(12) United States Patent (10) Patent No.: US 8,048,918 B2 Ward Et Al
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USOO8048918B2 (12) United States Patent (10) Patent No.: US 8,048,918 B2 Ward et al. (45) Date of Patent: Nov. 1, 2011 (54) TREATMENT OF HYPERPROLIFERATIVE FOREIGN PATENT DOCUMENTS DISEASES EP 0284.879 A2 10, 1988 EP O610511 8, 1994 GB 2023001. A * 12, 1979 (75) Inventors: Simon Ward, Sheffield (GB); Claes WO WO 97.15298 5, 1999 Bavik, Sheffield (GB); Michael Cork, WO WOO1/30383 5, 2001 Sheffield (GB); Rachid Tazi-Aahnini, WO WO O2/OO2O74 1, 2002 Sheffield (GB) WO WO O2/O72084 9, 2002 (73) Assignee: Vampex Limited, Manchester (GB) OTHER PUBLICATIONS NapoliJL. “Retinol Metabolism in LLC-PK1 Cells. Characterization (*) Notice: Subject to any disclaimer, the term of this of Retinoic Acid Synthesis by an Established Mammalian Cell Line.” patent is extended or adjusted under 35 Journal of Biological Chemistry, 1986:261 (29): 13592-13597.* “Glucocorticoid”. Stedman's Medical Dictionary (Twenty-Second U.S.C. 154(b) by 385 days. Edition). The Williams and Wilkins Company, 1972. p. 527.* Ghosh et al. “Mechanism of Inhibition of 3alpha,20beta (21) Appl. No.: 10/085,239 hydroxysteroid Dehydrogenase by a Licorice-Derived Steroidal Inhibitor”. Structure, Oct. 15, 1994; 2(10):973-980.* (22) Filed: Feb. 27, 2002 Kelloff et al. “Chemopreventive Drug Development: Perspectives and Progress”. Cancer Epidemiology, Biomarkers and Prevention. 3. (65) Prior Publication Data 1994:85-98.* Bavik, Claes et al., “Retinol-Binding Protein Mediates Uptake of US 2003/O1197.15A1 Jun. 26, 2003 Retinol to Cultured Human Keratinocytes'. Exp. Cell Res., vol. 216, pp. 358-62 (1996). Melhus, Hakan et al., “Epitope Mapping of a Monoclonal Antibody Related U.S. Application Data that Blocks the Binding of Retinol-Binding Protein to its Receptor'. (63) Continuation-in-part of application No. Biochem. Biophys. Res. Comm., vol. 210, pp. 105-112 (1995). Connor, M.J. "Modulation of Tumor Promotion in Mouse Skin by the PCT/GB01/03694, filed on Aug. 17, 2001. Food Additive Citral (3,7-dimethyl-2,6-octadienal)', Cancer Lett. vol. 56, pp. 25-28 (1991). (30) Foreign Application Priority Data Estrov, Zeev et al., “Neoplasia: Phenylarsine Oxide Blocks Interleukin-1 (B-Induced Activation of the Nuclear Transcription Fac Aug. 17, 2000 (GB) ................................... OO2O351.3 tor NF-kB, Inhibits Proliferation and Induces Apoptosis of Acute Myelogenous Leukemia Cells'. Blood, pp. 2844-2853 (1999). (51) Int. Cl. AOIN37/02 (2006.01) * cited by examiner AOIN37/10 (2006.01) A6 IK3I/22 (2006.01) Primary Examiner — Leslie A Royds Draper A6 IK3I/9 (2006.01) (74) Attorney, Agent, or Firm — Mintz Levin Cohn Ferris (52) U.S. Cl. ........................................ 514/546; 514/569 Glovsky and Popeo, P.C. (58) Field of Classification Search .................. 514/476, (57) ABSTRACT 514/.406, 504, 703 We describe methods and compositions for treating a patient See application file for complete search history. Suffering from a hyperproliferative disorder or photoageing. (56) References Cited Our methods involve blocking the activity of a retinol binding protein receptor (RBPr) in cells of the patient, and/or admin U.S. PATENT DOCUMENTS istering to the patient an antagonist of a retinol binding pro tein receptor (RBPr) and/or lowering the endogenous level of 4,870,101 A * 9/1989 Ku et al. ....................... 514,476 retinoic acid (RA) in cells of said patient. 5.438,073. A * 8/1995 Saurat et al. 514,452 5,858,750 A * 1/1999 Bandman et al. ............. 435/190 5,917,082 A * 6/1999 Vuligonda et al. ............ 560/100 8 Claims, 11 Drawing Sheets U.S. Patent Nov. 1, 2011 Sheet 1 of 11 US 8,048,918 B2 Figure 1 Cell-death e 9. Therapeutic • Therapeutic target area for target area for 3 5 proposed current therapy 5 therapy 5. 2 Switch-point s C9 5 92 S l Vitamin A Status U.S. Patent Nov. 1, 2011 Sheet 2 of 11 US 8,048,918 B2 Figure 2 Figure 3 RBP normal skin RBPrpsoriatic skin U.S. Patent Nov. 1, 2011 Sheet 3 of 11 US 8,048,918 B2 Figure 4 Proliferation experiment - Anti RBP receptor antibody 25OOO 20000 15OOO 10000 5000 KGM KGM KGM KGM KGM Ca2+ Ca2+ Ca2+ Ca2+ RBP RBP RBP P142 Control IgM U.S. Patent Nov. 1, 2011 Sheet 4 of 11 US 8,048,918 B2 Figure 5 KGM KGM KGM Ca2+ Ca2+ Ca2+ P42 RBP U.S. Patent Nov. 1, 2011 Sheet 5 of 11 US 8,048,918 B2 Figure 6 KGM KGM KGM KGM Ca2+ Ca2+ Ca2+ Ca2+ RBP RBP RBP Peptide 589 Peptide 592 U.S. Patent Nov. 1, 2011 Sheet 6 of 11 US 8,048,918 B2 Figure 7 CoS-1 24 Hours Post Treatment DMEM MEM - P142 DDMEM + Control fg a DMEM - 592 EDMEM + 589 w EDMEM + Control Peptide COS-1 48 Hours Post Treatment DMEM DMEM - P142 L. DMEM + Control ig DMEM + 592 is DMEM - 589 DMEM + Control Peptide U.S. Patent Nov. 1, 2011 Sheet 7 of 11 US 8,048,918 B2 Figure 8 CoS-7 24 Hours Post Treatment DMEM DMEM + P142 TDMEM + Controllg 2. DMEM - 592 DMEM - 589 DMEM + Control Peptide CoS-748 Hours Post Treatment 14OOOO DMEM 120000 . OMEM - P142 1OOOOO 8OOOO DDMEM + Controllg 6OOOO DMEM + 592 40000 20000 E. DMEM + 589 O O OMEM - Conto Peptide U.S. Patent Nov. 1, 2011 Sheet 8 of 11 US 8,048,918 B2 Figure 9 Fibroblast 24 Hours Post Treatment FBGM FBGM + P142 DFBGM+ Control ig a FBGM + 592 a FBGM+589 | E FBGM + Control Peptide Fibroblast after 4 Days of Treatment FBGM FBGM + P142 FBGM + 592 FBGM - 589 | E.E FBGM + Control Peptide U.S. Patent Nov. 1, 2011 Sheet 9 of 11 US 8,048,918 B2 Figure 10 Proliferation Experiment-RA Synthesis inhibitors 25OOO 2OOOO 15OOO 1OOOO 5OOO O KGM KGM KGM KGM KGM KGM KGM Cell Ca2+ ROL DisulfiROL CitraROL. R. RA Numbers a. Carben. U.S. Patent Nov. 1, 2011 Sheet 10 of 11 US 8,048,918 B2 Figure 11 KGM KGM KGM KGM Ca2+ Ca2+ Ca2+ Ca2+ ROL ROL ROL Disulfiram Citral U.S. Patent Nov. 1, 2011 Sheet 11 of 11 US 8,048,918 B2 Figure 12 US 8,048,918 B2 1. 2 TREATMENT OF HYPERPROLIFERATIVE inoids on hyperproliferative cells, i.e., reduced proliferation DISEASES and/or enhanced differentiation, as well as reversing the effects of photoageing, without exposing cells of a diseased or CROSS REFERENCE TO RELATED affected patient to pharmacological doses of retinoids. Such APPLICATIONS pharmacological doses are described below. This application is a continuation-in-part of international We have found that these physiological effects of retinoid application PCT/GB01/03694, filed Aug. 17, 2001 and therapy are achieved by reducing the endogenous level of claims priority from Great Britain Application No. retinoic acid in hyperproliferative cells or cells suffering from 0020351.3, filed Aug. 17, 2000. The above-mentioned appli photoageing. Reduction of the endogenous level of retinoic cations, as well as all documents cited herein and documents 10 acid in cells may beachieved in various ways, for example, by referenced or cited in documents cited herein, are hereby blocking the activity of a retinol binding protein receptor incorporated herein by reference. (RBPr) which transports retinol into the cell. Such blocking may be done by administering an antagonist of retinol bind FIELD 15 ing protein receptor to the patient. The antagonist as This invention relates to the treatment of diseases associ described above preferably comprises an agent which is ated with cellular hyperproliferation in a patient, including capable of inhibiting the interaction of retinol binding protein psoriasis and cancer. The invention also relates to the treat receptor with retinol binding protein. The antagonist may ment or alleviation of symptoms associated with photoage inhibit the interaction by binding to one or other, or both, of 1ng. the retinol binding protein receptor and the retinol binding protein. Furthermore, inhibition of any of the enzymatically BACKGROUND catalysed reactions in a pathway responsible for retinoic acid biosynthesis may also be used to reduce retinoic acid levels in A number of diseases are associated with hyperprolifera the cell. tion of cells, including psoriasis, the ichthyoses, cancer and 25 cutaneous viral infections. Psoriasis is a chronic inflamma According to a first aspect of the invention, we provide a tory disease characterised by hyperproliferation and impaired method of treating a patient Suffering from a hyperprolifera differentiation of keratinocytes. Currently, the symptoms of tive disorder or photoageing, which method comprises low psoriasis are treated in a number of ways, including topical ering the endogenous level or activity of retinoic acid (RA) in administration of retinoids to the patient. Other diseases such a cell of the patient. Other aspects of the invention, and as acne Vulgaris and photoageing also respond to retinoid 30 preferred embodiments, are set out in the independent and therapy and are believed to involve additional retinoid-medi dependent claims as well as in the description. ated mechanisms. Retinoids have also been used for both treatment and pre BRIEF DESCRIPTION OF THE DRAWINGS vention of the development of cancers (e.g. treatment of acute promyelocytic leukaemia and prevention of the development 35 FIG. 1 is a diagram representing the relationship between of cutaneous malignancies in renal transplant patients). current forms of retinoid therapy and an embodiment of a Current retinoid therapy is based upon the effect of car method according to our invention. The figure shows cell boxylic acid derivatives of vitamin A (in particular, retinoic response, as measured by its resting State of proliferation, acid, the endogenously active compound) which are able to differentiation or death (cytotoxicity leading to necrosis), to transcriptionally regulate target genes. Exposure to retinoic 40 increasing concentrations of retinoic acid (endogenous vita acid and retinoids results in proliferating cells withdrawing min A signal derived from retinol in the blood and delivered from the cell cycle and differentiating in response to retinoic to the cell by retinol binding protein-retinol binding protein acid-induced transcription of a possible excess of 300 target receptor interaction).