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(19) TZZ _ Z _T (11) EP 2 812 024 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 39/015 (2006.01) C07K 14/445 (2006.01) 11.04.2018 Bulletin 2018/15 (86) International application number: (21) Application number: 13704077.0 PCT/EP2013/052557 (22) Date of filing: 08.02.2013 (87) International publication number: WO 2013/117705 (15.08.2013 Gazette 2013/33) (54) TARGETING OF CHONDROITIN SULFATE GLYCANS TARGETING VON CHONDROITINSULFATGLYCANEN CIBLAGE DE GLYCANES DE SULFATE DE CHONDROÏTINE (84) Designated Contracting States: • MADELEINE DAHLBÄCK ET AL: "The AL AT BE BG CH CY CZ DE DK EE ES FI FR GB chondroitin sulfate A-binding site of the GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO VAR2CSA protein involves multiple N-terminal PL PT RO RS SE SI SK SM TR domains", JOURNAL OF BIOLOGICAL Designated Extension States: CHEMISTRY, AMERICAN SOCIETY FOR BA ME BIOCHEMISTRY AND MOLECULAR BIOLOGY, INC, BETHESDA, MD, USA, vol. 286, no. 18, 6 May (30) Priority: 09.02.2012 US 201261596931 P 2011 (2011-05-06), pages 15908-15917, XP002669767, ISSN: 1083-351X, DOI: (43) Date of publication of application: 10.1074/JBC.M110.191510 [retrieved on 17.12.2014 Bulletin 2014/51 2011-03-11] cited in the application • SRIVASTAVA A ET AL: "Var2CSA Minimal CSA (73) Proprietor: Var2 Pharmaceuticals ApS Binding Region Is Located within the N-Terminal 2200 Copenhagen N (DK) Region", PLOS ONE, PUBLIC LIBRARY OF SCIENCE, US, vol. 6, no. 5, 19 May 2011 (72) Inventors: (2011-05-19), pages E20270-1, XP002669766, • SALANTI, Ali ISSN: 1932-6203, DOI: DK-2700 Brønshøj (DK) 10.1371/JOURNAL.PONE.0020270 • THEANDER, Thor, Grundtvig • BITA BORDBAR ET AL: "Identification of DK-2670 Greve (DK) Id1-DBL2Xof VAR2CSA as a key domain inducing • DAUGAARD, Mads highly inhibitory and cross-reactive antibodies", Vancouver, British Columbia V6H 3T5 (CA) VACCINE, vol. 30, no. 7, 1 February 2012 • NIELSEN, Morten (2012-02-01), pages 1343-1348, XP055019210, DK-3460 Birkerød (DK) ISSN: 0264-410X, DOI: • DAHLBÄCK, Madeleine 10.1016/j.vaccine.2011.12.065 S-23391 Swedala (SE) • BIGEY PASCAL ET AL: "The NTS-DBL2X region • CLAUSEN, Thomas, Mandel of VAR2CSA induces cross-reactive antibodies DK-1068 Copenhagen K (DK) that inhibit adhesion of several Plasmodium falciparumisolates tochondroitin sulfate A", THE (74) Representative: Inspicos P/S JOURNAL OF INFECTIOUS DISEASES UNITED Kogle Allé 2 STATES 15 DEC 2010, INFECTIOUS DISEASES 2970 Hørsholm (DK) SOCIETY OF AMERICA, US, vol. 204, no. 7, 1 October 2011 (2011-10-01), pages 1125-1133, (56) References cited: XP009156487, ISSN: 1537-6613 WO-A1-2004/067559 WO-A2-2006/039652 WO-A2-2012/014073 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 2 812 024 B1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 812 024 B1 • ADAM F. SANDER ET AL: "Multiple var2csa-Type • T.M. CLAUSEN ET AL: "Structural and Functional PfEMP1 Genes Located at Different Insight into How the Plasmodium falciparum Chromosomal Loci Occur in Many Plasmodium VAR2CSA Protein Mediates Binding to falciparum Isolates", PLOS ONE, vol. 4, no. 8, 1 Chondroitin Sulfate A in Placental Malaria", January 2009 (2009-01-01) , page e6667, JOURNAL OF BIOLOGICAL CHEMISTRY, vol. XP55057871, ISSN: 1932-6203, DOI: 287, no. 28, 6 July 2012 (2012-07-06) , pages 10.1371/journal.pone.0006667 cited in the 23332-23345, XP55058098, ISSN: 0021-9258, DOI: application 10.1074/jbc.M112.348839 • RESENDE M ET AL: "Chondroitin sulphate A (CSA)-binding of single recombinant Duffy-binding-like domains is not restricted to Plasmodium falciparum Erythrocyte Membrane Protein 1 expressed by CSA-binding parasites", INTERNATIONAL JOURNAL OF PARASITOLOGY, PERGAMON PRESS, GB, vol. 39, no. 11, 1 September 2009 (2009-09-01), pages 1195-1204, XP026322957, ISSN: 0020-7519, DOI: 10.1016/J.IJPARA.2009.02.022 [retrieved on 2009-03-24] cited in the application 2 EP 2 812 024 B1 Description FIELD OF THE INVENTION 5 [0001] The present invention relates to functional binding fragments comprising the minimal binding fragments of VAR2CSA, to antibodies against such binding fragments of VAR2CSA, nucleic acids encoding such fragments of VAR2CSA as well as methods for their production. The invention further relates to conjugates and fusion proteins of VAR2CSA polypeptides including the minimal binding fragments and their use, in particular in the treatment of conditions associated with expression of chondroitin sulfate A (CSA), such as an inappropriate expression of chondroitin sulfate A 10 (CSA). BACKGROUND OF THE INVENTION [0002] Proteoglycans are proteins conjugated to one or more glycosaminoglycan (GAG) chains. These proteins are 15 distributed inside cells, on the cell membrane and in the extracellular matrix serving a variety of functions: cartilage matrix formation; the structural organization of tissues; organizations of basement membranes; regulating the role of secretory vesicles; binding of cytokines, chemokines, growth factors, and morphogens; protease receptors and protease inhibitors; co-receptors, tyrosine-kinase-type growth factor receptors; as endocytic receptors; facilitate cell attachment, cell-cell interactions, and cell motility as well as cell migration. 20 [0003] The malaria parasite Plasmodium falciparum utilizes host cell proteoglycans in almost all stages of its complex life cycle. The sporozoite infects hepatocytes in the liver through surface-expressed circumsporozoite protein interacting with highly sulfated heparan sulfate proteoglycans (HSPG). Merozoite infection of the erythrocytes is mediated by EBA- 175 binding to sialic acid on glycophorin A. In addition, a number of Plasmodium falciparum Erythrocyte Membrane Protein 1 (PfEMP1) proteins, mediating host endothelial adhesion, have been described as glycan-binding. One of these 25 is VAR2CSA, which is a unique member of the PfEMP1 protein family. VAR2CSA binds with high affinity to an unusual, low-sulfated form of chondroitin sulfate A (CSA), attached to proteoglycans, so called Chondroitin Sulfate Proteoglycan (CSPG), in the intervillous spaces of the placenta. VAR2CSA is a large multi-domain protein (350 kDa) expressed on the surface of P. falciparum-infected erythrocytes (IEs), and the VAR2CSA-CSA interaction is responsible for placenta specific sequestration in placental malaria (PM). Importantly, recombinant full-length VAR2CSA ecto-domain from FCR3 30 and 3D7 type parasites has shown affinity for CSA in the low nano-molar range. [0004] CSA belongs to the family of glycosaminoglycans (GAGs), which are linear polymers of alternating amino sugars and hexuronic acid residues, attached to proteoglycans. There are several types of GAGs including; chondroitin sulfate (CS), dermatan sulfate (DS or CSB), heparan sulfate (HS) and heparin. While the polysaccharide backbone of these GAGs is simple, considerable diversity arises in modifications such as sulfation and uronate epimerization. This 35 is the basis for the wide variety in domain structure and biological activities of different GAGs. [0005] CS interacts with many important factors such as growth hormones, cytokines, chemokines, and adhesion molecules and is thought to be involved in structural stabilization, cytokinesis, cell proliferation, differentiation, cell mi- gration, tissue morphogenesis, organogenesis, infection, and wound repair. CS chains are composed of alternating units of N-acetyl-D-galactosamine (GalNAc) and glucuronic acid residues. Glucuronic acid can be sulfated at its C2 position 40 and GalNAc can be sulfated at C4 and/or C6, giving rise to various disaccharide units. Varying modifications of the sugar backbone allows structural and functional heterogeneity of the CS chains. Placenta adheringP. falciparum parasites specifically associate with low sulfated CSA with sulfation only at C4 of GalNAc. [0006] Early studies pinpointed CSA as being responsible for IE sequestration in the placenta. The specific receptor was however not known. Upon further research it was found that the human placenta contained three distinct types of 45 chondroitin sulfate proteoglycans (CSPG), but that the IE adhered specifically to low sulfated CSPG in the intervillous spaces. What is special for this type of CSPG is that only 2-8% of the disaccharide units are C4 sulfated. In an accom- panying study, aimed to identify the specific structural requirements for the CSA, it was found that parasite adhesion to CSPG is inhibited by CSA containing between 30-50% C4 sulfation, with the remaining 50-70% disaccharide units being unsulfated. The minimal inhibition of binding requirements for CSA was shown to be a dodecasaccharide (six disaccha- 50 rides) containing a minimum of 2-3 or 4-5 C4 sulfated disaccharide units. [0007] Chondroitin sulfate proteoglycan 4 (CSPG4), also known as High Molecular Weight-Melanoma Associated Antigen (HMW-MAA) or melanoma-associated chondroitin sulfate proteoglycan (MSCP), is a cell surface proteoglycan which has been shown to be expressed by melanoma cells. [0008] CSPG4/MSCP/HMV-MAA is a large proteoglycan characterized by having CS chains on the protein backbone. 55 The sulfation of these CS chains seems to be primarily on C4 of GalNAc (CSA), although
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  • Abrin Fact Sheet

    Abrin Fact Sheet

    ABRIN FACT SHEET What is abrin? Abrin is a natural poison that is found in the seeds of a plant called rosary pea. Abrin can be made in the form of a powder, a mist and a pellet, or it can be dissolved in water. Abrin is a stable substance that can last for a long time in the environment regardless of extreme hot or cold temperature conditions. Avoid exposure to abrin because there is no antidote that exists. How can you be exposed to abrin? It will take a deliberate act to obtain abrin from rosary pea seeds and use it to poison people. Breathing in abrin (mist or powder) can expose you. You could be exposed if you touch any surfaces where the particles or droplets have landed or if the droplets have landed on your skin or in your eyes. You could ingest abrin if it is in the food or water. Abrin poisoning is not contagious. It cannot be spread from one person to another through casual contact. What are the immediate symptoms of exposure to abrin? If you inhale abrin, within a few hours you may have the following symptoms: difficulty breathing, fever, cough, nausea, heavy sweating, tightness in the chest and fluid building up in the lungs. If you ingest a large amount of abrin, you will develop vomiting and diarrhea that may become bloody. Next, severe dehydration followed by low blood pressure. Other symptoms may include hallucinations, seizures and blood in the urine. If you have skin and eye exposure, the mist or powder abrin can cause redness and pain of the skin and the eyes.