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(19) TZZ ¥¥_T (11) EP 2 285 833 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07K 16/28 (2006.01) A61K 39/395 (2006.01) 17.12.2014 Bulletin 2014/51 A61P 31/18 (2006.01) A61P 35/00 (2006.01) (21) Application number: 09745851.7 (86) International application number: PCT/EP2009/056026 (22) Date of filing: 18.05.2009 (87) International publication number: WO 2009/138519 (19.11.2009 Gazette 2009/47) (54) AMINO ACID SEQUENCES DIRECTED AGAINST CXCR4 AND OTHER GPCRs AND COMPOUNDS COMPRISING THE SAME GEGEN CXCR4 UND ANDERE GPCR GERICHTETE AMINOSÄURESEQUENZEN SOWIE VERBINDUNGEN DAMIT SÉQUENCES D’ACIDES AMINÉS DIRIGÉES CONTRE CXCR4 ET AUTRES GPCR ET COMPOSÉS RENFERMANT CES DERNIÈRES (84) Designated Contracting States: (74) Representative: Hoffmann Eitle AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Patent- und Rechtsanwälte PartmbB HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL Arabellastraße 30 PT RO SE SI SK TR 81925 München (DE) (30) Priority: 16.05.2008 US 53847 P (56) References cited: 02.10.2008 US 102142 P EP-A- 1 316 801 WO-A-99/50461 WO-A-03/050531 WO-A-03/066830 (43) Date of publication of application: WO-A-2006/089141 WO-A-2007/051063 23.02.2011 Bulletin 2011/08 • VADAY GAYLE G ET AL: "CXCR4 and CXCL12 (73) Proprietor: Ablynx N.V. (SDF-1) in prostate cancer: inhibitory effects of 9052 Ghent-Zwijnaarde (BE) human single chain Fv antibodies" CLINICAL CANCER RESEARCH, THE AMERICAN (72) Inventors: ASSOCIATION FOR CANCER RESEARCH, US, • BLANCHETOT, Christophe vol.10, no. 16, 15 August 2004 (2004-08-15), pages 9070 Destelbergen (BE) 5630-5639, XP002397863 ISSN: 1078-0432 • SMIT, Martine • MISUMI SHOGO ET AL: "A novel cyclic peptide 1060 TP Amsterdam (NL) immunization strategy for preventing HIV- 1/AIDS • LEURS, Regorius infection and progression." THE JOURNAL OF 1075 CB Amsterdam (NL) BIOLOGICAL CHEMISTRY 22 AUG 2003, vol. 278, • JÄHNICHEN, Sven no. 34, 22 August 2003 (2003-08-22), pages 27327 Schwarme (DE) 32335-32343, XP002544062 ISSN: 0021-9258 • SAUNDERS, Michael, John, Scott • CARNEC XAVIER ET AL: "Anti-CXCR4 1190 Brussels (BE) monoclonal antibodies recognizing overlapping • DE HAARD, Johannes, Joseph, Wilhelmus epitopes differ significantly in their ability to 4436 NA Oudelande (NL) inhibit entry of human immunodeficiency virus • VANLANDSCHOOT, Peter type 1" JOURNAL OF VIROLOGY, THE 9881 Bellem (BE) AMERICAN SOCIETY FOR MICROBIOLOGY, US, vol. 79, no. 3, 1 February 2005 (2005-02-01), pages 1930-1933, XP002518542 ISSN: 0022-538X Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 285 833 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 285 833 B1 • HOFFMAN T L ET AL: "A biosensor assay for • B. Lagane ET AL: "CXCR4 dimerization and studying ligand-membrane receptor -arrestin-mediated signaling account for the interactions: Binding of antibodies and HIV- 1 Env enhanced chemotaxis to CXCL12 in WHIM to chemokine receptors" PROCEEDINGS OF THE syndrome", Blood, vol. 112, no. 1, 1 January 2008 NATIONAL ACADEMY OF SCIENCES OF USA, (2008-01-01), pages 34-44, XP55042244, ISSN: NATIONAL ACADEMY OF SCIENCE, 0006-4971, DOI: 10.1182/blood-2007-07-102103 WASHINGTON,DC, US, vol. 97, no.21, 10 October 2000 (2000-10-10), pages 11215-11220, XP003006201 ISSN: 0027-8424 • KIM JIN C ET AL: "Enhancement of colorectal tumor targeting using a novel biparatopic monoclonal antibody against carcinoembryonic antigen in experimental radioimmunoguided surgery", INTERNATIONAL JOURNAL OF CANCER,JOHN WILEY & SONS, INC, NEW YORK, NY; US, vol. 97, no. 4, 1 February 2002 (2002-02-01), pages542-547, XP002609360, ISSN: 0020-7136, DOI: 10.1002/IJC.1630 2 EP 2 285 833 B1 Description [0001] The present invention relates to amino acid sequences, in particular to polypeptides that are directed against (as defined herein) CXCR4 as defined in the claims, as well as to compounds or constructs, and in particular proteins 5 and polypeptides, that comprise or essentially consist of one or more such amino acid sequences (also referred to herein as "amino acid sequences of the invention", "compounds of the invention", and "polypeptides of the invention", respec- tively). [0002] The invention also relates to nucleic acids encoding such amino acid sequences and polypeptides (also referred to herein as "nucleic acids of the invention" or "nucleotide sequences of the invention"); to host cells expressing or 10 capable of expressing such amino acid sequences or polypeptides; to compositions, and in particular to pharmaceutical compositions, that comprise such amino acid sequences, polypeptides, nucleic acids and/or host cells; and to uses of such amino acid sequences or polypeptides, nucleic acids, host cells and/or compositions, in particular for prophylactic, therapeutic or diagnostic purposes, such as the prophylactic, therapeutic or diagnostic purposes mentioned herein. [0003] Other aspects, embodiments, advantages and applications of the invention will become clear from the further 15 description herein. [0004] GPCRs are a well-known class of receptors. Reference is for example made to the following reviews: Surgand et al., Proteins 62:509-538 (2006); Vassilatis et al., Proc Natl Acad Sci U S A 100:4903-4908 (2003) and Pierce et al., Nat Rev Mol Cell Biol 3:639-650 (2002); as well as to for example: George et al., Nat Rev Drug Discov 1:808-820 (2002); Kenakin,Trends Pharmacol Sci 25:186-192 (2002); Rios et al., PharmacolTher 92:71-87 (2001); Jacoby et al., ChemMed- 20 Chem 2006, 1, 760-782; and Schlyer and Horuk, Drug Discovery Today, 11, 11/12. June 2006, 481; and also for example to Rosenkilde, Oncogene (2001), 20, 1582-1593 and Sadee et al., AAPS PharmSci 2001; 3; 1-16; as well as to the further references cited therein. [0005] G-protein-coupled receptors (GPCRs) are the largest class of cell-surface receptors (more than 1000 genes are present in the human genome). They can be activated by a diverse array of stimuli, e.g. hormone, peptides, amino 25 acids, photons of light, and these receptors play a large role in the central nervous system and in the periphery. GPCRs are proteins with 7 transmembrane domains with highly conserved domains. [0006] As half of all known drugs work through G-protein coupled receptors, it is commercially very attractive to select Nanobodies against this protein family. It was estimated that in the year 2000 half of all modem drugs and almost one- quarter of the top 200 best-selling drugs are directed against or modulate GPCR targets (approximately 30 in total). 30 However, due to their architecture of 7 membrane-spanning helices and their strong tendency to aggregate, it’s a very challenging target class. [0007] GPCRs can be grouped on the basis of sequence homology into several distinct families. Although all GPCRs have a similar architecture of seven membrane-spanning α-helices, the different families within this receptor class show no sequence homology to one another, thus suggesting that the similarity of their transmembrane domain structure 35 might define common functional requirements. Depending on the size of the extracellular domain three families are discriminated. - Members of Family 1 (also called family A or rhodopsin-like family) only have small extracellular loops and the interaction of the ligands occurs with residues within the transmembrane cleft. This is by far the largest group (>90% 40 of the GPCRs) and contains receptors for odorants, small molecules such as catecholamines and amines, (neu- ro)peptides and glycoprotein hormones. Rhodopsin, which belongs to this family, is the only GPCR for which the structure has been solved. - Family 2 or family B GPCRs are characterized by a relatively long amino terminal extracellular domain involved in ligand-binding. Little is known about the orientation of the transmembrane domains, but it is probably quite different 45 from that of rhodopsin. Ligands for these GPCRs are hormones, such as glucagon, gonadotropin-releasing hormone and parathyroid hormone. - Family 3 members also have a large extracellular domain, which functions like a "Venus fly trap" since it can open and close with the agonist bound inside. Family members are the metabotropic glutamate, the Ca2+-sensing and the γ-aminobutyric acid (GABA)B receptors. 50 [0008] Traditionally small molecules are used for development of drugs directed against GPCRs, not only because pharmaceutical companies have historical reasons to work with these, but more importantly because of the structural constraints of Family 1 GPCRs, which have the ligand binding site within the transmembrane cleft (Nat Rev Drug Discov. (2004) The state of GPCR research in 2004. Nature Reviews Drug Discovery GPCR Questionnaire Participants 3(7):575, 55 577-626). For this reason it proved to be difficult or impossible to generate monoclonal antibodies against this target class. The amino acid sequences of the invention (and in particular VHH sequences of the invention) can solve this particular problem by means of their intrinsic property of binding via extended CDR loops into cavities (as further described herein). In the following, the term "Nanobodies of the invention" refers to VHH sequences of the invention. 3 EP 2 285 833 B1 [0009] Some non-limiting examples of therapeutically relevant GPCRs are for example the following, which are all targets of known drugs that have either been approved or are in clinical development. The text between brackets indicates the desired action of an amino acid sequence, a Nanobody or a polypeptide (i.e.
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  • Cerebral Histamine H1 Receptor Binding Potential Measured With

    Cerebral Histamine H1 Receptor Binding Potential Measured With

    Cerebral Histamine H1 Receptor Binding Potential Measured with PET Under a Test Dose of Olopatadine, an Antihistamine, Is Reduced After Repeated Administration of Olopatadine Michio Senda1, Nobuo Kubo2, Kazuhiko Adachi3, Yasuhiko Ikari1,4, Keiichi Matsumoto1, Keiji Shimizu1, and Hideyuki Tominaga1 1Division of Molecular Imaging, Institute of Biomedical Research and Innovation, Kobe, Japan; 2Department of Otorhinolaryngology, Kansai Medical University, Osaka, Japan; 3Department of Mechanical Engineering, Kobe University, Kobe, Japan; and 4Micron, Inc., Kobe, Japan Some antihistamine drugs that are used for rhinitis and pollinosis have a sedative effect as they enter the brain and block the H1 Antihistamines are widely used as a medication for receptor, potentially causing serious accidents. Receptor occu- common allergic disorders such as seasonal pollinosis, pancy has been measured with PET under single-dose adminis- tration in humans to classify antihistamines as more sedating or chronic rhinitis, and urticaria. Some antihistamine drugs as less sedating (or nonsedating). In this study, the effect of re- have a sedative side effect as they enter the brain and block peated administration of olopatadine, an antihistamine, on the histamine H1 receptor, potentially causing traffic accidents cerebral H1 receptor was measured with PET. Methods: A total and other serious events, but the sedative effect is difficult to of 17 young men with rhinitis underwent dynamic brain PET with evaluate because of a large variation in neuropsychological 11 C-doxepin at baseline, under an initial single dose of 5 mg of measures and subjective symptoms. Measurement of cere- olopatadine (acute scan), and under another 5-mg dose after re- 11 peated administration of olopatadine at 10 mg/d for 4 wk (chronic bral histamine H1 receptor occupancy using PET with C- doxepin under a single administration of antihistamines has scan).