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Title:
MODULATORS OF C1Q, IN PARTICULAR OF THE INTERACTION OF APOE WITH C1Q, AND USES OF THE MODULATORS IN THE THERAPY OF NEURONAL DISEASES AND INFLAMMATION
Document Type and Number:
WIPO Patent Application WO/2019/137922
Kind Code:
A1
Abstract:
The present invention relates to modulators of complex 1 protein q (C1q) that preferably mimic and/or stabilize the interaction of inhibitor apolipoprotein-E (ApoE) with C1q, and their uses in the prevention or treatment of C1q-related diseases or conditions, such Alzheimer's disease (AD), atherosclerosis, kidney diseases, and ageing.

Inventors:
SKERKA, Christine (Schillbachstraße 34, Jena, 07743, DE)
ZIPFEL, Peter (Schillbachstraße 34, Jena, 07743, DE)
ACKERMANN, Susanne (Zeppelinplatz 5, Weimar, 99423, DE)
Application Number:
EP2019/050354
Publication Date:
July 18, 2019
Filing Date:
January 08, 2019
Export Citation:
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Assignee:
LEIBNIZ-INSTITUT FÜR NATURSTOFF-FORSCHUNG UND INFEKTIONSBIOLOGIE (HANS-KNÖLL-INSTITUT, Beutenbergstraße 11a, Jena, 07745, DE)
International Classes:
A61P25/28; A61P9/00; A61P13/12; A61P21/00; C07K14/435; G01N33/50
Domestic Patent References:
WO2017196432A12017-11-16
WO2005002513A22005-01-13
WO2015006504A12015-01-15
WO2008132723A22008-11-06
WO2017196874A12017-11-16
WO2005002513A22005-01-13
Foreign References:
EP2333074A12011-06-15
KR20090061727A2009-06-17
US20150337030A12015-11-26
US20090117098A12009-05-07
Other References:
ROUMENINA L. ET AL.: "Complement Clq-target proteins recognition is inhibited by electric moment effectors", J MOL RECOGNIT, vol. 20, no. 5, September 2007 (2007-09-01), pages 405 - 15
ROOS, A. ET AL.: "Specific Inhibition of the Classical Complement Pathway by Clq-Binding Peptides", J IMMUNOL, vol. 167, no. 12, 15 December 2001 (2001-12-15), pages 7052 - 7059, XP001056046
THIELENS N.M. ET AL.: "Clq: A fresh look upon an old molecule", MOL IMMUNOL, vol. 89, September 2017 (2017-09-01), pages 73 - 83, XP085162865, DOI: doi:10.1016/j.molimm.2017.05.025
HAJISHENGALLIS G ET AL.: "Novel mechanisms and functions of complement", NAT IMMUNOL, vol. 18, no. 12, 16 November 2017 (2017-11-16), pages 1288 - 1298
HASKARD DO ET AL.: "The role of complement in atherosclerosis", CURR OPIN LIPIDOL, vol. 19, no. 5, October 2008 (2008-10-01), pages 478 - 82
LIU ET AL.: "Targeted mouse complement inhibitor CR2-Crry protects against the development of atherosclerosis in mice", ATHEROSCLEROSIS, vol. 234, no. l, May 2014 (2014-05-01), pages 237 - 43
YONG SHEN: "What does complement do in Alzheimer's disease? Old molecules with new insights", TRANSL NEURODEGENER, vol. 2, 2013, pages 21, XP021165528, DOI: doi:10.1186/2047-9158-2-21
SPEIDL WS ET AL.: "Complement in atherosclerosis: friend or foe?", J THROMB HAEMOST, vol. 9, no. 3, March 2011 (2011-03-01), pages 428 - 40
ANDREI SA ET AL.: "Stabilization of protein-protein interactions in drug discovery", EXPERT OPIN DRUG DISCOV, vol. 12, no. 9, September 2017 (2017-09-01), pages 925 - 940
WILES MV ET AL.: "CRISPR-Cas9-mediated genome editing and guide RNA design", MAMM GENOME, vol. 26, no. 9-10, October 2015 (2015-10-01), pages 501 - 10
SAVIC N; SCHWANK G: "Advances in therapeutic CRISPR/Cas9 genome editing", TRANSL RES, vol. 168, February 2016 (2016-02-01), pages 15 - 21, XP029385959, DOI: doi:10.1016/j.trsl.2015.09.008
GABORIAUD C. ET AL.: "The crystal structure of the globular head of complement protein Clq provides a basis for its versatile recognition properties", J BIOL CHEM., vol. 278, no. 47, 2003, pages 46974 - 82, XP002597310, DOI: doi:10.1074/JBC.M307764200
MAJOR ET AL.: "Calcium-dependent conformational flexibility of a CUB domain controls activation of the complement serine protease Clr", J BIOL CHEM., vol. 285, no. 16, 2010, pages 11863 - 9
ALMITAIRI JOM ET AL.: "Structure of the C1r-C1s interaction of the C1 complex of complement activation", PROC NATL ACAD SCI USA., vol. 115, no. 4, 2018, pages 768 - 773
ALMITAIRI JOM ET AL.: "Structure of the Clr-Cls interaction of the C1 complex of complement activation", PROC NATL ACAD SCI USA, vol. 115, no. 4, 2018, pages 768 - 773
BELL, R. D. ET AL.: "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A", NATURE, vol. 485, 2012, pages 512 - 516
HOFMAN, A. ET AL.: "Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study", LANCET, vol. 349, 1997, pages 151 - 154, XP005061658, DOI: doi:10.1016/S0140-6736(96)09328-2
HOLTZMAN, D. M.; HERZ, J.; BU, G.: "Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease", COLD SPRING HARB PERSPECT MED, vol. 2, 2012, pages a006312
KANEKIYO, T.; XU, H.; BU, G.: "ApoE and Ap in Alzheimer's Disease: Accidental Encounters or Partners?", NEURON, vol. 81, 2014, pages 740 - 754, XP028616093, DOI: doi:10.1016/j.neuron.2014.01.045
MAHLEY, R. W.; HUANG, Y.: "Apolipoprotein e sets the stage: response to injury triggers neuropathology", NEURON, vol. 76, 2012, pages 871 - 885, XP028960119, DOI: doi:10.1016/j.neuron.2012.11.020
ZLOKOVIC, B. V.: "Cerebrovascular effects of apolipoprotein E: implications for Alzheimer disease", JAMA NEUROL, vol. 70, 2013, pages 440 - 444
SHUVAEV, V. V.; LAFFONT, I.; SIEST, G.: "Kinetics of apolipoprotein E isoforms-binding to the major glycosaminoglycans of the extracellular matrix", FEBS LETT, vol. 459, 1999, pages 353 - 357, XP004375859, DOI: doi:10.1016/S0014-5793(99)01285-5
WITZTUM, J. L.; LICHTMAN, A. H.: "The influence of innate and adaptive immune responses on atherosclerosis", ANNU REV PATHOL, vol. 9, 2014, pages 73 - 102
HANSSON, G. K.; HERMANSSON, A.: "The immune system in atherosclerosis", NAT IMMUNOL, vol. 12, 2011, pages 204 - 212
WEBER, C.; NOELS, H.: "Atherosclerosis: current pathogenesis and therapeutic options", NAT MED, vol. 17, 2011, pages 1410 - 1422
LIBBY, P.; RIDKER, P. M.; HANSSON, G. K.: "Progress and challenges in translating the biology of atherosclerosis", NATURE, vol. 473, 2011, pages 317 - 325
GOLDMANN, T. ET AL.: "Origin, fate and dynamics of macrophages at central nervous system interfaces", NAT IMMUNOL, vol. 17, 2016, pages 797 - 805
LUN, M. P.; MONUKI, E. S.; LEHTINEN, M. K.: "Development and functions of the choroid plexus-cerebrospinal fluid system", NAT REV NEUROSCI, vol. 16, 2015, pages 445 - 457
MOORE, G. R. ET AL.: "Complement and Humoral Adaptive Immunity in the Human Choroid Plexus: Roles for Stromal Concretions, Basement Membranes, and Epithelium", J NEUROPATHOL EXP NEUROL, vol. 75, 2016, pages 415 - 428
RANSOHOFF, R. M.; ENGELHARDT, B.: "The anatomical and cellular basis of immune surveillance in the central nervous system", NAT REV IMMUNOL, vol. 12, 2012, pages 623 - 635
SCHWARTZ, M.; BARUCH, K.: "The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus", EMBO J., vol. 33, 2014, pages 7 - 22
SHECHTER, R.; LONDON, A.; SCHWARTZ, M.: "Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates", NAT REV IMMUNOL, vol. 13, 2013, pages 206 - 218
BINDER, C. J.; PAPAC-MILICEVIC, N.; WITZTUM, J. L.: "Innate sensing of oxidation-specific epitopes in health and disease", NAT REV IMMUNOL, vol. 16, 2016, pages 485 - 497
WEISMANN, D. ET AL.: "Complement factor H binds malondialdehyde epitopes and protects from oxidative stress", NATURE, vol. 478, 2011, pages 76 - 81, XP055044028, DOI: doi:10.1038/nature10449
ZIPFEL, P. F.; SKERKA, C.: "Complement regulators and inhibitory proteins", NAT REV IMMUNOL, vol. 9, 2009, pages 729 - 740
ARLAUD, G. J.; BIRO, A.; LING, W. L.: "Enzymatically Modified Low-Density Lipoprotein Is Recognized by Clq and Activates the Classical Complement Pathway", JOURNAL OF LIPIDS, vol. 2011, 2011, pages 376092
WILSON, C. ET AL.: "Three-dimensional structure of the LDL receptor-binding domain of human apolipoprotein E", SCIENCE, vol. 252, 1991, pages 1817 - 1822
VENKATRAMAN GIRIJA, U. ET AL.: "Structural basis of the Clq/Cls interaction and its central role in assembly of the C1 complex of complement activation", PROC NATL ACAD SCI USA, vol. 110, 2013, pages 13916 - 13920
BRAAK, H. ET AL.: "Staging of Alzheimer disease-associated neurofibrillary pathology using paraffin sections and immunocytochemistry", ACTA NEUROPATHOL, vol. 112, 2006, pages 389 - 404, XP019442875, DOI: doi:10.1007/s00401-006-0127-z
THAI, D. R.; RUB, U.; ORANTES, M.; BRAAK, H.: "Phases of Ap-deposition in the human brain and its relevance for the development of AD", NEUROLOGY, vol. 58, 2002, pages 1791 - 1800
STARY, H. C.: "Natural history and histological classification of atherosclerotic lesions: an update", ARTERIOSCLER THROMB VASC BIOL, vol. 20, 2000, pages 1177 - 1178
ZHANG, B. ET AL.: "Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer's disease", CELL, vol. 153, 2013, pages 707 - 720, XP028589810, DOI: doi:10.1016/j.cell.2013.03.030
HOVLAND, A. ET AL.: "The complement system and toll-like receptors as integrated players in the pathophysiology of atherosclerosis", ATHEROSCLEROSIS, vol. 241, 2015, pages 480 - 494
CRAMER, P. E. ET AL.: "ApoE-directed therapeutics rapidly clear beta-amyloid and reverse deficits in AD mouse models", SCIENCE, vol. 335, 2012, pages 1503 - 1506, XP055159821, DOI: doi:10.1126/science.1217697
DINARELLO, C. A.: "Anti-inflammatory Agents: Present and Future", CELL, vol. 140, 2010, pages 935 - 950
GLASS, C. K. ET AL.: "Mechanisms Underlying Inflammation in Neurodegeneration", CELL, vol. 140, 2010, pages 918 - 934, XP055280584, DOI: doi:10.1016/j.cell.2010.02.016
HESS, C.; KEMPER, C.: "Complement-Mediated Regulation of Metabolism and Basic Cellular Processes", IMMUNITY, vol. 45, 2016, pages 240 - 254, XP029687772, DOI: doi:10.1016/j.immuni.2016.08.003
TABAS, I.; GLASS, C. K.: "Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities", SCIENCE, vol. 339, 2013, pages 166 - 172
ZIPFEL, P. F.; C. SKERKA: "Complement regulators and inhibitory proteins", NAT REV IMMUNOL, vol. 9, 2009, pages 729 - 740
SARMA, J. V.; P. A. WARD: "The complement system", CELL TISSUE RES, vol. 343, 2011, pages 227 - 235, XP019870471, DOI: doi:10.1007/s00441-010-1034-0
MATHERN, D. R.; P. S. HEEGER: "Molecules Great and Small: Complement System", CLIN JAM SOC NEPHROL, 2015
RICKLIN D.; HAJISHENGALLIS G.; YANG K.; LAMBRIS J.D.: "The Complement - a key system for immune surveillance and homeostasis", NAT IMMUNOL, vol. 11, no. 9, 2010, pages 785 - 797, XP055306904, DOI: doi:10.1038/ni.1923
FLEMING S.D.: "Naturally occuring autoantibodies mediate ischemia/reperfusion-induced tissue injury", ADV. EXP. MED. BIOL., 2012, pages 750174 - 85
MILLER, CHOI S.H.; WIESNER P.; FANG L.; HARKEWICZ R; HARTVIGSEN K.; BOULLIER A.; GONEN A.; DIEHL C.J.; QUE X.; MONTANO E.: "Oxidation-Specific Epitopes are Danger Associated Molecular Patterns Recognized by Pattern Recognition Receptors of Innate", IMMUNITY CIRC RES, vol. 108, no. 2, 2011, pages 235 - 248
GRONWALL C; SILVERMAN GJ: "Natural IgM: Beneficial autoantibodies for the control of inflammatory and autoimmune disease", J CLIN. IMMUNOL., vol. 34, no. 1512-21, 2014
PANDA S; DING JL: "Natural antibodies bridge innate and adaptive immunity", J CLIN. IMMUNOL., vol. 194, 2015, pages 13 - 20, XP055456790, DOI: doi:10.4049/jimmunol.1400844
Attorney, Agent or Firm:
BOEHMERT & BOEHMERT (Krauss, JanPettenkoferstraße 20-22, München, 80336, DE)
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