WO2017201200A1 - Compositions thérapeutiques contenant des antagonistes de rar-alpha - Google Patents

Compositions thérapeutiques contenant des antagonistes de rar-alpha Download PDF

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WO2017201200A1
WO2017201200A1 PCT/US2017/033172 US2017033172W WO2017201200A1 WO 2017201200 A1 WO2017201200 A1 WO 2017201200A1 US 2017033172 W US2017033172 W US 2017033172W WO 2017201200 A1 WO2017201200 A1 WO 2017201200A1
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cancer
subject
cells
rara
effective
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WO2017201200A8 (fr
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Scott Mcnear THACHER
Paul Damian CROWE
Haiyan TAO
Raj Kumar Raheja
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Orphagen Pharmaceuticals, Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/39—Heterocyclic compounds having sulfur as a ring hetero atom having oxygen in the same ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • RAR retinoic acid receptor
  • All-trans retinoic acid (RA or atRA) is derived from the essential nutrient Vitamin A (retinol) and has a central role in embryonic and adult tissue development as well homeostasis of the immune system (Clagett-Dame and Knutson 2011).
  • Retinoic acid acts by binding to the retinoic acid receptors (RARs), which then binds to DNA as a heterodimer with one of the retinoid X receptors (RXRs) in DNA regions called retinoic acid response elements (RAREs). Binding of RA to an RAR alters the conformation of the RAR, which affects the binding of coregulatory proteins that either induce or repress transcription of nearby target genes.
  • RARa Three subtypes of RARs have been identified: RARa, RARJ3 and RARy. These have separate tissue distributions and, by means of individual gene deletion studies, are shown to have different functions (Thacher, Vasudevan, and Chandraratna 2000).
  • Retinoid agonists have been widely suggested to have anti-cancer effects. Examples include treatment of acute promyelocytic leukemia (APL) with all-trans RA, treatment of cutaneous T cell lymphoma with 9-cis retinoic acid or bexarotene, and treatment of preneoplastic lesions of the skin with tazarotene or other topical retinoids. Retinoids also suppress carcinogenesis in animal models of carcinogenesis (Bushue and Wan 2010; Uray, Dmitrovsky, and Brown 2016).
  • APL acute promyelocytic leukemia
  • RA cutaneous T cell lymphoma
  • 9-cis retinoic acid or bexarotene treatment of preneoplastic lesions of the skin with tazarotene or other topical retinoids.
  • Retinoids also suppress carcinogenesis in animal models of carcinogenesis (Bushue and Wan 2010; Uray, Dmitrovsky, and Brown 2016).
  • An embodiment provides a method of treating cancer, comprising identifying a subject in need of cancer treatment; and administering a RARa antagonist to the subject in an amount that is effective to treat the cancer.
  • the subject is a human.
  • Various embodiments of the method of treating cancer provide for administering a RARa antagonist to the subject in an amount that is effective to treat the cancer.
  • the amount that is effective to treat the cancer is an amount that is effective to inhibit RALDH activity in CDl lc+ CD 103+ dendritic cells in the subject.
  • the amount that is effective to treat the cancer is an amount that is effective to reduce the frequency of CDl lc+ CD103+ dendritic cells in the subject.
  • the amount that is effective to treat the cancer is an amount that is effective to inhibit inducible Treg formation in the subject.
  • the amount that is effective to treat the cancer is an amount that is effective to elevate the fraction of CD4+ or CD8+ T cells expressing CD 103 in the subject. In an embodiment, the amount that is effective to treat the cancer is an amount that is effective to reduce the fraction of CD4+ or CD8+ T cells expressing ⁇ 4 ⁇ 7 in the subject.
  • the aforementioned embodiments of amounts that are effective to treat the cancer can be practiced singly or in any combination thereof.
  • identifying the subject in need of cancer treatment comprises identifying the subject as being in need of retinoic acid antagonism.
  • identifying the subject in need of cancer treatment comprises identifying the subject as having been previously treated with an immune checkpoint inhibitor.
  • the subject in need of cancer treatment has a cancer that is selected from the group consisting of prostate cancer, breast cancer, bladder cancer, stomach cancer, cancer of the oropharynx, cancer of the nasopharynx, cancer of the esophagus, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, ovarian cancer, testicular cancer, colon cancer, cancer of the rectum, cancer of the anus, lung cancer, thyroid cancer, brain cancer, cancer of the head and neck, cancer of the hematopoietic system and skin cancer.
  • a cancer that is selected from the group consisting of prostate cancer, breast cancer, bladder cancer, stomach cancer, cancer of the oropharynx, cancer of the nasopharynx, cancer of the esophagus, stomach cancer, pancreatic cancer, liver cancer, kidney cancer, ovarian cancer, testicular cancer, colon cancer, cancer of the rectum, cancer of the anus, lung cancer, thyroid cancer, brain cancer, cancer of the head and neck, cancer of the hematop
  • the cancer of the hematopoietic system is selected from the group consisting of Hodgkin's lymphoma, Non- Hodgkin's lymphoma, acute leukemia, chronic leukemia, lymphoid leukemia and myeloid leukemia.
  • the skin cancer is selected from the group consisting of basal cell carcinoma, squamous cell carcinoma and melanoma.
  • Various embodiments of the method of treating cancer provide for administering a RARa antagonist to the subject.
  • the RARa antagonist is selected from the group consisting of AGN 194301, AGN 194574, ER50891, LEI 35, Ro 41- 5253 and BMS 195614.
  • any of the aforementioned methods of treating cancer can comprise administering a second chemotherapeutic agent to the subject.
  • Another embodiment provides a pharmaceutical composition, comprising amounts of a RARa antagonist and a second chemotherapeutic agent that is effective to treat a cancer.
  • FIG. 1 Structure of AGN 194301.
  • FIG. 2A-D Dose response of Ro41-5243 and LE 135 in Chinese Hamster Ovary (CHO) cell assays of transcription.
  • CHO cells were transfected with an expression plasmid encoding a fusion of the DNA-binding domain (DBD) of the yeast transcriptional factor Gal4 with the ligand-binding domain of human RARa, ⁇ or ⁇ .
  • a luciferase reporter containing a 5xGal4 response element at its promoter region was cotransfected with the receptor chimera.
  • Ro41-5253 or LE 135 were added in DMSO and each point is the mean of triplicate values, normalized to a DMSO-only control.
  • Ro41-5253 was tested in the presence (2A and 2C) or absence (2B and 2D) of 1 nM all-trans retinoic acid (RA).
  • LE135 was tested in the presence (2A and 2C) or absence (2B and 2D) of 0.5 nM TTNPB.
  • FIG. 3A-F Dose response of AGN 194301, ER50891, and BMS 195614 in CHO cell assays of transcription.
  • CHO cells were transfected with an expression plasmid encoding a fusion of the DNA-binding domain (DBD) of the yeast transcriptional factor Gal4 with the ligand-binding domain of human RARa, ⁇ or ⁇ .
  • a luciferase reporter containing a 5xGal4 response element at its promoter region was cotransfected with the receptor chimera.
  • the compounds were tested in the presence (3A-C) or the absence (3D-F) of 1 nM RA.
  • the compounds were added in DMSO and each point is the mean of triplicate values, normalized to a DMSO-only control.
  • FIG. 4 Dose response of ER 50891, AGN 194301, LE 135 and Ro 41-5253 in a CHO cell assay of PPARy transcription.
  • CHO cells were transfected with an expression plasmid encoding a fusion of the DNA-binding domain (DBD) of the yeast transcriptional factor Gal4 with the ligand-binding domain of human PPARy.
  • DBD DNA-binding domain
  • Gal4 yeast transcriptional factor
  • a luciferase reporter containing a 5xGal4 response element at its promoter region was cotransfected with the receptor chimera.
  • the compounds were added in DMSO and each point is the mean of triplicate values, normalized to a DMSO-only control.
  • FIG. 5 Dose response of AGN 194301 in a mouse Treg differentiation assay.
  • Naive mouse CD4+ T cells were cultured for 5 days with 5 ng/mL TGFP in the presence or absence of all-trans retinoic acid (RA) and AGN 194301 (AGN).
  • the percentage of CD4+ T cells expressing CD25 and FoxP3 was determined by flow cytometry.
  • FIG. 6 Pharmacokinetics of AGN 194301 in mice after a single intravenous (1 mg/kg) or oral (10 mg/kg) administration.
  • the plasma concentration of AGN 194301 was determined by LC/MS.
  • FIG. 7A-B Effect of AGN 194301 on the expression of homing receptors in mouse splenocytes.
  • Male Balb/c mice (7-8 weeks old) were administered AGN 194301 daily for 9 days by oral gavage.
  • the percentage of CD103+ FoxP3+ CD4+ splenocytes (7 A) and ⁇ 4 ⁇ 7+ CD44+ CD103+ FoxP3+ CD4+ splenocytes (7B) were determined by flow cytometry.
  • Female C57B1/6 mice (7-8 weeks old) were administered AGN 194301 (1, 3 or 10 mg/kg) daily for 3 days by oral gavage.
  • the percentage of CD103+CD4+ splenocytes and CD103+CD8+ splenocytes were determined by flow cytometry (7C).
  • FIG. 8A-B Regulation of integrin expression in tumor-infiltrating lymphocytes by AGN 194301. 4T1 breast cancer tumor-bearing mice were treated with AGN 194301 (10 mg/kg, PO for 21 days). Tumor-infiltrating lymphocytes were isolated and analyzed by flow cytometry A. a 4 p 7 expression or B. CD103 expression in CD4+ T cells. ***p ⁇ 0.005.
  • FIG. 9A-B Effect of AGN 194301 on Treg induction in a model of oral immunotolerance.
  • Naive DO 11.10 CD4+ T-cells were adoptively transferred into BALB/c mice on Day 0.
  • AGN 194301 (10 mg/kg) or Vehicle (5% DMSO, 95% hydroxypropyl-p-cyclodextrin) was administered by daily oral gavage from Day 1-6.
  • Mice received oral exposure to chicken ovalbumin (OVA, 1% in drinking water) from Day 2-7.
  • OVA ovalbumin
  • the percentage of FoxP3+CD4+DO11.10+ cells (9A) or FoxP3+CD4+ cells (9B) in mesenteric lymph nodes was determined by flow cytometry.
  • *p ⁇ 0.05 vs OVA+Veh Data shown are the mean ⁇ SEM, a representative from three independent experiments
  • Fig. 10A-B Effect of AGN 194301 on aldehyde dehydrogenase (ALDH) activity in mesenteric lymph node and lamina intestinal.
  • BALB/c mice were exposed to chicken ovalbumin (OVA, 1% in drinking water) for 6 consecutive days.
  • AGN 194301 (10 mg/kg) or Vehicle (5% DMSO, 95% hydroxypropyl-P-cyclodextrin) was administered by daily oral gavage concurrent with OVA exposure.
  • the percentage of Aldefluor+ CD103+CDl lc+ as a percentage of total CD103+CDl lc+ cells in mesenteric lymph nodes (10A) or lamina limbal (10B) was determined by flow cytometry.
  • Non-specific fluorescence was determined in the presence of DEAB, a specific inhibitor of ALDH. *p ⁇ 0.05 vs Veh.
  • Fig 11A-E Effect of AGN 194301 on subcutaneous tumor growth in E.G7 tumor-bearing mice.
  • Female C57BL/6 mice (6-7 weeks old) were implanted with 0.5xl0 6 E.G7- OVA tumor cells (ATCC #CRL 2113) by subcutaneous injection in the right flank.
  • AGN 14301 (10 mg/kg) or Vehicle (5% DMSO, 95% hydroxypropyl-P-cyclodextrin) was administered by daily oral gavage beginning three days after tumor cell injection.
  • Anti-CTLA-4 monoclonal antibody 100 ⁇ g/mouse, clone 9D9, Bioxcell # BE0164
  • saline was administered by intraperitoneal injection on days 6, 9 and 12.
  • Tumor volume was determined by caliper measurement 3 times per week.
  • the present disclosure relates to treatment of cancer using RARa antagonists which manipulate retinoid signaling, resulting in inhibition of Treg differentiation and regulation of T cell migration.
  • Cancer treatment with such antagonists will enhance tumor eradication, as well as the action of chemotherapeutic agents and forms of immunotherapy, such as treatment with checkpoint inhibitors, when used in combination with the antagonists.
  • cancer in a mammal means the presence of cells possessing characteristics typical of cancer cells, such as uncontrolled proliferation, immortality, metastatic potential, rapid growth and proliferation rate, and certain characteristic morphological or biochemical features. Cancer cells can form a tumor or circulate in the blood stream as independent cells, such as leukemic cells.
  • Cancer as used herein may include, but is not limited to any pathologic variation of: cancer of the prostate, breast, bladder, stomach, oropharynx, nasopharynx, esophagus, stomach, pancreas, liver, kidneys, ovaries, testicles, colon, rectum, anus, lung, thyroid, brain, head and neck, hematopoietic system (including, but not limited to Hodgkin's and Non-Hodgkin's lymphoma, acute and chronic lymphoid and myeloid leukemias) and skin (including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma).
  • tumor growth has a general meaning in oncology and refers to, unless otherwise indicated, the increase in mass or volume of the tumor, primarily as a result of tumor cell growth.
  • tumor microenvironment means the interaction of malignant (transformed) cells with non-malignant cells of the immune system (i.e. T lymphocytes, B lymphocytes, tumor associated macrophages), the tumor vasculature and lymphatic system (Joyce and Pollard 2009).
  • inflammatory or autoimmune disease means a condition where T cells and B cells initiate an inflammatory response in a mammal.
  • Autoimmune disease as used herein may include, but is not limited to, systemic lupus erythematosus, Hashimoto's disease, rheumatoid arthritis, graft-versus-host disease, Sjogren's syndrome, pernicious anemia, Addison disease, scleroderma, Goodpasture's syndrome, Crohn's disease, ulcerative colitis, inflammatory bowel disease, psoriasis, multiple sclerosis, autoimmune hemolytic anemia, sterility, myasthenia gravis, Basedow's disease, thrombotic thrombocytopenia, thrombopenia purpurea, insulin-dependent diabetes myelitis, allergy, asthma, atopic disease, arteriosclerosis, myocarditis, cardiomyopathy, glomerularnephritis, hypoplastic anemia.
  • T regulatory cell refers to a T cell expressing FoxP3 that can inhibit effector T cell activity.
  • effector T cell means any T lymphocyte that secretes pro-inflammatory cytokines or cytolytic enzymes including granzymes that can mediate tumor cell lysis or can enhance the anti-tumor response of other immune cells.
  • Effector T cells may include, but are not limited to TH17 cells (CD4+ T helper 17 lymphocytes that secrete IL-17), or cytotoxic T lymphocytes (CTLs).
  • cytotoxic T cell refers to a T cell expressing CD8+ on its surface that exhibits antigen-specific killing of cancer cells.
  • the term "immune checkpoint inhibitor” means a molecule that interferes with the activity of one or more inhibitory checkpoint proteins. Interference may mean inhibition of activity or reduction of expression. Inhibitory checkpoint proteins inhibit T- cell activation or function. Numerous checkpoint proteins are known, such as CTLA-4 and its gands CD80 and CD86; and PD1 with its gands PDL1 and PDL2 (Pardoll 2012).
  • retinoic acid nuclear receptors or RARs means nuclear retinoic acid (RA) receptors (RARa, ⁇ and ⁇ ) that are ligand dependent transcriptional regulators, which control the expression of specific gene subsets.
  • RARa refers to retinoic acid receptor alpha.
  • Alternative nomenclature includes NR1B1 and RAR alpha.
  • RAR antagonist means a compound that attenuates the stimulatory effect of retinoic acid (or another RAR agonist molecule) on RAR transcriptional activity by binding to the RAR ligand binding domain.
  • RAR-selective antagonist means an RAR antagonist compound that attenuates the stimulatory effect of retinoic acid (or another RAR agonist molecule) on RAR transcriptional activity with a half-maximal inhibitory concentration that is at least 100-fold lower than the half-maximal inhibitory concentration, or the half-maximal stimulatory concentration, for any other nuclear receptor transcription factor.
  • RARa-selective antagonist means any agent that attenuates the stimulatory effect of retinoic acid (or another RAR agonist molecule) on RARa transcriptional activity with a half-maximal inhibitory concentration at least 10-fold lower than the half-maximal inhibitory concentration for either RARJ3 or RARy, or at least 30-fold lower than the half-maximal inhibitory concentration for either RARJ3 or RARy, or at least 100-fold lower than the half-maximal inhibitory concentration for either RARJ3 or RARy, and with a half- maximal inhibitory concentration of at least 50-fold lower than the half-maximal inhibitory or stimulatory concentration for any other nuclear receptor transcription factor.
  • AGN 194301 means 2-Fluoro-4-[[[8-bromo-2,2-dimethyl-4-(4- methylphenyl)-6-chromanyl]carbonyl]amino]benzoic Acid.
  • AGN 194574 means 2,6-Difluoro-4-[[[8-bromo-2,2-dimethyl-4- (4-methylphenyl)-6-chromanyl)carbonyl]amino]benzoic acid.
  • ER 50891 means 4-[5-[8-(l-Methylethyl)-4-phenyl-2- quinolinyl] - 1 H-pyrrolo-2-benzoic acid.
  • BMS 195614 means 4-[[[5,6-Dihydro-5,5-dimethyl-8-(3- quinolinyl)-2-naphthalenyl] carbonyl] amino] benzoic acid.
  • Ro 41-5253 means 4-[(E)-2-(7-Heptoxy-4,4-dimethyl-l,l - dioxo-2,3-dihydrothiochromen-6-yl)prop-l -enyl]benzoic acid.
  • LE 135 means 4-(7,8,9,10-Tetrahydro-5,7,7,10,10-pentamethyl- 5H-benzo [e] naphtho[2,3 -b] [1,4] diazepin- 13 -yl)benzoic acid.
  • RAR agonist means a compound which binds to the ligand binding domain of RARa, RARP or RARy and activates it, producing a biological response (e.g., transcriptional activation).
  • CD 103 means an integrin heterodimer that recognizes the epithelial cell-specific ligand, E-cadherin.
  • ⁇ 4 ⁇ 7 means an integrin heterodimer which binds a specific ligand that directs Tregs to migrate to the gut.
  • CD 103 and ⁇ 4 ⁇ 7 are both examples of homing receptors on T cells.
  • treatment means administering a therapeutically effective amount of an RARa antagonist to a mammal in need of such treatment.
  • a "pharmaceutical composition” refers to a mixture of one or more of the compounds described here with one or more pharmaceutically acceptable excipients diluents or carriers.
  • the term "subject” or "patient” or “host” or “mammal” means mammalian animals, including humans.
  • RA all-trans retinoic acid
  • RA may be synthesized locally and thus exposure to high levels of RA is spatially restricted.
  • An example is the intestine where local RA synthesis is required for mucosal immunity.
  • RA induces gut homing receptors on T cells and enhances the differentiation of regulatory T cells (Tregs), a T cell subtype (CD4 + FoxP3 + ) that suppresses inflammatory responses to self antigens and to dietary antigens (Iwata et al. 2004; Kang et al. 2009).
  • Dendritic cells (DC) in the small intestine lamina intestinal (LP) expressing ocE integrin CD 103 have a high capacity to produce RA (Coombes et al. 2007). Following antigen exposure in the small intestine, these CD 103 DCs migrate to mesenteric lymph nodes (MLN) where they interact with stromal cells to shape T cell responses by inducing Treg formation and up-regulating the gut-homing molecules integrin ⁇ 4 ⁇ 7 and CCR9 on T and B lymphocytes (Coombes et al. 2007; Jaensson et al. 2008). [0055] RA is also elevated in the tumor microenvironment during cancer progression (Guo et al. 2012; Hong et al. 2015). DCs in tumor-draining lymph nodes can metabolize vitamin A to RA, driving Treg differentiation (Guo et al. 2012; Hong et al. 2015).
  • retinoic acid acts by binding to the retinoic acid receptors (RARs), which then binds to DNA as a heterodimer with one of the retinoid X receptors (RXRs) in DNA regions called retinoic acid response elements (RAREs). Binding of RA to an RAR alters the conformation of the RAR, which affects the binding of coregulatory proteins that either induce or repress transcription of nearby target genes.
  • RARa Three subtypes of RARs have been identified: RARa, RARp and RARy. These have separate tissue distributions and, by means of individual gene deletion studies, are shown to have different functions (Thacher, Vasudevan, and Chandraratna 2000).
  • RARa appears to be the most important mediator of the effects of Vitamin A and pharmacologically-active retinoids in the immune system. Knockout of RARa within the T cell lineage mimics many of the effects of Vitamin A deprivation, including loss of CD8 + T cell homing to the gut and compromised immunity upon exposure to infectious agents (Guo et al. 2014; Guo et al. 2015). Stimulation of T cells in the presence of transforming growth factor- ⁇ dramatically upregulates the expression of RARa (Schambach et al. 2007).
  • RA augments the expression of the lineage specific transcription factor forkhead box P3 (FoxP3) in naive or committed CD4+ T cells to generate suppressive extrathymic Treg cells and this effect is abrogated in mice deficient in RARa but not in mice deficient in RARP or RARy (Hill et al. 2008).
  • FoxP3 lineage specific transcription factor forkhead box P3
  • the immune system plays an important role in the eradication of cancer cells but tumors employ a variety of immune-tolerance mechanisms to promote their survival.
  • a recent major focus in oncology has been the development of therapies that stimulate tumor immune attack, especially by targeting T-cell "checkpoint" pathways (e.g., via CTLA-4, PD-1, and PD-L1 blocking antibodies) that restrain cytotoxic T lymphocyte (CTL or CD8 + T-cell) activity (Pardoll 2012).
  • T-cell "checkpoint” pathways e.g., via CTLA-4, PD-1, and PD-L1 blocking antibodies
  • CTL or CD8 + T-cell activity cytotoxic T lymphocyte activity
  • checkpoint inhibitors While the recently-approved checkpoint inhibitors have unprecedented effects, producing in some cases striking long-term remissions, these have been limited to certain cancers such as melanoma, and even then benefit only a fraction of patients (Naidoo, Page, and Wolchok 2014).
  • a retinoid antagonist that inhibits Treg formation enhances cancer immunotherapy, either as a single agent or in combination with clinical checkpoint inhibitors, novel immunostimulatory agents, and/or known forms of cancer chemotherapy, radiotherapy or targeted therapy.
  • RAR antagonist preferably a selective RARa antagonist, or a composition containing a selective RARa antagonist.
  • Such methods involve administering to a subject any selective RARa antagonist
  • the RARa antagonist is selective for RARa over RARJ3 and RARy in a transcriptional assay by a factor of greater thanl 0-fold, greater than 30-fold or greater than 100-fold.
  • the RARa antagonist is selective over activation of PPARy by a factor of >50-fold.
  • the selective RARa antagonists provided herein include but are not limited to AGN 194301, ER50891 , AGN 194574, LE135, Ro 41 -5253 and/or BMS 195614.
  • compositions containing any one or more of the RARa antagonists described herein contain a plurality of RARa antagonists.
  • compositions herein can be pharmaceutical compositions.
  • the compositions contain an additional therapeutic agent that can be formulated with the RARa antagonist.
  • therapeutic agents that can be included in the compositions provided herein are chemotherapeutic agents, analgesic agents, anti-inflammatory agents, or cancer immunotherapies.
  • the RARa antagonist can be administered in combination with chemotherapeutic agents: these include, but are not limited to irinotecan, oxalip latin, 5- fluorouracil (5-FU), Xeloda, Camptosar, Eloxatin, Adriamycin, paclitaxel, docetaxel, Cisplatin, gemcitabine, carboplatin, vintorethine tartrate, etoposide, Doxorubin, ifosfamide, cyclophosphamide, methotrexate.
  • chemotherapeutic agents include, but are not limited to irinotecan, oxalip latin, 5- fluorouracil (5-FU), Xeloda, Camptosar, Eloxatin, Adriamycin, paclitaxel, docetaxel, Cisplatin, gemcitabine, carboplatin, vintorethine tartrate, etoposide, Doxorubin, ifosfamide,
  • the RARa antagonist can be administered in combination with molecular targeting therapeutic agents: these include, but are not limited to bevacizumab, imatinib, erlotinib, gefitinib, everolimus, niraparib, olaparib, vemurafenib, vorinoristat or palbociclib.
  • molecular targeting therapeutic agents include, but are not limited to bevacizumab, imatinib, erlotinib, gefitinib, everolimus, niraparib, olaparib, vemurafenib, vorinoristat or palbociclib.
  • the RARa antagonist can be administered before, after, or during the same treatment period as cancer immunotherapies such as the immune checkpoint inhibitor antibodies pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab or cancer therapies targeting other immune pathways including, but not limited to CD 137/4- IBB, GITR, OX40, CD40, LAG3 (lymphocyte activation gene-3), ICOS (inducible T-cell stimulator), CD27, CD47, IDO or A2A.
  • cancer immunotherapies such as the immune checkpoint inhibitor antibodies pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab or cancer therapies targeting other immune pathways including, but not limited to CD 137/4- IBB, GITR, OX40, CD40, LAG3 (lymphocyte activation gene-3), ICOS (inducible T-
  • the RARa antagonist can be administered in combination with other therapeutic modalities for the treatment of cancer. These include, but are not limited to surgery or radiation. Other combination modalities could be with therapeutic cancer vaccines including dendritic cell vaccines, or with an oncolytic therapy, such as talimogene laherparepvec, which can also enhance anti-tumor immunity.
  • an active dose of RARa antagonist can be selected for therapeutic use according to modulation of markers on circulating Tregs or effector T cells. These include, but are not limited to, CD 103, CCR9 or ⁇ 4 ⁇ 7. Or, more generally, an active dose of RARa antagonist may also be selected by modulation of CD 103 or ⁇ 4 ⁇ 7 on CD4 + or CD8 + cells.
  • RA By modulating transcriptional responses through activation of the RARs, RA regulates cell function, proliferation and differentiation in diverse organs and the immune system. As described herein, the use of a selective RARa antagonist decreases Treg differentiation. In addition, a selective RARa antagonist will modify the expression of homing receptors, such as CD103 and ⁇ 4 ⁇ 7 on Tregs. Selective RARa antagonists bind to receptors of the RARa subtype, i.e. the RAR antagonist selectively binds to a single RARa subtype. Other embodiments are directed to methods for the treatment of cancer in a mammal thereby employing at least one selective RARa antagonist. Other embodiments are directed to methods for the treatment of graft-versus-host disease in a mammal thereby employing at least one selective RARa antagonist.
  • RARa antagonists to RARa are any agent that competitively inhibits binding of retinoic acid or RAR agonists to the RARa ligand-binding domain or inhibits the transcriptional activity of RARa elicited by retinoic acid or another RAR agonist.
  • RARa antagonists may be used in the formulations and for the methods described herein.
  • Exemplary RARa antagonists include selective antagonists of RARa ligand binding domain-dependent transcriptional activation in the presence of retinoic acid or other RAR agonists, including but not limited to, AGN 194301 (Teng et al. 1997), ER50891 (Kikuchi et al.
  • RARa-selective antagonists may be greater than 10-fold selective for RARa over RARp and RARy and greater that 50-fold selective for RARa over PPARy.
  • RARa-selective antagonists may be greater than 30-fold selective for RARa over RARP and RARy and greater that 50-fold selective for RARa over PPARy.
  • RARa-selective antagonists may be greater than 100-fold selective for RARa over RARp and RARy and greater than 50-fold selective for RARa over PPARy.
  • Representative examples of RARa selective antagonist include AGN 194301, AGN 194574 (Teng et al.
  • AGN 194301 is a greater than 30-fold selective antagonist for RARa over RARp and RARy and greater than 50-fold selective antagonist for RARa over PPARy.
  • RARa antagonists reported in the published literature include those known as AGN 194301, AGN 194574, ER50891, LE135, Ro 41-5253 and BMS 195614, which have the following chemical structures.
  • RARa selective retinoic acid nuclear receptor alpha
  • kits for modulating the immune response in a subject employing at least one RARa selective antagonist by contacting cells expressing retinoic acid nuclear receptor and reducing the number of T regulatory cells in the cellular microenvironment.
  • the cells can be cancer cells themselves or cells within the tumor microenvironment. Tumor eradication and the reduction of the number of T regulatory cells in tumor microenvironment may be linked to the migration of T cells to the tumor microenvironment or associated lymph nodes modulated by the expression of homing receptors.
  • Tumor eradication and the reduction of the number of CD4+ T regulatory cells in tumor microenvironment may be linked to the migration of T cells to the tumor microenvironment or associated lymph nodes modulated by the expression of homing receptors.
  • the present invention modulates the expression of homing receptors (integrins) on Tregs.
  • Tumor eradication may be linked to the number of Thl 7 cells in the tumor microenvironment.
  • RA suppresses Thl7 differentiation (Mucida et al. 2007).
  • the present invention can increase the number of Thl7 cells by blocking RA suppression of Thl7 differentiation in an inflammatory environment.
  • the disease or condition is a tumor, cancer or metastasis.
  • the condition or disease is cancer of the prostate, breast, bladder, stomach, oropharynx, nasopharynx, esophagus, stomach, pancreas, liver, kidneys, ovaries, testicles, colon, rectum, anus, lung, thyroid, brain, head and neck, hematopoietic system (including, but not limited to Hodgkin's and Non-Hodgkin's lymphoma, acute and chronic lymphoid and myeloid leukemias) and skin (including, but not limited to, basal cell carcinoma, squamous cell carcinoma and melanoma).
  • the disease or condition is graft-versus-host disease.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s).
  • suitable carriers or excipient(s) include butylene glycol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, s, glycerin, glycerin, glycerin, aditol, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, colophon, ,
  • Suitable routes of administration may, for example, include oral, rectal, topical, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.
  • compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences, above.
  • the RARa antagonists of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks 's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination of the invention, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • the compounds may be formulated for administration to the epidermis as ointments, gels, creams, pastes, salves, gels, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also containing one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, including sublingually which include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane,
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common cosolvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM , and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80TM; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.
  • hydrophobic pharmaceutical compounds may be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acid or base forms.
  • compositions suitable for use in the present invention include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • compositions of the present invention can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 p. 1).
  • dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Note that for almost all of the specific compounds mentioned in the present disclosure, human dosages for treatment of at least some condition have been established.
  • the present invention will use those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage.
  • a suitable human dosage can be inferred from ED 50 or ⁇ D 5 o values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals. [0102] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 6000 mg of each ingredient, preferably between 1 mg and 5000 mg, e.g. 25 to 5000 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions of the present invention or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • the compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2500 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • the dose of the pharmaceutical composition comprising a RARa antagonist or a pharmaceutically acceptable salt, prodrug, derivative or metabolite thereof, is from about 10 to about 50 mg per day.
  • the RARa antagonist is administered daily without resulting in weight loss or hypertriglyceridemia.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vivo data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen that maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • the amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • compositions described herein may also be used in the preparation of a medicament for treatment of any of the disorders described above.
  • a tumor, cancer or metastasis in a subject responsive to treatment employing at least one RARa selective antagonist and a monoclonal antibody that blocks checkpoint inhibitors.
  • the immune system is kept in check by transmembrane cell-surface checkpoint inhibitors that limit damage to normal tissues by, for example, blocking the action of CD8 + cytotoxic T cells (Naidoo, Page, and Wolchok 2014). But these inhibitory pathways are co-opted in cancer to inhibit immune responses to cancer neoantigens.
  • ipilimumab which blocks the checkpoint cell surface protein CTLA-4
  • nivolumab and pembrolizumab which block PD-1
  • NSCLC non-small cell lung cancer
  • Additional cell surface regulators are also potentially modulated for cancer immunotherapy, including PD-L1, PD-L2, OX40, and others.
  • the pharmaceutical composition can further comprise administration of one or more anticancer agents, immune checkpoint inhibitors or other treatments formulated as a single composition or as separate compositions and administered sequentially (before or after), simultaneously or intermittently.
  • Anticancer agents or treatments may be selected from among irinotecan, oxaliplatin, 5-fluorouracil (5-FU), Xeloda, Camptosar, Eloxatin, Adriamycin, paclitaxel, docetaxel, Cisplatin, gemcitabine, carboplatin, vintorethine tartrate, etoposide, Doxorubin, ifosfamide, cyclophosphamide, methotrexate, surgery and radiation.
  • irinotecan oxaliplatin
  • 5-fluorouracil (5-FU) 5-fluorouracil
  • Xeloda Camptosar
  • Eloxatin Adriamycin
  • paclitaxel docetaxel
  • Cisplatin gemcitabine
  • carboplatin vintorethine tartrate
  • etoposide Doxorubin
  • ifosfamide ifosfamide
  • cyclophosphamide methotre
  • Immune checkpoint inhibitors block T cell activation through interaction with PD-1, PD-Ll (programmed cell death 1 ligand 1), CTLA-4 (Cytotoxic T-Lymphocyte Associated Protein 4), B- and T-cell attenuator (BTLA), lymphocyte activation gene 3 (LAG3), and inducible T-cell costimulator (ICOS).
  • PD-1 PD-Ll
  • CTLA-4 Cytotoxic T-Lymphocyte Associated Protein 4
  • BTLA B- and T-cell attenuator
  • LAG3 lymphocyte activation gene 3
  • ICOS inducible T-cell costimulator
  • Immune checkpoint inhibitors can include the monoclonal antibodies pembrolizumab, nivolumab, or ipilimumab, directed to PD-1 or CTLA-4 or agonist antibodies directed to glucocorticoid-induced TNFR-related protein (GITR) (Naidoo, Page, and Wolchok 2014).
  • GITR glucocorticoid-induced TNFR-related protein
  • Retinoic acid receptor (RARa) antagonists were synthesized or obtained as follows:
  • ER50891 (Kikuchi et al. 2001) was purchased from Santa Cruz Biotech (cat. # sc-362733).
  • LE 135 was purchased from Santa Cruz Biotech (cat. # sc-204053).
  • Ro41-5253 was purchased from Santa Cruz Biotech (cat. # sc-471345).
  • BMS 195614 was purchased from Santa Cruz Biotech (cat. # sc-362715).
  • Each receptor is assayed as a GAL4 hybrid.
  • the retinoid receptors were tested in the presence and absence of RA or TTNPB which activates all three of the RAR subtypes (Thacher, Vasudevan, and Chandraratna 2000).
  • pGal4DBD_RARa LBD (SEQ ID NO: 1) was generated by cloning polymerase chain reaction fragments encoding human RARa (aal 56-462 of human RARa isoform 1 (PI 0276-1)) ligand-binding domain (LBD) in frame with the DNA- binding domain (DBD) of the yeast transcriptional factor Gal4 encoded by the pFA-CMV vector (Stratagene, La Jolla, CA) (SEQ ID NO:2).
  • RARa (aal 56-462) (SEQ ID NO: 3) was amplified from a human MGC clone (Invitrogen, San Diego, CA).
  • pGal4DBD_RARP LBD (SEQ ID NO: 6) and pGal4DBD_RARy LBD (SEQ ID NO: 7) were generated by inserting fragments encoding either human RARP (aal56-455 of human RARP isoform 1 (P10826-1), BamHl- Hindlll) (SEQ ID NO:8) or human RARy (aal 58-454 of human RARy isoform 1 (P13631-1), BamHl -Hindlll) (SEQ ID NO: 9) ligand-binding domain (LBD) in frame with the DNA-binding domain (DBD) of the yeast transcriptional factor Gal4 encoded by the pFA-CMV vector (Stratagene, La Jolla, CA).
  • PPARy (aa203-505 of human Peroxisome proliferator-activated receptor gamma isoform 2 (P37231-1)) (SEQ ID NO: 11) was amplified from a human fetal liver cDNA library (Clontech). Xbal and Kpnl sites introduced by the primers 5'-TAT ATC TAG AGA TGT CTC ATA ATG CCA TCA G-3' (forward) (SEQ ID NO: 12) and 5' -TAT AGG TAC CCT CTG CTA GTA CAA GTC CTT G-3' (reverse) (SEQ ID NO: 13) were used for subcloning the amplicon into pFA-CMV.
  • CHO-K1 cells were transiently cotransfected with either 250 ng of pGaWDBD RARa LBD plasmid, pGaWDBD RARP LBD plasmid or pGaWDBD RARy LBD plasmid in combination with 9 ⁇ g of pG51uc (Promega, Madison, WI) (SEQ ID NO: 14) and 8.75 ⁇ g of empty pcDNA3.1 (Invitrogen), in 1.2 ml of Ham's F-12 media containing 54 ⁇ of TransIT-CHO reagent and 9 ⁇ of TransIT-CHO Mojo reagent, according to the manufacturer's protocol (Mirus Bioproducts, Madison, WI).
  • Flasks were then placed back in the incubator at 37°C, 5% C02 and 95% relative humidity.
  • cells were trypsinized and suspended to a concentration of 1.6 X 10 5 cells/ml in supplemented Ham's F-12 media.
  • 50 ⁇ of transfected cell suspension were dispensed into each well (i.e., 8000 cells/well) of a white solid-bottomed 384-well plate (Corning) using a Titer-Tek 384 liquid dispenser.
  • cells were treated with 2.1 ⁇ diluted test compounds or DMSO alone using a Janus mini workstation (PerkinElmer Life and Analytical Sciences, Waltham, MA) with 384-well disposable tips.
  • Figure 2 A demonstrates that transcriptional activation of RARa, ⁇ and ⁇ stimulated by 1 nM atRA is inhibited by Ro41-5253.
  • Figure 2B demonstrates that Ro41- 5253 does not stimulate RARs since it is tested in the absence of 1 nM atRA.
  • Figure 2C shows that transcriptional activation of RARa and ⁇ stimulated by 1 nM atRA is inhibited by LE 135, whereas LE 135 has no effect on RA-stimulated transcriptional activity of RARy.
  • Figure 2D demonstrates that LE 135 stimulates RARy transcriptional activity but has no effect on RARa or ⁇ in the absence of 1 nM atRA.
  • Figure 3A demonstrates that transcriptional activation of RARa, ⁇ and ⁇ stimulated by 1 nM atRA is fully inhibited by AGN 194301.
  • Figure 3B demonstrates that transcriptional activation of RARa, ⁇ and ⁇ stimulated by 1 nM RA is inhibited by ER50891.
  • Figure 3C demonstrates that transcriptional activation of RARa, ⁇ and ⁇ stimulated by 1 nM atRA is fully inhibited by BMS 195614.
  • Figure 3D demonstrates that AGN 194301 does not stimulate RAR transcriptional activity when tested at concentrations up to 3.2 ⁇ .
  • Figure 3E demonstrates that ER 50891 stimulates transcriptional activity of RAR ⁇ but has no effect on RARa or ⁇ .
  • Figure 3F demonstrates that BMS 195614 does not stimulate RAR transcriptional activity when tested at concentrations up to 20 ⁇ .
  • Table 1 Potencies of compounds tested in Chinese Hamster Ovary (CHO) cell assays of transcription in the presence of RA or TTNPB.
  • CHO cells were transfected with an expression plasmid encoding a fusion of the DNA-binding domain (DBD) of the yeast transcriptional factor Gal4 with the ligand-binding domain of human RARa, ⁇ or ⁇ .
  • DBD DNA-binding domain
  • Gal4 yeast transcriptional factor
  • a luciferase reporter containing a 5xGal4 response element at its promoter region was cotransfected with the receptor chimera.
  • Compounds were added in DMSO in the presence of 1 nM all-trans retinoic acid (RA).
  • RA all-trans retinoic acid
  • LEI 35 was tested in the presence of 0.5 nM TTNPB in the RARp and RARy assays. Luciferase activity was determined after 40 hours. IC 50 values were determined by 4-parameter logistic curve fitting using GraphPad Prism (San Diego, CA).
  • Table 2 Agonist potencies of compounds tested in Chinese Hamster Ovary (CHO) cell assays of transcription in the absence of atRA. CHO cells were transfected with an expression plasmid encoding a fusion of the DNA-binding domain (DBD) of the yeast transcriptional factor Gal4 with the ligand-binding domain of human RARa, ⁇ or ⁇ . A luciferase reporter containing a 5xGal4 response element at its promoter region was cotransfected with the receptor chimera. Compounds were added in and luciferase activity was determined after 40 hours. EC 50 values, based on elevation of luciferase activity, were determined by 4-parameter logistic curve fitting using GraphPad Prism (San Diego, CA). The Table is based on Figures 2 and 3.
  • Figure 4 demonstrates that Ro41-5253 stimulates PPARy transcriptional activity at concentrations >30 nM.
  • AGN 194301, ER50891 and LE 135 do not stimulate PPARy transcriptional activity at concentrations up to 1 ⁇ .
  • AGN 194301 inhibits Tree formation from naive murine CD4 + T cells in the presence of TGFp and RA.
  • DMSO fetal bovine serum
  • AGN 194301 dose-dependently inhibited FoxP3 expression in activated CD4+CD25+ T cells cultured in the presence of 10 nM RA and 5 ng/ ml TGFp. Half-maximal suppression of FoxP3 expression occurred with 10 nM AGN 194301, and maximal suppression was seen with 100 nM. AGN 194301 had no inhibitory effect in the absence of the added 10 nM RA.
  • Microsomes were obtained from XenoTech LLC (Kansas City, KS, USA) or BD Biosciences (San Jose, CA, USA). Characterization of the specific cytochrome P450 content and activity of the microsome lot is performed by the vendor. Microsomes were stored at or about -70 °C until use. Microsomes were thawed in a 37 °C water bath for approximately 5 minutes just prior to use.
  • the mixtures were incubated in a 37°C water bath with gentle shaking and sampled as described below.
  • the 0-minute samples were prepared by addition of a 40- ⁇ aliquot of each incubation mixture to 300 ⁇ acetonitrile to precipitate proteins.
  • the samples were vortexed, and a 10 ⁇ aliquot of the cofactor solution was added.
  • the reaction was initiated by addition of 200 uL NADPH solution to 800 ⁇ of each incubation mixture.
  • the final incubation conditions achieved in 1 mL were: 0.25 mg/mL microsomal protein, 1.0 ⁇ test article, 0.34 mg/mL NADP, 1.68 mg/mL glucose 6 phosphate, 1.2 Units/mL glucose 6 phosphate dehydrogenase.
  • AGN 194301 was dissolved in DMSO and ultrasonicated until dissolved, then (2-Hydroxypropyl)-beta- cyclodextrin ( ⁇ - ⁇ -CD) (20% in water) was added, vortexed and ultrasonicated until getting a colorless solution.
  • the final formulation contained 5% DMSO and 95% ⁇ - ⁇ -CD (20%).
  • the nominal concentration of AGN 194301 was 0.2 mg/mL for IV dosing and 1 mg/mL for PO dosing.
  • AGN 194301 is well absorbed after oral administration with high oral bioavailability.
  • AGN 194301 has a low volume of distribution and low plasma clearance suggesting that good plasma exposure can be achieved with once daily oral dosing in mice.
  • Dead cells were excluded from analysis using Live/Dead reagent (Invitrogen).
  • Live/Dead reagent Invitrogen
  • AGN 194301 1, 3 or 10 mg/kg
  • spleen cells were isolated, stained with fluorochrome-labeled antibodies (eBioscience) to CD3, CD4, CD8, CD 103 and analyzed by flow cytometry.
  • Dead cells were excluded from analysis using Live/Dead reagent (Invitrogen).
  • CD 103 expression in CD3+ CD4+ and CD3+ CD8+ splenocytes was increased by AGN 194301 in a dose-dependent manner following three days of dosing (Figure 7C).
  • AGN 194301 was dissolved in 5% DMSO/95% ⁇ - ⁇ -CD (20%) at a concentration of 1 mg/ml and administered once daily by oral gavage (10 mL/kg). Dosings were performed between 9am and noon each day beginning two days prior to tumor cell injection and continuing for 20 consecutive days.
  • Spleens from tumor bearing mice were harvested and dissociated mechanically into single cell suspension in ice-cold PBS.
  • Splenocytes were treated with RBC lysis buffer (eBioscience), washed twice with PBS and resuspended in PBS supplemented with 4% FBS.
  • An aliquot of approximately 10 6 splenocytes was pre-incubated with 10 ug/mL anti- CD 16/32 for 10 min before phenotyping antibody cocktail was added to specifically stain immune cells.
  • Tumor infiltrating lymphocytes were prepared by mincing tissue followed by digestion in collagenase and DNAse.
  • AGN 194301 significantly decreased the percentage of CD4+ tumor-infiltrating lymphocytes expressing ⁇ 4 ⁇ 7 (p ⁇ 0.005) ( Figure 8 A) and increased the percentage of tumor-infiltrating lymphocytes expressing CD 103 (p ⁇ 0.005) ( Figure 8B). These results demonstrate that AGN 194301 modulates the expression of cell surface receptors involved in lymphocyte trafficking in sub-populations of tumor-infiltrating lymphocytes.
  • mice Female BALB/c mice (6-8 weeks of age) were injected intraperitoneally with 10 7 chicken ovalbumin (OVA) -specific CD4+ T cells, isolated by magnetic bead sorting (CD4+ T cell selection kit ⁇ , Miltenyi, Germany), from the spleens and lymph nodes of DO11.10 mice. 24 h after injection of OVA-specific T cells, mice were administered AGN 194301 (10 mg/kg, 10 mL/kg) or vehicle (5% DMSO/95% ⁇ - ⁇ -CD (20%) by daily oral gavage for 6 days. 48 h after injecting OVA-specific T cells, mice were administered OVA (1% in drinking water) for 6 days.
  • OVA ovalbumin
  • mice Seven days after injecting OVA-specific T cells, mice were sacrificed and the MLNs collected. MLN cell suspensions were prepared and analyzed by flow cytometry for the presence of OVA-specific KJ1.26+CD4+ T cells. The expression of FoxP3 was determined among the KJ1.26+CD4+T cells.
  • mice Female BALB/c mice (6-8 weeks of age) were administered AGN 194301 (10 mg/kg, 10 mL/kg) or vehicle (5% DMSO/95% ⁇ - ⁇ -CD (20%) by daily oral gavage for 6 days. One day after beginning dosing, mice received oral exposure to chicken ovalbumin (OVA, 1% in drinking water) for 6 days. On day 7, MLN and lamina intestinal were collected and cell suspensions were prepared and analyzed by flow cytometry for the presence of CDl lb, CDl lc, CD8a, CD103, B220 and CD3.
  • OVA chicken ovalbumin
  • Dead cells and irrelevant cell populations were excluded from analysis using a 'dump channel', which contains live/dead dye and antibodies specific for unwanted cells (B220 for B cells, CD3 for T cells) in one fluorescence channel.
  • Cells expressing high levels of the enzyme aldehyde dehydrogenase (ALDH) were identified using the Aldefluor reagent kit (StemCell Technologies). The amount of fluorescent reaction product, proportional to the ALDH activity in the cells, was measured by flow cytometry.
  • a specific inhibitor of ALDH, diethylaminobenzaldehyde (DEAB) was used to control for background fluorescence.
  • Table 4 Percentage of CD103 ⁇ CDl lc ⁇ cells in mesenteric lymph node (MLN) and lamina intestinal (LP) of mice treated with AGN 194301. BALB/c mice were exposed to chicken ovalbumin (OVA, 1% in drinking water) for 6 consecutive days. AGN 194301 (10 mg/kg) or Vehicle (5% DMSO, 95% hydroxypropyl-P-cyclodextrin) was administered by daily oral gavage concurrent with OVA exposure. On day 7, the percentage of CD103+CDl lc+ as a percentage of total CDl lc+ cells in mesenteric lymph nodes or laminalitis was determined by flow cytometry. ***p ⁇ 0.001 vs Veh.
  • Dendritic cells that have been matured in vitro with TLR agonists, such as CpG, and pulsed with heat-shocked, irradiated tumor cells are effective cell-based vaccines against murine tumors.
  • TLR agonists such as CpG
  • RARa selective antagonist and a dendritic cell vaccine.
  • the clinical success of vaccination with tumor antigen-loaded dendritic cells has been limited, in part due to immune suppression mediated by the tumor microenvironment.
  • Provided herein are methods to improve the immunostimulatory activity of dendritic cells vaccines including combination therapy with an RARa selective antagonist.
  • Galvin et al. (Galvin et al. 2013) recently demonstrated that pre-treatment of DC in vitro with Ro41-5253, an RAR antagonist, significantly suppressed TGF- ⁇ and IL-10, and enhanced IL-12 production by DC in a tumor model (Galvin et al. 2013).
  • This protective effect was associated with significant reduction in what might potentially be tumor-infiltrating FoxP3+ and IL-10+ Treg cells, and a corresponding increase in tumor-infiltrating CD4+ and CD8+ T cells that secreted IFN- ⁇ .
  • Bone marrow-derived immature DCs are pretreated with RARa antagonist for 15 min, then loaded with heat-shocked (43°C for 1 h) ⁇ -irradiated (200 Gy) B16F10 melanoma cells at a 1 : 1 ratio followed by stimulation with CpG oligonucleotide (ODN1585, 5 ⁇ g/ml, Invivogen, San Diego, CA) for 18 h.
  • CpG oligonucleotide ODN1585, 5 ⁇ g/ml, Invivogen, San Diego, CA
  • the mouse B16F10 melanoma cell line is purchased from the American Type Culture Collection (Manassas, VA) and used for tumor induction in female C57BL/6 mice, by subcutaneous (s.c.) administration into the flank. Bone marrow-derived immature DCs are pretreated with RARa antagonist for 15 min. DCs are then loaded at a 1 : 1 ratio with heat- shocked (43°C for 1 h), ⁇ -irradiated (200 Gy) B16F10 melanoma cells followed by stimulation with CpG (5 ⁇ g/ml) for 18 h. DCs are washed and injected (5 x 10 5 ) s.c. in a volume of 100 ⁇ into the tumor site 3, 10 and 17 days after tumor inoculation. Tumor growth is recorded every 2- 3 days, producing a significant reduction of tumor volume.
  • Pretreatment of human or other mammalian dendritic cells in culture by an RARa-specific antagonist is carried out by similar methods with species-specific reagents as a method to enhance cancer vaccine effectiveness combining patient dendritic cells and patient cancer cells.
  • An RARa antagonist may also be used as a systemic co-treatment for patients who are treated with a dendritic cell vaccine for treatment of cancer.
  • GVHD acute graft-versus-host disease
  • a subject responsive to treatment employing at least one RARa selective antagonist is a serious and often life-threatening complication that results from immune-mediated attack of recipient tissue by donor T cells contained in transplanted hematopoietic stem cells, bone marrow or other tissues.
  • the gastrointestinal tract, skin and liver are major target organs in acute GVHD.
  • the gastrointestinal tract is an especially important target organ because it plays a major role in amplifying systemic tissue damage in the skin, liver and other organs. Aoyama (Aoyama et al. 2013) and Chen (Chen et al.
  • retinoic acid signaling plays a critical role in pathophysiology of gastrointestinal GVHD.
  • Administration of exogenous RA increases gut homing molecule expression on donor T cells, enhances the accumulation of proinflammatory T cells in the gut mucosa, and exacerbates colonic GVHD leading to increased mortality.
  • Depletion of RA in host mice by vitamin A deprivation, or disruption of RAR signaling by transgenic expression of a dominant negative RAR in donor T cells decreases gut homing molecule expression on donor T cells and attenuates pathological damage in the colon.
  • mice are exposed to a lethal dose of whole body irradiation as a single exposure at a dose rate of 74 cGy within 24 hours prior to injection of donor bone marrow and lymphocytes.
  • Donor lymphocytes (0.5 - 5 x 10 6 ) isolated from spleen or lymph nodes are combined with 10 7 T cell-depleted bone marrow cells in a volume of 1 mL and injected into the tail vein of each host mouse using a 3 cc syringe fitted with a 27g needle. Survival of mice and the extent of colonic damage following concurrent treatment with an RARa antagonist such as AGN 194301 or vehicle control is followed over time to evaluate the protective effect of treatment with RARa antagonist.
  • RARa antagonist such as AGN 194301 or vehicle control is followed over time to evaluate the protective effect of treatment with RARa antagonist.
  • AGN 194301 was dissolved in 5% DMSO/95% ⁇ - ⁇ -CD (20%) at a concentration of 1 mg/ml and administered once daily by oral gavage (10 mL/kg). Dosings were performed between 9am and noon each day beginning three days post tumor cell injection.
  • AGN 194301 significantly decreased subcutaneous tumor growth in E.G7-OVA tumor-bearing mice.
  • AGN 194301 in combination with anti-CTLA-4 also significantly inhibited tumor growth, whereas the effect of anti-CTLA-4 alone was not significant ( Figure 11).
  • Retinoid antagonist treatment is likely to be more effective in patients that have an elevated level of retinoic acid in the tumor environment or in draining lymph nodes. For example, elevation of ⁇ 4 ⁇ 7, or an increase in the frequency of CD103+CDl lc+ dendritic cells, or increased expression of RALDH in CD103+CDl lc+ dendritic cells, can each result from increased activation of RARa by an endogenous retinoid. Thus, tumors with elevated retinoid signaling could be identified by increased levels of these markers and tumors selected for treatment based on degree of elevation of these and other markers of RARa activation that may be identified.
  • a similar strategy can be effective.
  • the expression of a RAR-regulated marker such as ⁇ 4 ⁇ 7 is compared before and after the start of treatment with an immune checkpoint inhibitor, such as pembrolizumab, nivolumab, ipilimumab, atezolizumab, avelumab, durvalumab, or cancer therapies targeting other immune pathways including, but not limited to CD137/4-1BB, GITR, OX40, CD40, LAG3 (lymphocyte activation gene-3), ICOS (inducible T-cell stimulator), CD27, CD47, IDO or A2A. Elevation of one or a combination of the markers noted above could identify therapies that induce retinoic acid levels as a compensatory mechanism or identify patients in which elevation of retinoic acid is a response to therapy. Patients exhibiting these responses could then be selected for therapy.

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Abstract

L'invention porte sur des procédés associés à l'utilisation d'antagonistes sélectifs du récepteur de l'acide rétinoïque (RAR), tels que des antagonistes sélectifs de RARα, pour une thérapie à agent unique ou une polythérapie du cancer, de tumeur ou de métastases tumorales.
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AU2017278220B2 (en) * 2016-06-10 2022-07-21 Io Therapeutics, Inc. Receptor selective retinoid and rexinoid compounds and immune modulators for cancer immunotherapy
AU2017278220C1 (en) * 2016-06-10 2022-10-13 Io Therapeutics, Inc. Receptor selective retinoid and rexinoid compounds and immune modulators for cancer immunotherapy
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EP3651764A4 (fr) * 2017-07-13 2021-09-22 IO Therapeutics, Inc. Composés rétinoïdes et rexinoïdes immunomodulateurs en combinaison avec des modulateurs immunitaires pour l'immunothérapie du cancer
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US10874694B2 (en) 2017-08-31 2020-12-29 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
US11786555B2 (en) 2017-08-31 2023-10-17 Io Therapeutics, Inc. RAR selective agonists in combination with immune modulators for cancer immunotherapy
WO2021127250A1 (fr) 2019-12-19 2021-06-24 Orphagen Pharmaceuticals, Inc. Composés rar-alpha contre une maladie inflammatoire et contraception masculine
CN115335367A (zh) * 2019-12-19 2022-11-11 奥弗恩制药公司 用于炎性疾病和雄性避孕的RAR-α化合物

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