CCR5 inhibitor does not induce CCR5 internalization.

[0286] 70. The use according to embodiment 69, wherein the CCR5 inhibitor results in 20% or less receptor cryptic activity as measured by a CCR5 surface downregulation assay.

[0287] 71. The use according to embodiment 64, wherein the signature sequence is QGP[P or L][L or G or S or M][M or D or S or Q or G].

[0288] 72. The use according to embodiment 64, wherein the signature sequence is QGP[P or L][L or G][M or D or S].

[0289] 73. The use according to embodiment 64, wherein the signature sequence is QGP[P or L][L or G or S or M][M or D or S or Q or G]XX[Q or G or L or A or T or S]X, wherein X represents any natural or modified amino acid.

[0290] 74. The use according to embodiment 64, wherein the signature sequence is QGP[P or L][L or G][M or D or S]XX[Q or G or L]X, wherein X represents any natural or modified amino acid.

[0291] 75. The use according to embodiment 64, wherein the signature sequence is QGP[P or L]LM or QGPPG[D or S].

[0292] 76. The use according to embodiment 64, wherein the signature sequence is QGPPLM or QGPPGD.

[0293] 77. The use according to embodiment 64, wherein the signature sequence is QGP[P or L][L or M][M or Q][A or W or G or Q or N]X[Q or G or L][S or V or T or G], wherein X represents any natural or modified amino acid.

[0294] 78. The use according to embodiment 64, wherein the signature sequence is QGP[P or L][L or M][M or Q][A or W or G or Q or N][L or T or M or S or G or Q or R or Y][Q or G or L][S or V or T or G].

[0295] 79. The use according to embodiment 64, wherein the signature sequence is QGP[P or L]LM[A or W][L or T or M][Q or G][S or V or T or G].

[0296] 80. The use according to embodiment 64, wherein the signature sequence is QGPPLM[A or W][L or T or M][Q or G][S or V or T or G].

[0297] 81. The use according to embodiment 64, wherein the signature sequence is QGPP[G or L][M or Q]XX[Q or S][S or V], wherein X represents any natural or modified amino acid.

[0298] 82. The use according to embodiment 64, wherein the signature sequence is QGPP[G or L][M or Q][S or G or W or A or T][L or F or T or S or G or Y][Q or S][S or V].

[0299] 83. The use according to embodiment 64, wherein the signature sequence is selected from QGPPLMALQS (SEQ ID NO: 2), QGPPLMWMQV (SEQ ID NO: 3), QGPPLMWLQV (SEQ ID NO: 4), QGPPLMWTQS (SEQ ID NO: 5), QGPPLMWLQT (SEQ ID NO: 6), QGPPLMWTQV (SEQ ID NO: 7), QGPPLMWMQS (SEQ ID NO: 8), QGPPLMATQS (SEQ ID NO: 9), QGPPLMWLQS (SEQ ID NO: 10), QGPPLMALQV (SEQ ID NO: 11), QGPPLMWLGG (SEQ ID NO: 12), QGPPLMWRGS (SEQ ID NO: 13), QGPLLMWLQV (SEQ ID NO: 14), QGPPLMQTTP (SEQ ID NO: 15), QGPPLSWLQV (SEQ ID NO: 30), QGPPLSWLQS (SEQ ID NO: 31). NO:31), QGPPGQWSQV (SEQ ID NO:32), QGPPMMAGLS (SEQ ID NO:33), QGPPLSWQQS (SEQ ID NO:34), QGPPGMWSQS (SEQ ID NO:35), QGPPLQWRQS (SEQ ID NO:36), QGPPLMGTQS (SEQ ID NO:37), QGPPLMQLQV (SEQ ID NO:38), QGPPLSWSQV (SEQ ID NO:39), QGPPMSWSQS (SEQ ID NO:40), QGPPLMNLQV (SEQ ID NO:41), QGPPMSAYQV (SEQ ID NO:42) and QGPPMQGGLS (SEQ ID NO:43).

[0300] 84. The use according to embodiment 64, wherein the signature sequence is selected from QGPPLMALQS (SEQ ID NO: 2), QGPPLMWMQV (SEQ ID NO: 3), QGPPLMWLQV (SEQ ID NO: 4), QGPPLMWTQS (SEQ ID NO: 5), QGPPLMWLQT (SEQ ID NO: 6), QGPPLMWTQV (SEQ ID NO: 7), QGPPLMWMQS (SEQ ID NO: 8), QGPPLMATQS (SEQ ID NO: 9), QGPPLMWLQS (SEQ ID NO: 10), QGPPLMALQV (SEQ ID NO: 11), QGPPLMWLGG (SEQ ID NO: 12), QGPPLMWRGS (SEQ ID NO: 13), QGPLLMWLQV (SEQ ID NO: 14) and QGPPLMQTTP (SEQ ID NO: 15).

[0301] 85. The use according to embodiment 64, wherein the signature sequence is QGPPLMATQS (SEQ ID NO: 9).

[0302] 86. The use according to any one of embodiments 64-85, wherein the characteristic sequence is located at the most N-terminal end.

[0303] 87. The use according to any one of embodiments 64-86, wherein the C-terminal portion is identical to SEQ ID NO: 1.

[0304] 88. The use according to any one of embodiments 64-87, wherein the cancer is colorectal cancer, breast cancer, lung cancer, prostate cancer, ovarian cancer, pancreatic cancer, esophageal cancer, gastric cancer, liver cancer or leukemia.

[0305] 89. The use according to any one of embodiments 64-88, wherein the cancer is colorectal cancer.

[0306] 90. The use according to any one of embodiments 64-88, wherein the cancer is breast cancer.

[0307] 91. The use according to any one of embodiments 64-88, wherein the cancer is lung cancer.

[0308] 92. The use according to any one of embodiments 64-88, wherein the cancer is prostate cancer.

[0309] 93. The use according to any one of embodiments 64-88, wherein the cancer is ovarian cancer.

[0310] 94. The use according to any one of embodiments 64-88, wherein the cancer is pancreatic cancer.

[0311] 95. The use according to any one of embodiments 64-88, wherein the cancer is esophageal cancer.

[0312] 96. The use according to any one of embodiments 64-88, wherein the cancer is gastric cancer.

[0313] 97. The use according to any one of embodiments 64-88, wherein the cancer is liver cancer.

[0314] 98. The use according to any one of embodiments 64-88, wherein the cancer is leukemia.

[0315] 99. The use according to embodiment 98, wherein the cancer is acute lymphoblastic leukemia (ALL).

[0316] 100. The use according to any one of embodiments 64-99, wherein the cancer is metastatic.

[0317] 101. The use according to any one of embodiments 64-100, wherein the cancer is refractory to chemotherapy or radiotherapy and / or resistant to chemotherapy or radiotherapy.

[0318] 102. The use according to embodiment 101, wherein the cancer is refractory and resistant to chemotherapy or radiotherapy.

[0319] 103. The use according to any one of embodiments 64-102, wherein the CCR5 inhibitor is administered together with a second active agent.

[0320] 104. The use according to embodiment 103, wherein the second active agent has therapeutic efficacy against cancer.

[0321] 105. The use according to any one of embodiments 64-104, wherein the CCR inhibitor is administered before the onset of cancer symptoms.

[0322] 106. The use according to any one of embodiments 64-105, wherein the CCR5 inhibitor is administered orally, sublingually, buccally, topically, rectally, via inhalation, transdermally, subcutaneously, intravenously, intraarterially or intramuscularly, via intracardiac administration, intraosseously, intradermally, intraperitoneally, intracerebrally, transmucosally, vaginally, intravitreally, epidermally, intraarticularly, intravesically, intrathecally, periarticularly or locally.

[0323] 107. The use according to any one of embodiments 64-106, wherein the CCR5 inhibitor is administered intravenously, orally or via inhalation.

[0324] 108. The use according to any one of embodiments 64-107, wherein the CCR5 inhibitor is administered intravenously, for example via an injectable controlled release depot device.

[0325] 109. The use according to any one of embodiments 64-108, wherein the CCR5 inhibitor is administered together with a pharmaceutical carrier.

[0326] 110. The use according to any one of embodiments 64-109, wherein the CCR5 inhibitor is administered in an amount of about 0.1 mg to about 400 mg.

[0327] 111. The use according to embodiment 110, wherein the CCR5 inhibitor is administered in an amount of about 1 mg.

[0328] 112. The use according to embodiment 110, wherein the CCR5 inhibitor is administered in an amount of about 2 mg.

[0329] 113. The use according to embodiment 110, wherein the CCR5 inhibitor is administered in an amount of about 3 mg.

[0330] 114. The use according to embodiment 110, wherein the CCR5 inhibitor is administered in an amount of about 5 mg.

[0331] 115. The use according to embodiment 110, wherein the CCR5 inhibitor is administered in an amount of about 10 mg.

[0332] 116. The use according to embodiment 110, wherein the CCR5 inhibitor is administered in an amount of about 20 mg.

[0333] 117. The use according to embodiment 110, wherein the CCR5 inhibitor is administered in an amount of about 40 mg.

[0334] 118. The use according to any one of embodiments 64-117, wherein the CCR5 inhibitor is administered once a day or divided into 2, 3, 4, 5 or 6 equal doses per day.

[0335] 119. The use according to any one of embodiments 64-118, wherein the CCR5 inhibitor is administered chronically.

[0336] 120. The use according to embodiment 119, wherein the CCR5 inhibitor is administered for one, two, three, four, five, six or seven days; for one, two, three or four weeks; for about one, two, three, four, five, six, seven, eight, nine, ten, eleven, twelve months or longer.

[0337] 121. The use according to embodiment 120, wherein the CCR5 inhibitor is administered for 24 weeks or longer.

[0338] 122. The use according to embodiment 121, wherein the CCR5 inhibitor is administered for 28 weeks or longer.

[0339] 123. The use according to any one of embodiments 119-122, wherein the CCR5 inhibitor is administered daily, six times a week, five times a week, four times a week, three times a week, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nine weeks, once every ten weeks, twice a month, once a month, once every two months or once every three months.

[0340] 124. The use according to embodiment 123, wherein the CCR5 inhibitor is administered daily.

[0341] 125. The use according to embodiment 123, wherein the CCR5 inhibitor is administered once a week.

[0342] 126. The use according to any one of embodiments 64-125, wherein the CCR5 inhibitor is administered or provided separately, sequentially or simultaneously in combination with other pharmacologically active compounds.

[0343] 127. The method according to embodiment 63, wherein the other pharmacologically active compound is a checkpoint inhibitor.

[0344] 128. The method according to embodiment 127, wherein the other pharmacologically active compound is an anti-PD-1 antibody.

[0345] 129. The method according to embodiment 127, wherein the other pharmacologically active compound is an anti-CTLA-4 antibody.

[0346] 130. The use according to embodiment 126, wherein the other pharmacologically active compound is a checkpoint inhibitor.

[0347] 131. The use according to embodiment 130, wherein the other pharmacologically active compound is an anti-PD-1 antibody.

[0348] 132. The use according to embodiment 130, wherein the other pharmacologically active compound is an anti-CTLA-4 antibody.

[0349] Example

[0350] Example 1: 5P12-RANTES is more effective than several other CCR5 inhibitors in inhibiting signaling through human CCR5.

[0351] Chinese hamster ovary cells engineered to express human CCR5 plus an aequorin calcium sensor to detect receptor signaling activity were treated with the indicated inhibitors at increasing concentrations and then treated with the natural CCR5 agonist human MIP-1β / CCL4. Signaling activity measured in cells at each inhibitor concentration is expressed as a percentage of the signal elicited by the agonist in the absence of the inhibitor (n=2) ( Figure 1A , 1B and 1C). Figure 1A The fitted dose-inhibition curves (GraphPadPrism) show that the IC 50 The values ​​were 2.7nM and 0.12nM, respectively. Figure 1B The fitted dose-inhibition curves (GraphPad Prism) show that the IC of cencriviroc, BMS-0813160, maraviroc, and 5P12-RANTES 50 The values ​​were 51nM, 5.7nM, 4.3nM and 0.3nM respectively. Figure 1C The fitted dose-inhibition curves (GraphPadPrism) show that the IC of PRO-140, maraviroc, and 5P12-RANTES 50 The values ​​are 5.6 nM, 2.6 nM and 0.2 nM respectively.

[0352] Example 2: Comparison of the antiretroviral efficacy of 5P12-RANTES and MVC

[0353] 5P12-RANTES was directed against HIV-1 in a replication assay using peripheral blood mononuclear cells from a panel of U.S. donors (representing Caucasians, blacks, Asians, and Hispanics). BaL Antiretroviral efficacy (log IC 50 ) were compared with the reference compounds AZT and maraviroc (MVC) ( Figure 2 ). For each donor, each compound was evaluated in triplicate at 9 concentrations. Each point represents the log IC of a single donor. 50BD: below (ie, more potent than) the limit of detection of the assay. These data indicate that 5P12-RANTES is 10-30 times more potent than MVC in inhibiting HIV-1 replication.

[0354] Example 3: Determination of the inhibitory activity of 5P12-RANTES on human CCR1 and CCR3

[0355] Using GTPγ 35 The inhibitory activity of 5P12-RANTES against recombinant human CCR1 receptor (FAST-058G) and CCR3 receptor (FAST-061G) was tested in a dose response and duplicate assay.

[0356] The assay buffer was 20 mM HEPES pH 7.4; 200 mM NaCl, 10 μg / ml saponin, MgCl2 at optimal concentration for the specific receptor, 0.1% BSA. CHO-K1 cell membrane extract expressing recombinant human receptor was thawed on ice, diluted in assay buffer and kept on ice. GDP was diluted in assay buffer to give the optimal concentration for the specific receptor. Beads were PVT-WGA (PerkinElmer, RPNQ001) diluted in assay buffer to the optimal concentration for the specific receptor. GTPγ 35 S (PerkinElmer NEG030X) was diluted to 0.1 nM in assay buffer.

[0357] For inhibition assays, membranes were mixed with GDP and incubated on ice for at least 15 min. In parallel, GTPγ 35 The following reagents were added successively to the wells of an Optiplate (PerkinElmer): 50 μL of detection or reference ligand, 20 μL of membrane: GDP mixture, 10 μL of historical EC 80 of reference agonist and 20 μL GTPγ 35 S: Bead mixture.

[0358] The plate was covered with a top seal, mixed on an orbital shaker for 2 min, and then incubated at room temperature for 1 hour. The plate was then centrifuged at 2000 rpm for 10 min, incubated at room temperature for 1 hour, and counted using a PerkinElmer TopCount counter at 1 min / well.

[0359] On each day of the experiment and before testing compounds, reference compounds (J113863 for CCR1; UCB35625 for CCR3) were tested in duplicate (n=2) at several concentrations to generate dose-response curves and estimated EC 50 / IC 50value.

[0360] The reference values ​​thus obtained for the assay were compared with historical values ​​obtained for the same receptors (4.89 nM for CCR1; 213 nM for CCR3) and used to validate the assay. The assay was considered valid only if the reference values ​​were found to be within a 0.5-log interval from the historical values.

[0361] For replicates, the maximum variability tolerated in the test is approximately + / - 20% of the replicate mean.

[0362] Dose-response data were analyzed with XLfit (IDBS) software using nonlinear regression applied to a sigmoidal dose-response model. At the highest concentration, 5P12-RANTES showed moderate enhancement of CCR1 signaling in this assay, but no antagonism ( Figure 3A 5P12-RANTES also did not show CCR3 antagonism ( Figure 3B ).

[0363] Example 4: Efficacy of 5P12-RANTES in an animal model of colorectal cancer

[0364] In one experiment, BALB / c mice were inoculated subcutaneously with the CT-26 colorectal cancer cell line. Three days after inoculation, intraperitoneal treatment was initiated with 5P12-RANTES, murine anti-PD-1 antibody, 5P12-RANTES + anti-PD-1, or saline placebo. This treatment was given daily or every three days. Figure 4A As shown, treatment with 5P12-RANTES alone resulted in statistically significant delayed tumor growth at multiple time points, and a more profound effect in the reduction of mean tumor volume was observed in the combined cohort of animals receiving 5P12-RANTES and anti-PD-1 antibody (P>0.05). No obvious adverse events were observed during treatment.

[0365] In another experiment, BALB / c mice were inoculated subcutaneously with the CT-26 colorectal cancer cell line. Ten days after inoculation, intraperitoneal treatment was initiated with 5P12-RANTES, anti-CTLA-4 antibody, 5P12-RANTES + anti-CTLA-4, or saline placebo. 5P12-RANTES treatment was given five times a week. Figure 4B As shown, treatment with 5P12-RANTES alone resulted in delayed tumor growth at multiple time points, with more profound effects in the reduction of mean tumor volume observed in the cohort where animals received the combination of 5P12-RANTES and anti-CTLA-4 antibody. No significant adverse events were observed during treatment.

[0366] All publications and patent applications cited in this specification are incorporated herein by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated herein by reference. The citation of any publication is for its disclosure prior to the filing date and should not be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention.

[0367] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one skilled in the art will readily appreciate, based on the teachings herein, that certain changes and modifications may be made to the present invention without departing from the scope of the appended claims.

[0368] It should be understood that any numerical value inherently includes some errors that are necessarily generated from the standard deviation found in each test measurement. In addition, as used herein, the term "about" generally means within 10%, 5%, 1% or 0.5% of a given value or range. Alternatively, when considered by one of ordinary skill in the art, the term "about" means within an acceptable standard error of the mean. Unless otherwise indicated, the numerical parameters set forth in the present invention and the appended claims are approximate values ​​that can be varied as desired. At a minimum, each numerical parameter should be understood at least in light of the value of the significant digits recorded and by applying ordinary rounding techniques.

[0369] It must be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural forms unless the context clearly dictates otherwise. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0370] The phrase "and / or" as used in the specification and claims should be understood to mean "either or both" of the elements so combined, i.e., elements that are present jointly in some cases and separately in other cases. Multiple elements listed with "and / or" should be interpreted in the same manner, i.e., "one or more" of the elements so combined. Other elements beyond those specifically identified by the "and / or" term may optionally be present, whether related or unrelated to those specifically identified. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open language such as "comprising," may refer to A alone (optionally including elements other than B) in one embodiment; to B alone (optionally including elements other than A) in another embodiment; to both A and B (optionally including other elements) in yet another embodiment; and so on.

[0371] As used herein in the specification and claims, "or" should be understood to include the same meaning as "and / or" as defined above. For example, when listing items in a list, "or" or "and / or" should be interpreted as inclusive, i.e., including at least one of a plurality or a series of elements, but also including more than one, and optionally including additional unlisted items.

[0372] As used herein, whether in the specification or in the appended claims, the transition terms "comprising," "including," "with," "having," "containing," "involving," and the like are to be understood as inclusive or open-ended (i.e., meaning including, but not limited to), and they do not exclude unrecited elements, materials, or method steps. Only the transition phrases "consisting of" and "consisting essentially of" are closed or semi-closed transition phrases for the claims and exemplary embodiment paragraphs herein, respectively. The transition phrase "consisting of" excludes any element, step, or ingredient not specifically recited. The transition phrase "consisting essentially of" limits the scope to the specified elements, materials, or steps and those elements, materials, or steps that do not materially affect the basic characteristic(s) of the invention disclosed and / or claimed herein. Sequence Listing <110> Olian Biotech Switzerland GmbH <120> Application of CCR5 inhibitors in cancer treatment <130> 85279715 <150> 62 / 677114 <151> 2018-05-28 <150> 62 / 792600 <151> 2019-01-15 <160> 72 <170> PatentIn version 3.5 <210> 1 <211> 59 <212> PRT <213> Homo sapiens <400> 1 Cys Cys Phe Ala Tyr Ile Ala Arg Pro Leu Pro Arg Ala His Ile Lys 1 5 10 15 Glu Tyr Phe Tyr Thr Ser Gly Lys Cys Ser Asn Pro Ala Val Val Phe 20 25 30 Val Thr Arg Lys Asn Arg Gln Val Cys Ala Asn Pro Glu Lys Lys Trp 35 40 45 Val Arg Glu Tyr Ile Asn Ser Leu Glu Met Ser 50 55 <210> 2 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 2 Gln Gly Pro Pro Leu Met Ala Leu Gln Ser 1 5 10 <210> 3 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 3 Gln Gly Pro Pro Leu Met Trp Met Gln Val 1 5 10 <210> 4 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 4 Gln Gly Pro Pro Leu Met Trp Leu Gln Val 1 5 10 <210> 5 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 5 Gln Gly Pro Pro Leu Met Trp Thr Gln Ser 1 5 10 <210> 6 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 6 Gln Gly Pro Pro Leu Met Trp Leu Gln Thr 1 5 10 <210> 7 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 7 Gln Gly Pro Pro Leu Met Trp Thr Gln Val 1 5 10 <210> 8 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 8 Gln Gly Pro Pro Leu Met Trp Met Gln Ser 1 5 10 <210> 9 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 9 Gln Gly Pro Pro Leu Met Ala Thr Gln Ser 1 5 10 <210> 10 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 10 Gln Gly Pro Pro Leu Met Trp Leu Gln Ser 1 5 10 <210> 11 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 11 Gln Gly Pro Pro Leu Met Ala Leu Gln Val 1 5 10 <210> 12 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 12 Gln Gly Pro Pro Leu Met Trp Leu Gly Gly 1 5 10 <210> 13 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 13 Gln Gly Pro Pro Leu Met Trp Arg Gly Ser 1 5 10 <210> 14 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 14 Gln Gly Pro Leu Leu Met Trp Leu Gln Val 1 5 10 <210> 15 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 15 Gln Gly Pro Pro Leu Met Gln Thr Thr Pro 1 5 10 <210> 16 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 16 Gln Gly Pro Pro Gly Asp Thr Val Leu Trp 1 5 10 <210> 17 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 17 Gln Gly Pro Pro Gly Asp Ile Val Leu Ala 1 5 10 <210> 18 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 18 Gln Gly Pro Pro Gly Ser Tyr Asp Tyr Ser 1 5 10 <210> 19 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 19 Gln Gly Pro Pro Gly Asp Gly Gly Ser Val 1 5 10 <210> 20 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 20 Gln Gly Pro Leu Ser Gly Gln Ser Thr Pro 1 5 10 <210> 21 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 21 Gln Gly Pro Pro Gly Asp Trp Leu Gln Val 1 5 10 <210> 22 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 22 Gln Gly Pro Pro Leu Met Ser Phe Gln Ser 1 5 10 <210> 23 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 23 Gln Gly Pro Pro Leu Met Ser Thr Gln Ser 1 5 10 <210> 24 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 24 Gln Gly Pro Pro Leu Met Ser Leu Gln Val 1 5 10 <210> 25 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 25 Gln Gly Pro Pro Leu Met Gly Leu Gln Val 1 5 10 <210> 26 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 26 Gln Gly Pro Leu Ser Gly Trp Leu Gln Val 1 5 10 <210> 27 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 27 Gln Gly Pro Pro Leu Met Ser Val Leu Ala 1 5 10 <210> 28 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 28 Gln Gly Pro Pro Gly Ser Trp Ser Ser Val 1 5 10 <210> 29 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 29 Gln Gly Pro Pro Leu Gly Ser Met Gly Pro 1 5 10 <210> 30 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 30 Gln Gly Pro Pro Leu Ser Trp Leu Gln Val 1 5 10 <210> 31 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 31 Gln Gly Pro Pro Leu Ser Trp Leu Gln Ser 1 5 10 <210> 32 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 32 Gln Gly Pro Pro Gly Gln Trp Ser Gln Val 1 5 10 <210> 33 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 33 Gln Gly Pro Pro Met Met Ala Gly Leu Ser 1 5 10 <210> 34 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 34 Gln Gly Pro Pro Leu Ser Trp Gln Gln Ser 1 5 10 <210> 35 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 35 Gln Gly Pro Pro Gly Met Trp Ser Gln Ser 1 5 10 <210> 36 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 36 Gln Gly Pro Pro Leu Gln Trp Arg Gln Ser 1 5 10 <210> 37 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 37 Gln Gly Pro Pro Leu Met Gly Thr Gln Ser 1 5 10 <210> 38 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 38 Gln Gly Pro Pro Leu Met Gln Leu Gln Val 1 5 10 <210> 39 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 39 Gln Gly Pro Pro Leu Ser Trp Ser Gln Val 1 5 10 <210> 40 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 40 Gln Gly Pro Pro Met Ser Trp Ser Gln Ser 1 5 10 <210> 41 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 41 Gln Gly Pro Pro Leu Met Asn Leu Gln Val 1 5 10 <210> 42 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 42 Gln Gly Pro Pro Met Ser Ala Tyr Gln Val 1 5 10 <210> 43 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 43 Gln Gly Pro Pro Met Gln Gly Gly Leu Ser 1 5 10 <210> 44 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 44 Gln Gly Pro Pro Leu Met Ser Leu Ala Val 1 5 10 <210> 45 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 45 Gln Gly Pro Pro Leu Met Ser Leu Thr Val 1 5 10 <210> 46 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 46 Gln Gly Pro Leu Ser Gly Trp Ala Gln Val 1 5 10 <210> 47 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 47 Gln Gly Pro Leu Ser Gln Ser Ser Gln Val 1 5 10 <210> 48 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 48 Gln Gly Pro Leu Ser Ser Gln Ser Gln Val 1 5 10 <210> 49 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 49 Gln Gly Pro Leu Gly Gln Gln Gly Gln Val 1 5 10 <210> 50 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 50 Gln Gly Pro Pro Leu Gln Trp Phe Gln Val 1 5 10 <210> 51 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 51 Gln Gly Pro Pro Leu Gln Trp Thr Gln Val 1 5 10 <210> 52 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 52 Gln Gly Pro Pro Leu Met Ala Leu Ser Val 1 5 10 <210> 53 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 53 Gln Gly Pro Pro Leu Met Trp Ser Gln Val 1 5 10 <210> 54 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 54 Gln Gly Pro Pro Gly Gln Trp Gly Gln Val 1 5 10 <210> 55 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 55 Gln Gly Pro Pro Gly Ser Trp Ser Gln Val 1 5 10 <210> 56 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 56 Gln Gly Pro Pro Leu Met Ser Ser Gln Ser 1 5 10 <210> 57 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 57 Gln Gly Pro Pro Leu Met Gly Leu Ser Val 1 5 10 <210> 58 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 58 Gln Gly Pro Pro Leu Met Thr Leu Gln Val 1 5 10 <210> 59 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 59 Gln Gly Pro Pro Gly Gln Trp Tyr Gln Ser 1 5 10 <210> 60 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 60 Gln Gly Pro Pro Leu Gln Trp Met Gln Ala 1 5 10 <210> 61 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 61 Gln Gly Pro Pro Leu Gln Trp Met Gln Val 1 5 10 <210> 62 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 62 Gln Gly Pro Pro Leu Met Ser Thr Gln Val 1 5 10 <210> 63 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 63 Gln Gly Pro Pro Leu Met Ser Leu Ser Val 1 5 10 <210> 64 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 64 Gln Gly Pro Pro Leu Met Ser Leu Gln Ser 1 5 10 <210> 65 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 65 Gln Gly Pro Pro Leu Met Ser Leu Gln Ala 1 5 10 <210> 66 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 66 Gln Gly Pro Pro Leu Met Ser Val Gln Ser 1 5 10 <210> 67 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 67 Gln Gly Pro Pro Leu Met Ser Ala Gln Ser 1 5 10 <210> 68 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 68 Gln Gly Pro Pro Leu Met Ser Gly Gln Ser 1 5 10 <210> 69 <211> 10 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 69 Gln Gly Pro Pro Leu Met Ser Gly Gln Val 1 5 10 <210> 70 <211> 69 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 70 Gln Gly Pro Pro Leu Met Ala Thr Gln Ser Cys Cys Phe Ala Tyr Ile 1 5 10 15 Ala Arg Pro Leu Pro Arg Ala His Ile Lys Glu Tyr Phe Tyr Thr Ser 20 25 30 Gly Lys Cys Ser Asn Pro Ala Val Val Phe Val Thr Arg Lys Asn Arg 35 40 45 Gln Val Cys Ala Asn Pro Glu Lys Lys Trp Val Arg Glu Tyr Ile Asn 50 55 60 Ser Leu Glu Met Ser 65 <210> 71 <211> 69 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 71 Gln Gly Pro Pro Gly Asp Ile Val Leu Ala Cys Cys Phe Ala Tyr Ile 1 5 10 15 Ala Arg Pro Leu Pro Arg Ala His Ile Lys Glu Tyr Phe Tyr Thr Ser 20 25 30 Gly Lys Cys Ser Asn Pro Ala Val Val Phe Val Thr Arg Lys Asn Arg 35 40 45 Gln Val Cys Ala Asn Pro Glu Lys Lys Trp Val Arg Glu Tyr Ile Asn 50 55 60 Ser Leu Glu Met Ser 65 <210> 72 <211> 69 <212> PRT <213> Artificial Sequence <220> <223> synthetic <400> 72 Gln Gly Pro Pro Leu Can Be Leu Gln Val Cys Phe Ala Tyr Ile 1 5 10 15 Ala Arg Pro Leu Pro Arg Ala His Ile Lys Glu Tyr Phe Tyr Thr Ser 20 25 30 Gly Lys Cys Ser Asn Pro Ala Val Val Phe Val Thr Arg Lys Asn Arg 35 40 45 Gln Val Cys Ala Asn Pro Glu Lys Lys Trp Val Arg Glu Tyr Ile Asn 50 55 60 Ser Leu Glu Met Ser 65

Claims

1. Use of a CCR5 inhibitor in the preparation of a medicament for treating colorectal cancer in a subject, wherein the CCR5 inhibitor consists of the amino acid sequence of SEQ ID NO:

70.

2. The use according to claim 1, wherein the CCR5 inhibitor inhibits HIV entry into cells, and the CCR5 inhibitor is selective for CCR5 compared to CCR1 and CCR3.

3. The use according to claim 2, wherein the CCR5 inhibitor inhibits only a subset of the CCR5 intracellular signaling pathway.

4. The use according to claim 3, wherein the CCR5 inhibitor inhibits or reduces the inflammatory effect of CCR5 and causes a signaling response that is 30% or less of the maximum response (Emax) elicited by PSC-RANTES when tested at a concentration of 300 nM in a calcium flux signaling assay.

5. The use according to claim 1, wherein the colorectal cancer is metastatic.

6. The use according to claim 1, wherein the colorectal cancer is refractory to chemotherapy or radiotherapy and / or resistant to chemotherapy or radiotherapy.

7. The use according to claim 1, wherein the colorectal cancer is characterized by tumor cells expressing CCR5 and / or solid tumors infiltrated by leukocytes expressing CCR5.

8. The use according to claim 1, wherein the CCR5 inhibitor is administered together with a second active agent.

9. The use according to claim 8, wherein the second active agent is an anti-CTLA4 antibody.

10. The use according to claim 8, wherein the second active agent is an anti-PD-1 antibody.

11. The use according to claim 8, wherein the second active agent is an anti-PD-L1 antibody.

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