WO2020264437A1 - Hdac6-activated macrophages, compositions, and uses thereof - Google Patents
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- WO2020264437A1 WO2020264437A1 PCT/US2020/040003 US2020040003W WO2020264437A1 WO 2020264437 A1 WO2020264437 A1 WO 2020264437A1 US 2020040003 W US2020040003 W US 2020040003W WO 2020264437 A1 WO2020264437 A1 WO 2020264437A1
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Classifications
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/15—Cells of the myeloid line, e.g. granulocytes, basophils, eosinophils, neutrophils, leucocytes, monocytes, macrophages or mast cells; Myeloid precursor cells; Antigen-presenting cells, e.g. dendritic cells
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
- A61K39/4614—Monocytes; Macrophages
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- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
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- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0645—Macrophages, e.g. Kuepfer cells in the liver; Monocytes
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- A61K2239/46—Indexing codes associated with cellular immunotherapy of group A61K39/46 characterised by the cancer treated
- A61K2239/57—Skin; melanoma
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
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- C—CHEMISTRY; METALLURGY
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- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2529/00—Culture process characterised by the use of electromagnetic stimulation
Definitions
- HDAC6-activated macrophages histone deacetylase 6 (HDAC6)-activated macrophages, compositions comprising HDAC6-activated macrophages, methods of making HDAC6-activated macrophages, and methods of treating diseases, e.g., cancer, by administering a therapeutically effective amount of HDAC6-activated macrophages or a pharmaceutical composition comprising HDAC6-activated macrophages.
- HDAC6 histone deacetylase 6
- Macrophages play an important role in host innate and adaptive immune responses. They help maintain tissue homeostasis, repair, and fight infections. Macrophages exhibit functional heterogeneity based on their phenotype. They are classified into “Ml” or “classically activated' and “M2" or “alternatively activated' macrophages. M2 macrophages secrete anti-inflammatory cytokines such as TGFP and IL-10, which are generally associated with tumors and function by promoting tumor growth, angiogenesis, tumor invasion, and migration. On the contrary, Ml macrophages secrete pro-inflammatory cytokines such as IL-12 and TNFa and have an anti-tumor function.
- cytokines such as TGFP and IL-10
- Ml macrophages also actively scan the tumor microenvironment (TME) for tumor-associated antigens (TAA) and present them to CD8 T-cells to elicit anti-tumor immunity.
- TME tumor microenvironment
- TAA tumor-associated antigens
- HDAC6-activated macrophages are reprogrammed outside the body (ex vivo) and polarized towards the anti-tumor Ml phenotype by treatment with a selective HDAC6 inhibitor. These HDAC6-activated macrophages can be administered to a subject to treat cancer and other diseases. [0005] In one aspect, the present disclosure provides HDAC6-activated macrophages.
- the present disclosure provides a composition comprising
- the present disclosure provides a method of making
- HDAC6-activated macrophages the method comprising isolating naive macrophages from a subject and treating the isolated naive macrophages ex vivo with a selective HDAC6 inhibitor.
- the present disclosure provides a method of treating a subject in need thereof comprising administering to the subject a therapeutically effective amount of HDAC6-activated macrophages or a composition comprising HDAC6-activated macrophages, wherein the subject has cancer, pulmonary fibrosis, liver fibrosis, or heart fibrosis.
- Fig. 1 is a line graph showing the SIINFEKL antigen levels derived from OVA peptide and detected by MHCI-SIINFEKL specific antibody as measured by FACS in bone marrow-derived macrophages from wild type or HDAC6 KO (knockout) mice. Macrophages were pre-treated with Nexturastat A (NextA) 5 mM and then polarized for 24 hours.
- Nexturastat A NextA
- Fig. 2 is a graph showing the MHCI-SIINFEKL levels in polarized macrophages derived from wild-type mice pre-treated with with NextA and incubated with OVA peptide for 24 hours.
- Fig. 3 is a bar graph showing the MHCI and MHCI-SIINFEKL levels after
- SMI -OVA SMI cells expressing OVA peptide
- MHCI and MHCI-SIINFEKL levels were measured by FACS.
- Fig. 4 is a bar graph showing the polarization level in the Ml phenotype with no treatment, pre-treatment, and post-treatment with NextA.
- Fig. 5 is a bar graph showing the polarization level in the M2 phenotype with no treatment, pre-treatment, or post-treatment with NextA.
- Fig. 6 is a line graph showing the tumor size in intratumoral transfer therapy in the
- Fig. 7 is a line graph showing the tumor size in intratumoral transfer therapy in the
- Fig. 8 is a line graph showing tumor size in intratumoral transfer therapy in the
- Fig. 9 is a bar graph showing the gene expression level of M2 phenotype marker
- Argl with Ml and M2 macrophages which were either untreated or pre-treated with a HDAC6 inhibitor. Gene expression levels were tested by quantitative real-time PCR.
- Fig. 10 is a bar graph showing gene expression level of M2 anti-inflammatory cytokine IL-10 with Ml and M2 macrophages which were either untreated or pre-treated with a HDAC6 inhibitor. Gene expression levels were tested by quantitative real-time PCR.
- Fig. 11 is a bar graph showing gene expression level of M2 anti-inflammatory cytokine TGFP with Ml and M2 macrophages which were either untreated or pre-treated with a HDAC6 inhibitor. Gene expression levels were tested by quantitative real-time PCR.
- Fig. 12 is a bar graph showing gene expression level of Ml pro-inflammatory cytokine IL-1B with Ml and M2 macrophages which were either untreated or pre-treated with a HDAC6 inhibitor. Gene expression levels were tested by quantitative real-time PCR.
- Fig. 13 is a bar graph showing gene expression level of Ml pro-inflammatory cytokine TNFa with Ml and M2 macrophages which were either untreated or pre-treated with a HDAC6 inhibitor. Gene expression levels were tested by quantitative real-time PCR.
- Fig. 14 is a line graph showing tumor growth curves of twenty mice engrafted with SMI melanoma monitored for 25 days.
- Fig. 15 is a scatter graph showing negative correlation of tumor size with anti tumor Ml macrophages.
- Fig. 16 is a scatter graph showing positive correlation of tumor size with pro tumor M2 macrophages.
- Fig. 17 is a scatter graph showing tumor size with M1/M2 Macrophage ratio.
- M1/M2 Macrophage ratio is an indicative of the immune status of tumor microenvironment (TME).
- Fig. 18 is a schematic illustration showing the dosing regimen in the SMI murine melanoma model.
- Fig. 19 is a line graph showing the tumor size after treatment with vehicle, Ml macrophages, a NextA, and Ml macrophages pre-treated with NextA in the SMI murine melanoma model.
- Fig. 20 is a Kaplan-Meier survival graph showing a survival percentage after treatment with vehicle, Ml macrophages, NextA, and Ml macrophages pre-treated with NextA in the SMI murine melanoma model.
- Fig. 21 is a line graph showing tumor size after treatment with vehicle and Ml macrophages derived from HDAC6KO (knockout) mice in the SMI murine melanoma model.
- Fig. 22 is a bar graph showing gene expression level of M2 anti-inflammatory cytokines CCL2, TGF-b and IL-10 with naive macrophages M0 which were either untreated or pre-treated with a HDAC6 inhibitor (NextA).
- Figure 23 is a bar graph showing gene expression level of Ml pro-inflammatory cytokines IL-12, TNF-a and IL-1B with naive macrophages M0 which were either untreated or pre-treated with a HDAC6 inhibitor (NextA).
- Fig. 24 is a panel of four graphs showing antigen presentation and processing genes TAPI, TAP2, TAPBP and ERAPl with naive macrophages M0, Ml, M2 either untreated or pre-treated with NextA.
- Fig. 25 is a panel of four bar graphs showing the MHCI-SIINFEKL levels when
- SMI cells stably expressing OVA (SMI -OVA cells) peptide are exposed to 4 Gy of radiation, NextA, or a combination at the times indicated.
- MHC-I mediated SIINFEKL antigen presentation was measured by flow cytometry.
- Fig. 26 is a bar graph showing MHCI-SIINFEKL levels when SMI cells stably expressing OVA peptide (SMI -OVA cells) are exposed to Vehicle, a sequencing of a HDAC6 inhibitor (NextA) and radiation treatment. MHC-I mediated SIINFEKL antigen presentation was measured by flow cytometry.
- Fig. 27 is a schematic illustration showing the work flow for antigen cross presentation by macrophages.
- Fig. 28 is a graph showing the SIINFEKL antigen levels derived from OVA peptide and detected by MHCI-SIINFEKL specific antibody as measured by FACS when bone marrow derived M0 (naive) macrophages were exposed to conditioned medium (CM) from radiation exposed SMI -OVA cells.
- Fig. 29 is a graph showing the SIINFEKL antigen levels derived from OVA peptide and detected by MHCI-SIINFEKL specific antibody as measured by FACS when bone marrow derived Ml macrophages exposed to conditioned medium (CM) from radiation exposed SMI -OVA cells.
- Fig. 30 is a graph showing the SIINFEKL antigen levels derived from OVA peptide and detected by MHCI-SIINFEKL specific antibody as measured by FACS when bone marrow derived M2 macrophages exposed to conditioned medium (CM) from radiation exposed SMI -OVA cells.
- Fig. 31 is a table showing the HDAC1 and HDAC6 activity of NextA, ACY241,
- Fig. 32 is a Western blot of showing PD-L1 expression after treatment with
- Fig. 33 is a bar graph showing IFN levels from CD8+ T-cells after treatment with
- Fig. 34 is a panel of three bar graphs showing the expression of cell death inducing Granyme B, FasL and TRAIL from NK cells after treatment with Vehicle or NextA.
- Fig. 35 is a line graph showing the cytotoxicity of HDAC inhibitors at the concentrations indicated.
- Fig. 36 is a line graph showing the cytotoxicity of HDAC inhibitors at the concentrations indicated.
- the present disclosure provides HDAC6-activated macrophages.
- the present disclosure provides compositions comprising
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor.
- the subject is a mammal.
- the subject is a human.
- the naive macrophages are allogeneic macrophages, autologous macrophages, or a combination of allogeneic macrophages and autologous macrophages.
- the naive macrophages are allogeneic macrophages.
- the naive macrophages are autologous macrophages.
- HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo one time with a selective HDAC6 inhibitor.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo two or more times with a selective HDAC6 inhibitor.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor for 6 hours or less, e.g., 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor and a macrophage polarizing agent.
- the macrophage polarizing agent comprises lipopolysaccharide (LPS), interferon-gamma, interleukin-4, or interleukin- 13, or a combination thereof.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor before treatment with the macrophage polarizing agent.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor after treatment with the macrophage polarizing agent.
- the isolated naive macrophages are simultaneously treated with the selective HDAC6 inhibitor and the macrophage polarizing agent.
- the ex vivo treatment with the macrophage polarizing agent is for 6 hours or less, e.g., 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor and a tumor antigen.
- the antigen comprises alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, MUC-1, Epithelial tumor antigen (ETA), tyrosinase, or melanoma-associated antigen (MAGE), p53, or a combination thereof.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor before treatment with the tumor antigen.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor after treatment with the tumor antigen.
- the isolated naive macrophages are simultaneously treated with the selective HDAC6 inhibitor and the tumor antigen.
- the ex vivo treatment with the tumor antigen is for 6 hours or less, e.g., 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor, a macrophage polarizing agent, and a tumor antigen.
- the naive macrophages can be treated with the selective HDAC6 inhibitor, the macrophage polarizing agent, and the tumor antigen simultaneously or separately in any order.
- the naive macrophages can be treated ex vivo first with the selective HDAC6 inhibitor followed by the macrophage polarizing agent followed by the tumor antigen; the naive macrophages can be treated ex vivo first with the macrophage polarizing agent followed by the selective HDAC6 inhibitor followed by the tumor antigen; the naive macrophages can be treated ex vivo first with the selective HDAC6 inhibitor followed by the tumor antigen followed by the macrophage polarizing agent; and so on.
- the ex vivo treatment is a selective HDAC6 inhibitor, a macrophage polarizing agent, and a tumor antigen, independently for each agent, for 6 hours or less, e.g., 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.
- HDAC6-activated macrophages may be formulated as pharmaceutical compositions or medicaments for clinical use and may comprise a pharmaceutically acceptable carrier, diluent, excipient or adjuvant.
- a pharmaceutically acceptable carrier diluent, excipient or adjuvant.
- Pharmaceutically acceptable carriers, diluents, excipients, or adjuvants are known in the art.
- composition may be formulated for parenteral, systemic, intracavitary, intravenous, intra-arterial, intramuscular, intrathecal, intraocular, intraconjunctival, intratumoral, subcutaneous, intradermal, intrathecal, oral or transdermal routes of administration which may include injection or infusion.
- Suitable formulations may comprise HDAC6-activated macrophages in a sterile or isotonic medium, e.g, water for injection (WFI).
- Medicaments and pharmaceutical compositions may be formulated in fluid, including gel, form. Fluid formulations maybe formulated for administration by injection or infusion (e.g. via catheter) to a selected region of the human or animal body.
- compositions comprising HDAC6-activated macrophages are formulated for intratumoral or intravenous administration, e.g., for macrophage-directed cancer immunotherapy. See, e.g., Mills et al., Cancer Research 7(5:513-516 (2016); Lee et al., J Control Release 240: 527-540 (2016).
- methods are provided for the production of pharmaceutically useful compositions, such methods of production may comprise one or more steps selected from isolating/purifying HDAC6-activated macrophages produced according to the methods described herein; and/or mixing HDAC6-activated macrophages produced according with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.
- one aspect of the present disclosure relates to a method of formulating or producing a medicament or pharmaceutical composition, the method comprising formulating a pharmaceutical composition or medicament by mixing HDAC6-activated macrophages produced according to the methods described herein with a pharmaceutically acceptable carrier, adjuvant, excipient or diluent.
- the selective HDAC6 inhibitor is a compound of Formula I:
- R a and R b are independently selected from the group consisting of hydrogen and Ci-4 alkyl; or
- R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclo
- R c is Ci-4 alkyl
- n 1, 2, or 3.
- R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy.
- the present disclosure provides that the selective HDAC6 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound of Formula II:
- R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 10-membered heterocyclo
- R c is Ci-4 alkyl
- n 1, 2, or 3.
- R 7a , R 7b , R 7c , R 7d , and R 7e are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy.
- the selective HDAC6 inhibitor is a compound of Formula II, or a pharmaceutically acceptable salt thereof, wherein n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound of Formula III:
- R 4a and R 4b are independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy;
- R 4C and R 4d are independently selected from the group consisting of hydrogen and methyl
- n 0 or 1 ;
- n 1, 2, or 3;
- the selective HDAC6 inhibitor is a compound of Formula III, or a pharmaceutically acceptable salt thereof, wherein n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor that is a compound of
- R 5a and R 5c are independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy;
- n 1, 2, or 3.
- the selective HDAC6 inhibitor is a compound of Formula IV, or a pharmaceutically acceptable salt thereof, wherein n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound of Table 1, see below, or a pharmaceutically acceptable salt thereof.
- the selective HDAC6 inhibitor is at least 20-fold selective over one or more other HD AC isoforms, e.g., HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, or HDAC11.
- the selective HDAC6 inhibitor is at least 100-fold selective over one or more other HD AC isoforms.
- the selective HDAC6 inhibitor is at least 600-fold selective over one or more other HD AC isoforms.
- the present disclosure provides methods of producing
- HDAC6-activated macrophages the methods comprising isolating naive macrophages from a subject and treating the isolated naive macrophages ex vivo with a selective HDAC6 inhibitor.
- the subject is a mammal.
- the subject is a human.
- the naive macrophages are allogeneic macrophages, autologous macrophages, or a combination of allogeneic macrophages and autologous macrophages.
- the naive macrophages are allogeneic macrophages.
- the naive macrophages are autologous macrophages.
- HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo one time with a selective HDAC6 inhibitor.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo two or more times with a selective HDAC6 inhibitor.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor for 6 hours or less, e.g., 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor and a macrophage polarizing agent.
- the macrophage polarizing agent comprises lipopolysaccharide (LPS), interferon-gamma, interleukin-4, or interleukin- 13, or a combination thereof.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor before treatment with the macrophage polarizing agent.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor after treatment with the macrophage polarizing agent.
- the isolated naive macrophages are simultaneously treated with the selective HDAC6 inhibitor and the macrophage polarizing agent.
- the isolated naive macrophages are treated with the macrophage polarizing agent for 6 hours or less, e.g., 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.
- the HDAC6-activated macrophages are produced from naive macrophages that have been isolated from a subject and treated ex vivo with a selective HDAC6 inhibitor and a tumor antigen.
- the antigen comprises alphafetoprotein (AFP), carcinoembryonic antigen (CEA), CA-125, MUC-1, Epithelial tumor antigen (ETA), tyrosinase, or nelanoma-associated antigen (MAGE), p53, or a combination thereof.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor before treatment with the tumor antigen.
- the isolated naive macrophages are treated with the selective HDAC6 inhibitor after treatment with the tumor antigen. In another aspect, the isolated naive macrophages are simultaneously treated with the selective HDAC6 inhibitor and the tumor antigen. In another aspect, the isolated naive macrophages are treated with the tumor antigen for 6 hours or less, e.g., 5 hours or less, 4 hours or less, 3 hours or less, 2 hours or less, 1 hour or less, or 30 minutes or less.
- the selective HDAC6 inhibitor is a compound of Formula I, or a pharmaceutically acceptable salt thereof. See above.
- R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy.
- n is 1.
- n is 2.
- n can be 3.
- the selective HDAC6 inhibitor is a compound of Formula II, or a pharmaceutically acceptable salt thereof. See above.
- R 7a , R 7b , R 7c , R 7d , and R 7e are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy.
- n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound of Formula III, or a pharmaceutically acceptable salt thereof. See above.
- n is 1.
- n is 2.
- n is 3.
- the selective HDAC6 inhibitor that is a compound of Formula
- n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof.
- the selective HDAC6 inhibitor is at least 20-fold selective over one or more other HD AC isoforms, e.g., HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, or HDAC11.
- the selective HDAC6 inhibitor is at least 100-fold selective over one or more other HD AC isoforms.
- the selective HDAC6 inhibitor is at least 600-fold selective over one or more other HD AC isoforms.
- HDAC6-activated macrophages or pharmaceutical compositions comprising
- HDAC6-activated macrophages may be useful for adoptive cell therapy.
- Adoptive cell therapy involves the introduction of cells into a subject in need of treatment.
- the cells are derived from the subject that they are introduced to (autologous cell therapy). See, e.g., Moroni et al., Nature Medicine 25:1560-1565 (2019). That is, cells, e.g., macrophages, may have been obtained from the patient, activated according to methods described herein, and then returned to the same subject. Methods disclosed herein may also be used in allogenic cell therapy, in which cells obtained from a different individual are introduced into the subject.
- the present disclosure provides methods of treating or preventing a disease or disorder a subject in need thereof, the methods comprising administering to the subject a therapeutically effective amount of HDAC6-activated macrophages or a composition comprising HDAC6-activated macrophages.
- the disease or disorder is cancer, pulmonary fibrosis, liver fibrosis, or heart fibrosis.
- the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, the methods comprising:
- the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, the methods comprising:
- the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, the methods comprising:
- the present disclosure provides methods of treating or preventing a disease or disorder in a subject in need thereof, the methods comprising:
- the subject from which the naive macrophages are isolated is the subject administered with HDAC6-activated macrophages, i.e., adoptive transfer is of autologous cells.
- the subject from which the naive macrophages are isolated is a different subject than the subject to which the HDAC6-activated macrophages are administered, i.e., adoptive transfer is of allogenic cells.
- methods of treating or preventing a disease or disorder in a subject comprise one or more of the following steps: taking a biological sample from the subject; isolating naive macrophages from the biological sample; treating the naive macrophages ex vivo with a selective HDAC6 inhibitor; treating the treated macrophages with a macrophage polarizing agent; collecting the HDAC6-activated macrophages; mixing the HDAC6-activated macrophages with an adjuvant, diluent, or carrier; administering the HDAC6-activated macrophages or composition thereof to the subject.
- the disease or disorder to be treated/prevented is pulmonary fibrosis.
- the disease or disorder to be treated/prevented is liver fibrosis.
- the disease or disorder to be treated/prevented is heart fibrosis.
- the disease or disorder to be treated/prevented is cancer.
- HDAC6-activated macrophages and pharmaceutical compositions comprising HDAC6-activated macrophages are capable of treating or preventing a cancer, e.g. inhibit the development/progression of the cancer, delay/prevent onset of the cancer, reduce/delay/prevent tumor growth, reduce/delay/prevent metastasis, reduce the severity of the symptoms of the cancer, reduce the number of cancer cells, reduce tumor size/volume, and/or increase survival (e.g. progression free survival)).
- a cancer e.g. inhibit the development/progression of the cancer, delay/prevent onset of the cancer, reduce/delay/prevent tumor growth, reduce/delay/prevent metastasis, reduce the severity of the symptoms of the cancer, reduce the number of cancer cells, reduce tumor size/volume, and/or increase survival (e.g. progression free survival)).
- the cancer is a solid tumor. In another aspect, the cancer is a hematological cancer. In another aspect, the cancer is any one or more of the cancers of Table 2.
- Exemplary hematological cancers include, but are not limited to, the cancers listed in Table 3.
- the hematological cancer is acute lymphocytic leukemia, chronic lymphocytic leukemia (including B-cell chronic lymphocytic leukemia), or acute myeloid leukemia.
- administering is in a "therapeutically effective” or “prophylactically effective” amount, this being sufficient to show benefit to the subject.
- Multiple doses of a HDAC6-activated macrophage or pharmaceutical composition comprising a HDAC6-activated macrophage may be administered to a subject.
- One or more, or each, of the doses may be accompanied by simultaneous or sequential administration of another therapeutic agent.
- Multiple doses may be separated by a predetermined time interval, which may be selected to be one of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21,
- doses may be given once every 7, 14, 21 or 28 days (plus or minus 3, 2, or 1 days).
- the present disclosure provides the method further comprising administering to a subject one or more of local radiation therapy, immune checkpoint blockade therapy, photothennal therapy, or chemotherapy.
- methods provided herein comprise administering HDAC6-activated macrophages or a composition comprising HDAC6-activated macrophages to a subject in combination with radiation therapy.
- the methods provided herein are not limited by the types, amounts, or delivery and administration systems used to deliver the therapeutic dose of radiation to a subject.
- the subject may receive photon radiotherapy, particle beam radiation therapy, other types of radiotherapies, and combinations thereof.
- the radiation is delivered to the subject using a linear accelerator.
- the radiation is delivered using a gamma knife.
- the source of radiation can be external or internal to the subject.
- External radiation therapy is most common and involves directing a beam of high-energy radiation to a tumor site through the skin using, for instance, a linear accelerator. While the beam of radiation is localized to the tumor site, it is nearly impossible to avoid exposure of normal, healthy tissue. However, external radiation is usually well tolerated by subjects.
- Internal radiation therapy involves implanting a radiation-emitting source, such as beads, wires, pellets, capsules, particles, and the like, inside the body at or near the tumor site including the use of delivery systems that specifically target cancer cells ( e.g ., using particles attached to cancer cell binding ligands). Such implants can be removed following treatment, or left in the body inactive.
- Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial irradiation, intracavity irradiation, radioimmunotherapy, and the like.
- the subject may optionally receive radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iododeoxyuridine (IudR), nitroimidazole, 5-substituted-4-nitroimidazoles, 2H-isoindolediones, [[(2-bromoethyl)-amino]methyl]- nitro-lH-imidazole-1 -ethanol, nitroaniline derivatives, DNA-affmic hypoxia selective cytotoxins, halogenated DNA ligand, 1,2,4 benzotriazine oxides, 2-nitroimidazole derivatives, fluorine-containing nitroazole derivatives, benzamide, nicotinamide, acridine- intercalator, 5-thiotretrazole derivative, 3-nitro- 1,2, 4-triazole, 4,5-dinitroimidazole derivative, hydroxylated texaphrins
- any type of radiation can be administered to a subject, so long as the dose of radiation is tolerated by the subject without unacceptable negative side-effects.
- Suitable types of radiotherapy include, for example, ionizing (electromagnetic) radiotherapy (e.g., X-rays or gamma rays) or particle beam radiation therapy (e.g., high linear energy radiation).
- Ionizing radiation is defined as radiation comprising particles or photons that have sufficient energy to produce ionization, i.e., gain or loss of electrons (as described in, for example, U.S. 5,770,581 incorporated herein by reference in its entirety).
- the effects of radiation can be at least partially controlled by the clinician.
- the dose of radiation is fractionated for maximal target cell exposure and reduced toxicity.
- the total dose of radiation administered to a subject is about .01
- about 10 Gy to about 65 Gy e.g., about 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy
- a complete dose of radiation can be administered over the course of one day, the total dose is ideally fractionated and administered over several days.
- radiotherapy is administered over the course of at least about 3 days, e.g., at least 3, 4, 5, 7, 10, 14, 17, 21, 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1-8 weeks).
- a daily dose of radiation will comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy), or 1-2 Gy (e.g., 1.5-2 Gy).
- the daily dose of radiation should be sufficient to induce destruction of the targeted cells. If stretched over a period, in one aspect, radiation is not administered every day, thereby allowing the animal to rest and the effects of the therapy to be realized. For example, in one aspect, radiation is administered on 5 consecutive days, and not administered for 2 days, for each week of treatment, thereby allowing 2 days of rest per week.
- radiation is administered 1 day/week, 2 days/week, 3 days/week, 4 days/week, 5 days/week, 6 days/week, or all 7 days/week, depending on the mammal's responsiveness and any potential side effects.
- Radiation therapy can be initiated at any time in the therapeutic period.
- radiation is initiated in week 1 or week 2, and is administered for the remaining duration of the therapeutic period.
- radiation is administered in weeks 1-6 or in weeks 2-6 of a therapeutic period comprising 6 weeks for treating, for instance, a solid tumor.
- radiation is administered in weeks 1-5 or weeks 2-5 of a therapeutic period comprising 5 weeks.
- methods provided herein comprise administering HDAC6-activated macrophages or a composition comprising HDAC6-activated macrophages to a subject in combination with immune checkpoint blockade therapy.
- Immune checkpoint inhibitors are therapies that block immune system inhibitor checkpoints. Immune checkpoints can be stimulatory or inhibitory. Blockade of inhibitory immune checkpoints activates immune system function and is useful for cancer immunotherapy. Pardoll, Nature Reviews. Cancer 72:252-64 (2012). Tumor cells turn off activated T cells when they attach to specific T-cell receptors. Immune checkpoint inhibitors prevent tumor cells from attaching to T cells, which results in T cells remaining activated.
- immune checkpoint inhibitors include PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, LAG3 inhibitors, TIM3 inhibitors, cd47 inhibitors, and B7-H1 inhibitors.
- the immune checkpoint inhibitor is selected from the group consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a LAG3 inhibitor, a TIM3 inhibitor, and a cd47 inhibitor.
- the immune checkpoint inhibitor is a programmed cell death protein (PD-1) inhibitor.
- PD-1 is a T-cell coinhibitory receptor that plays a pivotal role in the ability of tumor cells to evade the host's immune system. Blockage of interactions between PD-1 and PD-L1, a ligand of PD-1, enhances immune function and mediates antitumor activity.
- PD-1 inhibitors include antibodies that specifically bind to PD-1. Particular anti-PD-1 antibodies include, but are not limited to, nivolumab, pembrolizumab, STI-A1014, and pidilzumab.
- the immune checkpoint inhibitor is a PD-L1 (also known as B7-
- H1 or CD274 inhibitor examples include antibodies that specifically bind to PD-L1.
- Particular anti-PD-Ll antibodies include, but are not limited to, avelumab, atezolizumab, durvalumab, and BMS-936559.
- the immune checkpoint inhibitor is a CTLA-4 inhibitor.
- CTLA-4 also known as cytotoxic T-lymphocyte antigen 4 is a protein receptor that downregulates the immune system.
- CTLA-4 is characterized as a "brake” that binds costimulatory molecules on antigen-presenting cells, which prevents interaction with CD28 on T cells and also generates an overtly inhibitory signal that constrains T cell activation.
- CTLA-4 inhibitors include antibodies that specifically bind to CTLA-4.
- Particular anti-CTLA-4 antibodies include, but are not limited to, ipilimumab and tremelimumab.
- the immune checkpoint inhibitor is a LAG3 inhibitor.
- Lymphocyte Activation Gene 3 is a negative co-simulatory receptor that modulates T cell homeostatis, proliferation, and activation.
- LAG3 has been reported to participate in regulatory T cells (Tregs) suppressive function. A large proportion of LAG3 molecules are retained in the cell close to the microtubule-organizing center, and only induced following antigen specific T cell activation.
- Regs regulatory T cells
- Examples of LAG3 inhibitors include antibodies that specifically bind to LAG3.
- Particular anti-LAG3 antibodies include, but are not limited to, GSK2831781.
- the immune checkpoint inhibitor is a TIM3 inhibitor.
- TIM3, T- cell immunoglobulin and mucin domain 3 is an immune checkpoint receptor that functions to limit the duration and magnitude of THI and Tel T-cell responses.
- the TIM3 pathway is considered a target for anticancer immunotherapy due to its expression on dysfunctional CD8 + T cells and Tregs, which are two reported immune cell populations that constitute immunosuppression in tumor tissue.
- Examples of TIM3 inhibitors include antibodies that specifically bind to TIM3.
- the immune checkpoint inhibitor is a CD47 inhibitor.
- antibody is meant to include intact monoclonal antibodies, polyclonal antibodies, and multispecific antibodies formed from at least two intact antibodies, so long as they exhibit the desired biological activity.
- the antibodies are humanized monoclonal antibodies made by means of recombinant genetic engineering.
- Another class of immune checkpoint inhibitors include polypeptides that bind to and block PD-1 receptors on T-cells without triggering inhibitor signal transduction.
- Such peptides include B7-DC polypeptides, B7-H1 polypeptides, B7-1 polypeptides and B7-2 polypeptides, and soluble fragments thereof, as disclosed in U.S. Pat. 8,114,845.
- Another class of immune checkpoint inhibitors include compounds with peptide moieties that inhibit PD-1 signaling. Examples of such compounds are disclosed in U.S. Pat. 8,907,053.
- IDO indoleamine 2,3 dioxygenase
- the IDO enzyme inhibits immune responses by depleting amino acids that are necessary for anabolic functions in T cells or through the synthesis of particular natural ligands for cytosolic receptors that are able to alter lymphocyte functions.
- Particular IDO blocking agents include, but are not limited to levo-1 -methyl typtophan (L-1MT) and 1 -methyl-tryptophan (1MT).
- the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, STI-A1110, avelumab, atezolizumab, durvalumab, STI-A1014, ipilimumab, tremelimumab, GSK2831781, BMS-936559, or MED14736.
- methods provided herein comprise administering a composition comprising HDAC6-activated macrophages or a composition comprising HDAC6- activated macrophages to a subject in combination with chemotherapy.
- the chemotherapy comprises one of the anti-cancer drugs or anti-cancer drug combinations listed in Table 4.
- methods provided herein comprise administering HDAC6-activated macrophages or a composition comprising HDAC6-activated macrophages to a subject in combination with photothermal therapy.
- Photothermal therapy refers to efforts to use electromagnetic radiation (most often in infrared wavelengths) for the treatment of various medical conditions, including cancer. This approach is an extension of photodynamic therapy, in which a photosensitizer is excited with specific band light. This activation brings the sensitizer to an excited state where it then releases vibrational energy (heat), which is what kills the targeted cells. Unlike photodynamic therapy, photothermal therapy does not require oxygen to interact with the target cells or tissues. Current studies also show that photothermal therapy is able to use longer wavelength light, which is less energetic and therefore less harmful to other cells and tissues.
- HDAC6-activated macrophage refers to a naive macrophage that has been treated ex vivo with a selective HDAC6 inhibitor.
- the HDAC6-activated macrophage is first treated ex vivo with a selective HDAC6 inhibitor and then treated ex vivo with a macrophage polarizing agent and/or tumor antigen.
- the HDAC6-activated macrophage is first treated ex vivo with a macrophage polarizing agent and/or tumor antigen and then treated ex vivo with a selective HDAC6 inhibitor.
- selective HDAC6 inhibitor refers to a compound that preferentially inhibits histone deacetylase 6 over one or more other histone deacetylase isoforms, e.g., HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC7, HDAC8, HDAC9, HDAC10, and/or HDAC11, in a cell-based in vitro assay.
- the selective HDAC6 inhibitor preferentially inhibits HDAC6 over HDAC1.
- the selective HDAC6 inhibitor preferentially inhibits HDAC6 over HDAC1 and one or more other HD AC isoforms.
- the selective HDAC6 inhibitor is at least about 5-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 10-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 15-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 20-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 30-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 40-fold more selective over one or more other HDAC isoforms.
- the selective HDAC6 inhibitor is at least about 50-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 100-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 150-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 200-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 250-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 500-fold more selective over one or more other HDAC isoforms.
- the selective HDAC6 inhibitor is at least about 750-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 1000-fold more selective over one or more other HD AC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 2000-fold more selective over one or more other HD AC isoforms. In another aspect, the selective HDAC6 inhibitor is at least about 3000-fold more selective over one or more other HD AC isoforms. HDAC6 selectivity over the other HD AC isoforms in cell-based assays can be determined using methods known in the art.
- the selective HDAC6 inhibitor is at about 10-fold to about
- the selective HDAC6 inhibitor is at about 20-fold to about 3000-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at about 50-fold to about 3000-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at about 100-fold to about 3000-fold more selective over one or more other HDAC isoforms. In another aspect, the selective HDAC6 inhibitor is at about 500-fold to about 3000-fold more selective over one or more other HDAC isoforms.
- HDAC6 selectivity is determined using an isolated human, recombinant full-length HDAC from a baculovirus expression system in Sf9 cells.
- the reaction buffer is made up of 50 mM Tris-HCl pH 8.0, 127 mM NaCl, 2.7 mM KC1, 1 mM MgCfr, 1 mg/mL BSA, and a final concentration of 1% DMSO.
- the test compound is delivered in DMSO to the enzyme mixture with a pre-incubation of 5-10 min followed by substrate addition and incubation for 2 h at 30 °C.
- Trichostatin A and developer are added to quench the reaction and generate fluorescence, respectively.
- a dose-response curve is generated and the ICso value is determined from the resulting plot. See Bergman et al., J Med Chem. 55:9891-9899 (2012).
- the selective HDAC6 inhibitor is meant to include the parent compound and any pharmaceutically acceptable salts or solvates thereof.
- the selective HDAC6 inhibitor is a compound disclosed in Shen and
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
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- the selective HDAC6 inhibitor is a compound disclosed in
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- the selective HDAC6 inhibitor is a compound disclosed in
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- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
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- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound disclosed in
- the selective HDAC6 inhibitor is a compound having Formula
- X is selected from the group consisting of:
- R 1 is selected from the group consisting of hydrogen and Ci-4 alkyl
- R 2 is selected from the group consisting of optionally substituted C6-C14 aryl and aralkyl
- R 4C and R 4d are independently selected from the group consisting of hydrogen and Ci-4 alkyl; or
- R 8 is selected from the group consisting of hydrogen, Ci-4 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-C14 aryl, aralkyl, optionally substituted 5- to 14-membered heteroaryl, and heteroaralkyl;
- n 0, 1, or 2;
- n 1, 2, 3, 4, 5, or 6;
- ⁇ represents a single or double bond
- R a , R b , R d , and R e are independently selected from the group consisting of hydrogen, Ci- 6 alkyl, optionally substituted C3-6 cycloalkyl, optionally substituted C6-C14 aryl, optionally substituted 5- to 14-membered heteroaryl; or
- R a and R b taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo;
- R d and R e taken together with the nitrogen atom to which they are attached form an optionally substituted 3- to 12-membered heterocyclo
- R c is Ci -4 alkyl.
- the selective HDAC6 inhibitor is a compound having
- the selective HDAC6 inhibitor is a compound having Formula
- Z is -0-
- R 1 is selected from the group consisting of hydrogen and Ci-4 alkyl
- R 2 is optionally substituted C6-C14 aryl
- R 3 is selected from the group consisting of optionally substituted C6-C14 aryl and optionally substituted 5- to 14-membered heteroaryl;
- R 4C and R 4d are independently selected from the group consisting of hydrogen and Ci-4 alkyl
- R a and R b are independently selected from the group consisting of hydrogen and Ci- 6 alkyl; or
- R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclo
- R c is Ci -4 alkyl.
- the selective HDAC6 inhibitor is a compound having
- R 1 is hydrogen.
- R 2 is optionally substituted phenyl.
- R 2 is optionally substituted 1 -naphthyl.
- R 2 is optionally substituted 2-naphthyl.
- R 2 is aralkyl.
- the selective HDAC6 inhibitor is a compound having
- Formula V wherein X is X-2.
- Z is -0-.
- Z is -N(R 8 )-
- R 3 is optionally substituted C6-C14 aryl.
- R 3 is optionally substituted 5- to 14-membered heteroaryl.
- the selective HDAC6 inhibitor is a compound having
- the selective HDAC6 inhibitor is a compound having
- the selective HDAC6 inhibitor is a compound having
- the selective HDAC6 inhibitor is a compound having
- R a and R b are independently selected from the group consisting of hydrogen and Ci-4 alkyl; or
- R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclo
- R c is Ci-4 alkyl
- n 1, 2, or 3.
- the selective HDAC6 inhibitor is a compound having
- R 6a , R 6b , R 6c , R 6d , and R 6e are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy.
- the selective HDAC6 inhibitor is a compound having
- n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound having
- R a and R b are independently selected from the group consisting of hydrogen and Ci-4 alkyl; or
- R a and R b taken together with the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclo
- R c is Ci-4 alkyl
- n 1 , 2, or 3.
- the selective HDAC6 inhibitor is a compound having
- R 7a , R 7b , R 7c , R 7d , and R 7e are each independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy.
- the selective HDAC6 inhibitor is a compound having
- n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound having
- R 4a and R 4b are independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy;
- R 4C and R 4d are independently selected from the group consisting of hydrogen and methyl
- n 0 or 1 ;
- n 1, 2, or 3;
- ⁇ represents a single or double bond.
- the selective HDAC6 inhibitor is a compound having
- the selective HDAC6 inhibitor is a compound having
- the selective HDAC6 inhibitor is a compound having
- n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound having
- R 5a and R 5c are independently selected from the group consisting of hydrogen, halogen, cyano, Ci-4 alkyl, and Ci-4 alkoxy;
- n 1, 2, or 3.
- the selective HDAC6 inhibitor is a compound having
- n is 1. In another aspect, n is 2. In another aspect, n is 3.
- the selective HDAC6 inhibitor is a compound of Table 1, or a pharmaceutically acceptable salt thereof.
- Table 1
- macrophage polarizing agent refers to an agent that polarizes a macrophage.
- Macrophage polarization is a process by which macrophages adopt different functional programs in response to the signals from their microenvironment.
- the polarization of macrophages can give a diverse heterogenic function and phenotypes depending on their activation in respect to their duration of stimulation and spatial localization.
- Non-limiting exemplary macrophage polarizing agent include, but are not limited to, lipopolysaccharide (LPS), interferon-gamma (IFN-g), interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6, interleukin- 10, interleukin- 12, interleukin-13, interleukin- 18, interleukin-23, transforming growth factor beta (TGF-g), glucocorticoids, lipoteichoic acid (LTA), granulocyte-macrophage colony- stimulating factor (GM-CSF), tumor necrosis factor (TNF), immune complexes (IC), interleukin- 1/?, adenosines, or the combination thereof.
- LPS lipopolysaccharide
- IFN-g interferon-gamma
- IFN-g interleukin-2, interleukin-3, interleukin-4, interleukin-5, interleukin-6
- tumor antigen refers to an antigenic substance that can be produced in tumor cells and trigger an immune response in the host.
- Tumor antigens can be classified into two categories. One category is products of mutated oncogenes and tumor suppressor genes, and the other category is products of other mutated genes which include overexpressed or aberrantly expressed cellular proteins, tumor antigens produced by oncogenic viruses, oncofetal antigens, altered cell surface glycolipids and glycoproteins, and cell type-specific differentiation antigens.
- Non-limiting exemplary tumor antigens include, but are not limited to, Alphafetoprotein (AFP), Carcinoembryonic antigen (CEA), CA-125, MUC-1, Epithelial tumor antigen (ETA), Tyrosinase, Melanoma-associated antigen (MAGE), and p53.
- AFP Alphafetoprotein
- CEA Carcinoembryonic antigen
- CA-125 CA-125
- MUC-1 Epithelial tumor antigen
- ETA Epithelial tumor antigen
- Tyrosinase Melanoma-associated antigen
- MAGE Melanoma-associated antigen
- halo or "halogen” as used by itself or as part of another group refers to -Cl, -F, -Br, or -I. In one aspect, the halo is -Cl or -F. In one aspect, the halo is -Cl.
- nitro as used by itself or as part of another group refers to -NO2.
- cyano as used by itself or as part of another group refers to -CN.
- hydroxy as used by itself or as part of another group refers to -OH.
- alkyl refers to unsubstituted straight- or branched-chain aliphatic hydrocarbons containing from one to twelve carbon atoms, i.e., Ci-12 alkyl, or the number of carbon atoms designated, e.g., a Ci alkyl such as methyl, a C2 alkyl such as ethyl, a C3 alkyl such as propyl or isopropyl, a C1-3 alkyl such as methyl, ethyl, propyl, or isopropyl, and so on.
- the alkyl is a Ci-10 alkyl.
- the alkyl is a Ci-6 alkyl. In another aspect, the alkyl is a Ci-4 alkyl. In another aspect, the alkyl is a straight chain Ci-10 alkyl. In another aspect, the alkyl is a branched chain C3-10 alkyl. In another aspect, the alkyl is a straight chain Ci-6 alkyl. In another aspect, the alkyl is a branched chain C3-6 alkyl. In another aspect, the alkyl is a straight chain Ci-4 alkyl. In another aspect, the alkyl is a branched chain C3-4 alkyl. In another aspect, the alkyl is a straight or branched chain C3-4 alkyl.
- Non-limiting exemplary Ci-10 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, /c7-butyl, /vo-butyl, 3 -pentyl, hexyl, heptyl, octyl, nonyl, and decyl.
- Non-limiting exemplary Ci-4 alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, /e 7-butyl, and /so-butyl.
- cycloalkyl refers to saturated and partially unsaturated (containing one or two double bonds) cyclic aliphatic hydrocarbons containing one to three rings having from three to twelve carbon atoms, i.e., C3-12 cycloalkyl or the number of carbons designated.
- the cycloalkyl group has two rings.
- the cycloalkyl group has one ring.
- the cycloalkyl group is chosen from a C3-8 cycloalkyl group.
- the cycloalkyl group is chosen from a C3-6 cycloalkyl group.
- Non-limiting exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, norbomyl, decalin, adamantyl, cyclohexenyl, cyclopentenyl, and cyclohexenyl.
- the optionally substituted cycloalkyl is substituted with two substituents.
- the optionally substituted cycloalkyl is substituted with one substituent.
- alkenyl refers to an alkyl group as defined above containing one, two or three carbon-to- carbon double bonds.
- the alkenyl group is chosen from a C2-6 alkenyl group.
- the alkenyl group is chosen from a C2-4 alkenyl group.
- Non- limiting exemplary alkenyl groups include ethenyl, propenyl, isopropenyl, butenyl, sec- butenyl, pentenyl, and hexenyl.
- alkynyl refers to an alkyl group as defined above containing one to three carbon-to-carbon triple bonds.
- the alkynyl has one carbon-to-carbon triple bond.
- the alkynyl group is chosen from a C2-6 alkynyl group.
- the alkynyl group is chosen from a C2-4 alkynyl group.
- Non-limiting exemplary alkynyl groups include ethynyl, propynyl, butynyl, 2-butynyl, pentynyl, and hexynyl groups.
- haloalkyl refers to an alkyl group substituted by one or more fluorine, chlorine, bromine and/or iodine atoms.
- the alkyl group is substituted by one, two, or three fluorine and/or chlorine atoms.
- the haloalkyl group is a Ci- 6 haloalkyl group.
- the haloalkyl group is a Ci-4 haloalkyl group.
- Non limiting exemplary haloalkyl groups include fluoromethyl, 2-fluoroethyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 1,1-difluoroethyl, 2,2-difluoroethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, and trichloromethyl groups.
- alkoxy refers to an optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl or optionally substituted alkynyl attached to a terminal oxygen atom.
- the alkoxy group is chosen from a Ci-4 alkoxy group.
- the alkoxy group is chosen from a Ci- 6 alkoxy group.
- the alkoxy group is chosen from a Ci-4 alkyl attached to a terminal oxygen atom, e.g., methoxy, ethoxy, and /er/-butoxy.
- haloalkoxy as used by itself or as part of another group refers to a Ci-4 haloalkyl attached to a terminal oxygen atom.
- Non-limiting exemplary haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, and 2,2,2-trifluoroethoxy.
- aryl refers to a monocyclic, bicyclic, or tricyclic aromatic ring system having from six to fourteen carbon atoms, i.e., C 6 -CM aryl.
- Non-limiting exemplary aryl groups include phenyl (abbreviated as "Ph"), 1 -naphthyl, 1 -naphthyl, phenanthryl, anthracyl, indenyl, azulenyl, biphenyl, biphenylenyl, and fluorenyl groups.
- the aryl group is chosen from phenyl, 1 -naphthyl, or 2-naphthyl. In one aspect, the aryl is a bicyclic or tricyclic CIO-CM aromatic ring system.
- the optionally substituted aryl is an optionally substituted phenyl.
- the optionally substituted phenyl has four substituents. In another aspect, the optionally substituted phenyl has three substituents. In another aspect, the optionally substituted phenyl has two substituents. In another aspect, the optionally substituted phenyl has one substituent.
- Non-limiting exemplary substituted aryl groups include 2- methylphenyl, 2-methoxyphenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 3- methylphenyl, 3-methoxyphenyl, 3 -fluorophenyl, 3-chlorophenyl, 4-methylphenyl, 4- ethylphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 2,6-di-fluorophenyl, 2,6- di-chlorophenyl, 2-methyl, 3-methoxyphenyl, 2-ethyl, 3-methoxyphenyl, 3,4-di- methoxyphenyl, 3,5-di-fluorophenyl, 3,4-di-chlorophenyl, 3,5-di-methylphenyl, 3,5- dimethoxy, 4-methylphenyl, 2-fluoro-3-chlorophenyl, and 3-chloro-4
- heteroaryl refers to monocyclic, bicyclic, and tricyclic aromatic ring systems having 5 to 14 ring atoms, i.e., a 5- to 14-membered heteroaryl, wherein at least one carbon atom of one of the rings is replaced with a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur.
- the heteroaryl contains 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of oxygen, nitrogen and sulfur.
- the heteroaryl has three heteroatoms.
- the heteroaryl has two heteroatoms.
- the heteroaryl has one heteroatom.
- Non-limiting exemplary heteroaryl groups include thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, benzofuryl, pyranyl, isobenzofuranyl, benzooxazonyl, chromenyl, xanthenyl, 2 H- pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, isoindolyl, 3//-indolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, cinnolinyl, quinazolinyl, pteridinyl, 4a//-carbazolyl, carbazolyl, b- carb
- the heteroaryl is chosen from thienyl (e.g., thien-2-yl and thien-3-yl), furyl (e.g., 2-furyl and 3-furyl), pyrrolyl (e.g., lH-pyrrol-2-yl and lH-pyrrol-3-yl), imidazolyl (e.g., 2H-imidazol-2-yl and 2H-imidazol-4-yl), pyrazolyl (e.g., lH-pyrazol-3-yl, lH-pyrazol-4- yl, and lH-pyrazol-5-yl), pyridyl (e.g., pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl), pyrimidinyl (e.g., pyrimidin-2-yl, pyrimidin-4-yl, and pyrimidin-5-yl), thienyl
- the heteroaryl is a 5- or 6-membered heteroaryl.
- the heteroaryl is a 5-membered heteroaryl, i.e., the heteroaryl is a monocyclic aromatic ring system having 5 ring atoms wherein at least one carbon atom of the ring is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur.
- Non-limiting exemplary 5-membered heteroaryl groups include thienyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, imidazolyl, thiazolyl, isothiazolyl, and isoxazolyl.
- the heteroaryl is a 6-membered heteroaryl, e.g., the heteroaryl is a monocyclic aromatic ring system having 6 ring atoms wherein at least one carbon atom of the ring is replaced with a nitrogen atom.
- Non-limiting exemplary 6 membered heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, and pyridazinyl.
- the heteroaryl is a 9- to 14-membered bicyclic aromatic ring system, wherein at least one carbon atom of one of the rings is replaced with a heteroatom independently selected from the group consisting of oxygen, nitrogen and sulfur.
- Non limiting exemplary 9- to 14-membered bicyclic aromatic ring systems include:
- heterocycle or “heterocyclo” as used by itself or as part of another group refers to saturated and partially unsaturated, e.g., containing one or two double bonds, cyclic groups containing one, two, or three rings having from three to fourteen ring members, i.e., a 3- to 14-membered heterocyclo, wherein at least one carbon atom of one of the rings is replaced with a heteroatom.
- Each heteroatom is independently selected from the group consisting of oxygen, sulfur, including sulfoxide and sulfone, and/or nitrogen atoms, which can be oxidized or quatemized.
- heterocyclo is also meant to include groups having fused optionally substituted aryl groups, e.g., indolinyl.
- the heterocyclo group is chosen from a 5- or 6- membered cyclic group containing one ring and one or two oxygen and/or nitrogen atoms.
- heterocyclo can be optionally linked to the rest of the molecule through any available carbon or nitrogen atom.
- Non-limiting exemplary heterocyclo groups include dioxanyl, tetrahydropyranyl, 2-oxopyrrolidin-3-yl, piperazin-2-one, piperazine-2, 6-dione, 2-imidazolidinone, piperidinyl, morpholinyl, piperazinyl, pyrrolidinyl, and indolinyl.
- the term "aralkyl” as used by itself or as part of another group refers to an alkyl group substituted with one, two, or three optionally substituted aryl groups.
- the optionally substituted aralkyl group is a Ci-4 alkyl substituted with one optionally substituted aryl group.
- the aralkyl group is a Ci or C2 alkyl substituted with one optionally substituted aryl group.
- the aralkyl group is a Ci or C2 alkyl substituted with one optionally substituted phenyl group.
- Non-limiting exemplary aralkyl groups include benzyl, phenethyl, -CHPI12, -CH2(4-F-Ph), -CH 2 (4-Me-Ph), -CH 2 (4-CF -Ph), and -CH(4-F-Ph) 2.
- heteroaralkyl refers to an alkyl group substituted with one, two, or three optionally substituted heteroaryl groups.
- the heteroaralkyl group is a Ci-4 alkyl substituted with one optionally substituted heteroaryl group.
- the aralkyl group is a Ci or C2 alkyl substituted with one optionally substituted heteroaryl group.
- the heteroaralkyl group is a Ci or C2 alkyl substituted with one optionally substituted heteroaryl group.
- Non-limiting exemplary heteroaralkyl groups include:
- HD AC refers to a family of enzymes that remove acetyl groups from a protein, for example, the -amino groups of lysine residues at the N-terminus of a histone.
- the HD AC can be any human HD AC isoform including, HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, HDAC6, HDAC7, HDAC8, HDAC9, HDAC10, and HDAC11.
- the HD AC also can be derived from a protozoal or fungal source.
- treat refers to eliminating, reducing, relieving, reversing, and/or ameliorating a disease or condition and/or symptoms associated therewith. Although not precluded, treating a disease or condition does not require that the disease, condition, or symptoms associated therewith be completely eliminated, including the treatment of acute or chronic signs, symptoms and/or malfunctions.
- the terms “treat,” “treating,” “treatment,” and the like may include “prophylactic treatment,” which refers to reducing the probability of redeveloping a disease or condition, or of a recurrence of a previously-controlled disease or condition, in a subject who does not have, but is at risk of or is susceptible to, redeveloping a disease or condition or a recurrence of the disease or condition, "treatment” therefore also includes relapse prophylaxis or phase prophylaxis.
- treat and synonyms contemplate administering a therapeutically effective amount of a compound of the disclosure to an individual, e.g., a mammalian patient including, but not limited to, humans and veterinary animals, in need of such treatment.
- a treatment can be orientated symptomatically, for example, to suppress symptoms. It can be effected over a short period, be oriented over a medium term, or can be a long-term treatment, for example within the context of a maintenance therapy.
- terapéuticaally effective amount refers to an amount of the active ingredient(s) that, when administered, is (are) sufficient, to efficaciously deliver the active ingredient(s) for the treatment of condition or disease of interest to an individual, e.g., human patient, in need thereof.
- the therapeutically effective amount of the agent may reduce (i.e., retard to some extent and preferably stop) unwanted cellular proliferation; reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., retard to some extent and preferably stop) cancer cell infiltration into peripheral organs; inhibit (i.e., retard to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; reduce HD AC signaling in the target cells; and/or relieve, to some extent, one or more of the symptoms associated with the cancer.
- the administered compound or composition prevents growth and/or kills existing cancer cells, it may be cytostatic and/or cytotoxic.
- subject refers to any human or mammal that is in need of or might benefit from treatment with HDAC6-activated macrophages. Foremost among such subjects are humans, although the methods and compositions provided herein are not intended to be so limited. Other subjects include veterinary animals, e.g., cows, sheep, pigs, horses, dogs, cats and the like. In one embodiment, the subject is a human. In one embodiment, the subject is a mammal.
- Selective HDAC6 inhibitors can exist as salts. As used herein, the term
- “pharmaceutically acceptable salt” refers to salts or zwitterionic forms of the present compounds. Salts of the present compounds can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation.
- the pharmaceutically acceptable salts of the present compounds can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, tartaric, and citric.
- Nonlimiting examples of salts of selective HDAC6 inhibitors include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2-hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate,
- selective HDAC6 inhibitors can be quatemized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
- Any reference to compounds of the present disclosure appearing herein is intended to include selective HDAC6 inhibitors as well as pharmaceutically acceptable salts, solvates, or hydrates thereof
- SMI murine melanoma cells were obtained from Dr. A. Ribas at the University of California, Los Angeles, and cultured in an incubator in RPMI 1640, 1% penicillin-streptomycin, and 10% fetal bovine serum at 37°C with 5% CO2.
- RNA quantification was done using a NanoDrop One spectrophotometer (NanoDrop Technologies). Samples with absorbance at 260/280 nm ratios over 1.9 were used for cDNA synthesis with the iScript cDNA synthesis kit (Bio-Rad, 1708891). Synthesized cDNA from 1 pg of total RNA was diluted 1 :10 with nuclease-free water.
- the quantitative PCR analysis was performed using iQ SYBR Green Supermix (Bio-Rad, 1708882) on a CFX96 real-time system (Bio-Rad). Gene expression analysis was performed using the 2 DDa method, and target mRNA levels were normalized to GAPDH expression. Cycling conditions were used as per the manufacturer’s instructions. Single PCR product amplification was confirmed by melting curve analysis in all the experiments performed.
- mice Animal experiments involving mice were performed in accordance with the protocol (#A354) approved by the Institutional Care and Use Committee (IACUC) at The George Washington University. C57BL/6 female mice were purchased from the Charles River Laboratories (Wilmington, Massachusetts, USA). In vivo studies were performed using SMI tumor cells that were passaged in vivo from mouse to mouse for a minimum of five times before tumor implantation. Mice were injected subcutaneously with 1.0 x 10 6 in vivo passaged SMI melanoma cells suspended in 100 pL phosphate-buffered saline (PBS) (Coming, 21-040-CV). The pre-treatment arm was started once the tumors were palpable, which was about 5 days post tumor implantation.
- PBS phosphate-buffered saline
- mice were treated with the test article or vehicle control. Mice were treated until tumors in the control group reached maximum size according to our IACUC protocol. Tumor volume measurements were taken on alternate days using caliper measurements and calculated using the formula L x W 2 /2. All animal studies were performed with consideration for toxicity, and we routinely monitored for early signs of toxicity. Emphasis was given to mortality, body weight, and food consumption. At the endpoint, a postmortem evaluation, including gross visual examination of organs such as the liver for hepatotoxicity, splenomegaly, and lung metastatic nodules, was done for each condition. Shen et al., J Med Chem. 62 8557-8577 (2019).
- Bone marrow derived macrophages For macrophage isolation, bone marrow from 6-12 weeks old C57BL/6 mouse was used following an IACUC approved protocol. Briefly, femurs and tibia bones were isolated after removing the skeletal muscles. The bone marrow was flushed with RPMI complete medium supplemented with non-essential amino acids. A single-cell suspension of bone marrow was prepared with repeated pipetting and incubated with 20 ng/mL of mouse recombinant M-CSF (Biolegend) at 37°C for 4 days to differentiate into macrophages.
- M-CSF mouse recombinant M-CSF
- Flow cytometry was performed following the protocol described previously. Knox et al., Sci Rep. 2019 Oct 10;9(1): 14824. doi: 10.1038/s41598-019-51403-6. Briefly, mice were euthanized following the IACUC protocol, and tumor cells were processed into a single cell suspension for analysis by flow cytometry with tumor digestion buffer. The following antibodies were used to stain cell surface markers expressed by different immune cells. All the antibodies were purchased from Biolegend (San Diego, CA) unless otherwise specified.
- Myeloid cell surface markers are as follows: APC anti-mouse CD80 (clone 16-10A1), PE/Cy7 anti-mouse CD206 (MMR) (clone C068C2), APC/FireTM 750 anti-mouse CD45.2 (clone 104), FITC anti-mouse H-2 (clone Ml/42), Brilliant Violet 785TM anti-mouse F4/80 (clone BM8), and Alexa Fluor® 700 anti-mouse CD3 (clone 17A2).
- APC anti-mouse H-2Kb bound to SIINFEKF antibody clone 25-D1.16
- Multi-color flow data acquisition was performed on BD Celesta, and data analysis was performed with FlowJo software (version 10.3).
- Statistical analyses were performed with GraphPad Prism Software (version 7.03).
- Endogenous peptides are usually presented through MHC-I to CD8 T-cells and exogenous (from other cells such as tumors) peptides through MHC-II to CD4 T-cells.
- exogenous peptides when exogenous peptides are presented through MHC-I, it leads to anti-tumor immunity by activation of CD8 T-cells. This mechanism is called cross-presentation (XPT).
- Cross-presentation is highly relevant to radiation therapy, where a plethora of neoantigens is generated.
- SIINFEKL SEQ ID NO.
- SIINFEKL is an 8 amino acid peptide generated by proteolytic cleavage of ovalbumin which is loaded on MHC-I in the endoplasmic reticulum and transported to the cell surface for presentation to T-cell receptors (TCR). Taking advantage of a highly specific antibody recognizing MHC-I loaded with SIINFEKL peptide, efficiency of antigen XPT was determined.
- HD AC inhibitors decrease polarization of macrophages towards the M2 phenotype
- BMDMs bone marrow derived macrophages
- C57BL/6 mouse were differentiated into macrophages with M-CSF. These naive macrophages were pre-treated with NextA and polarized to Ml macrophages with LPS/IFNy or M2 macrophages with IL4/IL13. NextA pre-treatment decreased polarization of M2 macrophages but did not affect Ml macrophages as indicated by flow cytometry. See Fig. 5 and Fig. 4. [0252] Further validation of M2 polarization markers at gene expression levels by quantitative real-time PCR indicate that Arginase I, IL-10 and TGFp, which are tumor- promoting factors, were decreased. Fig. 9, Fig. 10, and Fig. 11.
- Ml polarization markers and anti-tumor, pro-inflammatory cytokines such as TNFa and IL-1B were increased.
- Fig. 12 and Fig. 13 These data suggest that pre-treatment with NextA affects cellular signaling and programming of naive macrophages in response to polarizing factors in the tumor microenvironment (TME).
- SMI murine melanoma cells resemble human melanoma tumors in terms of mutational burden.
- Adoptive transfer therapy with murine naive, Ml, and M2 macrophages when the tumor size was 5x5mm was performed, and the tumors were allowed to grow till the endpoint, which is a tumor size of 2cm diameter. See Fig. 6, Fig. 7, Fig. 8, and Fig. 14.
- Fig. 7 In the M2 macrophage therapy group, pre-treatment with NextA suppressed the tumor growth compared to Ml macrophages without NextA pre-treatment and control groups.
- Fig. 7. In the M2 macrophage therapy group, the growth of the tumor was detrimental to the mice and had to be sacrificed due to large tumor sizes.
- Fig. 8. Also, Fig. 15 and Fig. 16 show that the M1/M2 macrophage ratio is indicative of the immune status of TME. There is a negative correlation of anti-tumor Ml macrophages with tumor size and positive correlation of tumor size with pro-tumor M2 macrophages.
- Fig. 17 shows M1/M2 ratio correlation to tumor size.
- FIG. 18 A schematic showing the therapy regime in a separate SMI murine melanoma experiment is shown in Fig. 18.
- M1+ NextA shows a decrease in tumor size compared to vehicle group.
- Fig. 19 Survival analysis indicates that the Ml+NextA group has better survival compared to the other treatment groups.
- Ml macrophages derived from HDAC6KO also show a decrease in tumor growth suggesting a major role of HDAC6 in macrophage function.
- Fig. 21 A schematic showing the therapy regime in a separate SMI murine melanoma experiment is shown in Fig. 18.
- M1+ NextA shows a decrease in tumor size compared to vehicle group.
- Fig. 19 Survival analysis indicates that the Ml+NextA group has better survival compared to the other treatment groups.
- Fig. 20. Ml macrophages derived from HDAC6KO also show a decrease in tumor growth suggesting a major role of HDAC6 in macrophage function.
- MO macrophages treated with a selective HDAC6 inhibitor are like Ml macrophages
- MO macrophages treated with a selective HDAC6 inhibitor are like Ml macrophages with respect to their cytokine profile.
- Fig. 22 shows that the expression of M2 anti-inflammatory cytokines TGF beta and IL10 are decreased in MO macrophages treated with a selective HDAC6 inhibitor.
- Fig. 23 shows that Ml pro-inflammatory cytokines such as IL12, TNF alpha and IL1 beta expression increases after treatment with NextA.
- Fig. 24 shows that antigen presentation and processing genes such as TAPI,
- TAP2 TAP2, TAPBP, and ERAPl are increased in Ml macrophages compared to M0 after treatment with a NextA.
- the combination of radiation and HDAC6 inhibition increases antigen presentation in a time dependent manner.
- SMI cells stably expressing Ova peptide when exposed to 4 Gy of radiation, NextA, or a combination of both show a time dependent increases in presentation of MHC-I mediated SIINFEKL antigen presentation measured by flow cytometry.
- Radiation with HDAC6 inhibition increases antigen presentation in tumor cells.
- the sequencing of NextA and radiation treatment for effective antigen presentation in tumor cells is show in Fig. 26.
- FIG. 27 A schematic showing the work flow for antigen cross presentation by macrophages where SMI -OVA cells are exposed to 9-11 Gy of radiation which releases OVA peptide into the medium HDAC6 inhibition increases antigen cross presentation in macrophages is shown in Fig. 27.
- M0, Ml and M2 BMDMs bone marrow derived macrophages exposed to conditioned medium from radiation exposed SMI -OVA cells and antigen presentation measured by APC-MHC-I SIINFEKL antibody by flow cytometry is shown in Fig. 28, Fig, 29, and Fig. 30.
- Treatment with a HDAC6 inhibitor increases antigen cross presentation in macrophages.
- HD AC inhibitors with low selectivity toward HDAC6 do not induce as many immunological changes in tumor or immune cells as compared to HD AC inhibitors with high selectivity toward HDAC6.
- ACY1215 and ACY241, with 12- and 13-fold HDAC6 selectivity respectively (Fig. 31; see Bergman et al., J Med Chem. 55:9891-9899 (2012); Santo et al, Blood 779:2579-2589 (2012); Huang et al, Oncotarget 8: 2694-2707 (2017); Jochems et al., Neuropsychopharmacology 39: 389-400 (2014)), do not reduce the expression of PD-L1 (Fig. 32).
- HDAC6 inhibitors have lower cellular cytotoxicity as compared to pan- HDAC inhibitors, e.g., LBH589, which could induce undesired toxicity in non- transformed cells.
- Fig. 35 Macrophages are particularly susceptible to HDAC inhibition. However, NextA induced high cytotoxicity over 5 mM.
- Fig. 36
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US17/623,050 US20220401474A1 (en) | 2019-06-27 | 2020-06-26 | Hdac6-activated macrophages, compositions, and uses thereof |
BR112021026334A BR112021026334A2 (en) | 2019-06-27 | 2020-06-26 | HDac6-activated macrophages, compositions, and uses thereof |
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Cited By (8)
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CN113387840A (en) * | 2021-06-10 | 2021-09-14 | 中国药科大学 | PD-1/PD-L1 and HDACs double-target inhibitor, preparation method and application |
WO2022203429A1 (en) * | 2021-03-26 | 2022-09-29 | Chong Kun Dang Pharmaceutical Corp. | Composition for preventing or treating multiple sclerosis |
WO2023073600A1 (en) * | 2021-10-29 | 2023-05-04 | Chong Kun Dang Pharmaceutical Corp. | Compositions for preventing or treating idiopathic pulmonary fibrosis (ipf) |
WO2023144736A1 (en) * | 2022-01-28 | 2023-08-03 | Chong Kun Dang Pharmaceutical Corp. | Compositions for preventing or treating pulmonary arterial hypertension |
WO2023195809A1 (en) * | 2022-04-07 | 2023-10-12 | Chong Kun Dang Pharmaceutical Corp. | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and uses thereof |
WO2023217095A1 (en) * | 2022-05-09 | 2023-11-16 | Synrx Therapeutics (Hangzhou) Co., Ltd. | Heterocyclic compound, pharmaceutical composition and use thereof |
WO2024056738A1 (en) * | 2022-09-14 | 2024-03-21 | Technische Universität Dresden | Allogeneic human macrophages for cell therapy |
US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
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Cited By (8)
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US11938134B2 (en) | 2017-03-10 | 2024-03-26 | Eikonizo Therapeutics, Inc. | Metalloenzyme inhibitor compounds |
WO2022203429A1 (en) * | 2021-03-26 | 2022-09-29 | Chong Kun Dang Pharmaceutical Corp. | Composition for preventing or treating multiple sclerosis |
CN113387840A (en) * | 2021-06-10 | 2021-09-14 | 中国药科大学 | PD-1/PD-L1 and HDACs double-target inhibitor, preparation method and application |
WO2023073600A1 (en) * | 2021-10-29 | 2023-05-04 | Chong Kun Dang Pharmaceutical Corp. | Compositions for preventing or treating idiopathic pulmonary fibrosis (ipf) |
WO2023144736A1 (en) * | 2022-01-28 | 2023-08-03 | Chong Kun Dang Pharmaceutical Corp. | Compositions for preventing or treating pulmonary arterial hypertension |
WO2023195809A1 (en) * | 2022-04-07 | 2023-10-12 | Chong Kun Dang Pharmaceutical Corp. | 1,3,4-oxadiazole derivative compounds as histone deacetylase 6 inhibitor, and uses thereof |
WO2023217095A1 (en) * | 2022-05-09 | 2023-11-16 | Synrx Therapeutics (Hangzhou) Co., Ltd. | Heterocyclic compound, pharmaceutical composition and use thereof |
WO2024056738A1 (en) * | 2022-09-14 | 2024-03-21 | Technische Universität Dresden | Allogeneic human macrophages for cell therapy |
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CN115443329A (en) | 2022-12-06 |
US20220401474A1 (en) | 2022-12-22 |
CA3144985A1 (en) | 2020-12-30 |
BR112021026334A2 (en) | 2022-05-10 |
JP2022538284A (en) | 2022-09-01 |
EP3990618A4 (en) | 2023-08-09 |
EP3990618A1 (en) | 2022-05-04 |
AU2020302928A1 (en) | 2022-02-03 |
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