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(12) United States Patent (10) Patent N0.: US 7,267,820 B2 Vincent Et A] US007267820B2 (12) United States Patent (10) Patent N0.: US 7,267,820 B2 Vincent et a]. (45) Date of Patent: Sep. 11,2007 (54) NEUROTRANSMISSION DISORDERS Glass, D]. et a1. Agrin acts via a MuSK receptor complex. Cell. May 17, 1996;85(4):513-23. (75) Inventors: Angela Vincent, Oxford (GB); Werner Hoch W, et al., Auto-antibodies to the receptor tyrosine kinase Hoch, Houston, TX (US) MuSK in patients with myasthenia gravis without acetycholine receptor antibodies. Nat Med. Mar. 2001;7(3):365-8. (73) Assignees: Isis Innovation Limited, Oxford (GB); Hoch, W., et a1. Structural domains of agrin required for clustering of nicotinic acetylcholine receptors. EMBO J. Jun. 15, Max-Planck Gesellschaft zur 1994;13(12):2814-21. Foerderung der Wissenschaften e.V., Hopf. C., Hoch, W. Heparin inhibits acetycholine receptor-aggre Munich (DE) gation at two distinct steps in the agrin-induced pathway. Eur J Neurosci. Jun. 1997;9(6):1170-7. ( * ) Notice: Subject to any disclaimer, the term of this Hopf, C., Hoch, W. DimeriZation of the muscle-speci?c kinase patent is extended or adjusted under 35 induces tyrosine phosphorylation of acetycholine receptors and their U.S.C. 154(b) by 506 days. aggregation on the surface of myotubes. J Biol Chem. Mar. 13, 1998;273(11):6467-73. (21) Appl. No.: 10/311,575 Hopf, C., Hoch, W. Tyrosine phosphorylation of the muscle-speci?c kinase is exclusively induced by acetycholine receptor-aggregating (22) PCT Filed: Jun. 15, 2001 agrin fragments. Eur JBiochem. Apr. 15, 1998;253(2):382-9. Lindstrom, J ., Seybold,.M.E., Lennon, V.A., Whittingham, S., (86) PCT N0.: PCT/GB01/02661 Duane, D.D., Antibody to acetycholine receptor in myasthenia gravis. prevalence, clinical correlates and diagnostic values. Neu rology. Nov. 1976;26(11):1054-9. § 371 (0X1)’ Mier, A.K., Havard, C.W.H. Diaphragmatic myasthenia in mother (2), (4) Date: Jun. 6, 2003 and child. Postgraduate Med J. 611 725-727 (1985). Mossman, S., Vincent, A., Newsom-Davis, J. Myasthenia gravis (87) PCT Pub. No.: WO01/96601 without acetylcholine-receptor antibody: a distinct disease entity. Lancet. Jan. 18, 1986;1(8473):116-9. PCT Pub. Date: Dec. 20, 2001 Riemersma S, Vincent A. Beeson D, Newland C, Brueton L, Huson S, Newsom-Davis J. Association of arthrogryposis multiplex (65) Prior Publication Data congenita with maternal antibodies inhibiting fetalacetycholine receptor function. J Clin Invest. Nov. 15, 1996;98(10):2358-63. US 2004/0082010 A1 Apr. 29, 2004 Robertson, S.C., Tynan, J,A., Donoghue, D.J. RTK mutations and human syndromes: when good receptors turn bad. Trends Genet. (30) Foreign Application Priority Data Jun. 2000;16(6):265-71. Jun. 16, 2000 (GB) ............................... .. 00148783 Sanes, J.R., et al., Development of the vertebrate neuromuscular junction. Annual Review of Neuroscience 22, 389-442 (1999). Saunders, D.B., et al., Seronegative myasthenia gravis. Neurology. (51) Int. Cl. 48. S40-S45 (1997). A61K 39/395 (2006.01) Taylor, S.I., Barbetti, F., Accili, D., Roth, J.,Gorden, P, Syndromes A61K 39/00 (2006.01) of autoi mmunity and hypoglycaemia. Autoantibodies directed A61K 38/00 (2006.01) against insulin and its receptor. Endocrinol Metab Clin North Am. C07K 14/00 (2006.01) Mar. 1989;18(1):123-43. (52) US. Cl. ............................. .. 424/130.1; 424/184.1; 424/178.1; 514/2; 530/350 (Continued) (58) Field of Classi?cation Search ................... .. None Primary ExamineriEileen O’Hara See application ?le for complete search history. Assistant ExamineriSandra Wegert (74) Attorney, Agent, or F irmiHamilton, Brook, Smith & (56) References Cited Reynolds, PC. U.S. PATENT DOCUMENTS (57) ABSTRACT 5,814,478 A 9/1998 Bowen et al. There is disclosed a method for diagnosing neurotransmis FOREIGN PATENT DOCUMENTS sion or developmental disorders in a mammal comprising WO WO99/10494 A 3/1999 the step of detecting in a bodily ?uid of said mammal autoantibodies to an epitope of the muscle speci?c tyrosine kinase (MuSK). One such method comprises a) contacting OTHER PUBLICATIONS said bodily ?uid with said MuSK or an antigenic determi Sisman, et a1, 2004, Indian Pediatrics, 41:938-940.* nant thereof; and b) detecting any antibody-antigen com Blaes, F.,, Beeson, D., Plested, P., Lang, B., Vincent, A. IgG from plexes formed between said receptor tyrosine kinase or an seronegative myastheniagravis patients binds to a muscle cell line, antigenic fragment thereof and antibodies present in said TE671, but not to human acetylcholine receptor Ann Neurol. Apr. bodily ?uid, wherein the presence of said complexes is 2000;47(4):504-10. indicative of said mammal suffering from said neurotrans Brooks, E.B., Pachner, A.R., Drachman, D.B.,Kantor, F.S. A sen mission or developmental disorders. Also disclosed are kits sitive rosetting assay for detection of acetylcholine receptor anti for use in the diagnosis of neurotransmission and subsequent bodies using BC3H-1 cells: positive results in ‘antibody-negative’ myasthenia gravis. JNeuroimmunol. Jun. 1990;28(1):83-93. developmental disorders. Drachman, D.B. Myasthenia gravis. N Engl J Med. Jun. 23, 1994;330(25):1797-810. 12 Claims, 6 Drawing Sheets US 7,267,820 B2 Page 2 OTHER PUBLICATIONS Zhou, H., Glass, D.J., Yancopoulos, G.D., Sanes,J.R. Distinct domains of MuSK mediate its ability to induce and to associate with Valenzuela, D.M. et al. Receptor tyrosine kinase speci?c for the postsynaptic specializations. JCell Biol. Sep. 6, l999;l46(5):ll33 skeletal muscle lineage: expression in embryonic muscle, at the 46. neuromuscular junction, and after injury. Neuron. Sep. LiyanageY, Hoch W., Beeson D, Vincent A. 2001. The agrin/muscle l995;l5(3):573-84. speci?c kinase pathway; new targets for autoimmune and genetic Vincent A, Newland C, Brueton L. Beeson D. Riemersma S, Huson disorders at the neuromuscular junction. Invited Review. Muscle S, Newsom-Davis J. Arthrogryposis multiplex congenita with Nerve. Jan. 2002;25(l):4-l6. maternal autoantibodies speci?c for a fetal antigen Lancet. Jul. 1, Palace J. Vincent A, Beeson D. Myasthenia gravis: diagnostic and l995;346(8966):24-5. management dilemmas. Curr Opin Neurol. Oct. 2001; l4(5):583-9. Vincent, A., Newsom-Davis, J. Acetycholine receptor antibody as a Sanders DB, El-Salem K, Massey JM, Vincent A. Clinical Aspects diagnostic test for myasthenia gravis: results in 153 validated cases of MuSK Antibody Positive Seronegative MG., Neurology and 2967 diagnostic assays. J Neurol Neurosurg Psychiatry. Dec. 60(l2):l978-l980, 2003. l985;48(l2):l246-52. Vincent A. “Unraveling the pathogenesis of myasthenia gravis.” Nat Plested, CP, T. Tang, I. Spreadbury, E.T. Littleton, U. Kishore and Rev Immunol. Oct. 2002;2(l0):797-804. A. Vincent. AChR phosphorylation and indirect inhibition of AChR Vincent A, Brown J. Newsom-Davis J, McConville J. “Seronegative function in seronegative MG, Neurology 2002; 59:1682-8. generalized myasthenia gravis: clinical features, antibodies and Yamamoto, T. et al. Seronegative myasthenia gravis: a plasma factor their targets.” Lancet Neurology 2 99-106, 2003. inhibiting agonist-induced acetycholine receptor function copuri?es with IgM. Ann Neurol. Oct. l99l;30(4):550-7. * cited by examiner U.S. Patent Sep. 11,2007 Sheet 1 0f 6 US 7,267,820 B2 /76.’./ a MuSK constructs I914 lg1-2 Signal sequence Ig-like domain E Cysteine-rich E domain Kinase domain HCIMuSK SNMGIMUSKA l: n a c i’ ‘aa: me E, 0c: E, 550 ":5 550'‘: U.S. Patent Sep. 11, 2007 Sheet 2 0f 6 US 7,267,820 B2 W52 3 -.. O 2- =:. O ‘z. OD“492) 1 - .. .0 . I -1n- "1" a. L: Healthy SNMG AChR-Ab 0ND individuals pas 1'00 q + Musk lg1-4 + Musk 191-2 0.75 - OD(Am) --0— MUSk 193-4 050 _ 4- mock—transfecled -°-' HCIMusklg1-4 0.25 - 0.00 . 5 f ‘ ? 0 1 2 3 4 5 6 7 Dilution of plasma (1:6 serial dilutions) U.S. Patent Sep. 11,2007 Sheet 4 0f 6 US 7,267,820 B2 41 /‘74‘ 3- . n 2- ‘L O v; 11 I '1 o- {?x aiériilull '1" '1 o \- n “W I t O t 2 = 2 O o O U U (9 (9 E E Z Z a, m 4 /‘76.’ 6? 3d a a 2' ‘:l o 5. 1 ' ‘A Q: o“ “"535” E DEED t5‘ ‘3.. -1 D g I z 0 1CohortSNMG mothersAMC U.S. Patent Sep. 11,2007 Sheet 6 6f 6 US 7,267,820 B2 W618. SNMG El ?SNMG V5553E2562 7500 523%2 25 US 7,267,820 B2 1 2 NEUROTRANSMISSION DISORDERS extracellular side of the receptor, Which induces transmis sion of a signal cascade to intracellular target proteins. RTKs RELATED APPLICATIONS are classi?ed according to their function and members of these families share high homology in their amino acid This application is a national stage ?ling under 35 U.S.C. sequence as Well as functionality. § 371 of PCT International application PCT/GB01/02661, At the neuromuscular junction (NMJ) Where the motor ?led Jun. 15, 2001, Which Was published under PCT Article nerve axon dendrites meet the muscle cell basal membrane, 21(2) in English. important physiological signals are exchanged betWeen The present invention is concerned With neurotransmis these adjacent cells. An example of this is the chemical sion disorders and, in particular, With a method of diagnos transmitter acetyl choline Which passes through the synaptic ing such disorders in mammals. Also provided by the present cleft from the nerve cell, and is then rapidly and speci?cally invention are kits for use in said diagnosis. bound by the AChR at the muscle cell Wall. This in turn Myaslhenia gravis (MG) is a chronic autoimmune disor begins a cascade of events Which ultimately leads to con der of neuromuscular transmission resulting in muscle traction of the muscle cells.
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