The present invention is concerned with epitope regions of a thyrotrophin (TSH) receptor, uses thereof and antibodies thereto.
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1. A binding partner for a TSH receptor, the binding partner comprising an isolated monoclonal antibody or antigen binding fragment thereof that: binds to an epitope on the TSH receptor;has a binding affinity for the TSH receptor of at least about 108 molar−1;is positive for thyroid stimulating acti
1. A binding partner for a TSH receptor, the binding partner comprising an isolated monoclonal antibody or antigen binding fragment thereof that: binds to an epitope on the TSH receptor;has a binding affinity for the TSH receptor of at least about 108 molar−1;is positive for thyroid stimulating activity at a concentration of 20 μg/ml in a cyclic AMP thyroid cell assay, wherein the binding partner is classified as positive if the thyroid stimulating activity of the binding partner is greater than 180 percent in the cyclic AMP thyroid cell assay, said percent thyroid stimulating activity comprising 100×(ratio of cyclic AMP produced in the thyroid cell assay in the presence of said binding partner to cyclic AMP produced in the thyroid cell assay in the presence of sera pooled from healthy blood donors); andinhibits TSH binding, the binding partner inhibiting binding of TSH to the TSH receptor in a coated tube binding assay by 61% to 83.3% at a concentration of 2 μg/ml to 20 μg/ml wherein the TSH receptor is immobilized on a surface of the tube and wherein the TSH receptor is from a species selected from a group consisting of porcine, bovine, feline, canine, mouse, rat and ovine and wherein the monoclonal antibody comprises a VH domain comprising the three CDRs from SEQ ID NO:67 paired with a VL domain comprising the three CDRs from SEQ ID NO:68; or a VH domain comprising the three CDRs from SEQ ID NO:69 paired with a VL domain comprising the three CDRs from SEQ ID NO:70; or a VH domain comprising the three CDRs from SEQ ID NO:71 paired with a VL domain comprising the three CDRs from in SEQ ID NO:72. 2. The binding partner according to claim 1, wherein the binding partner is positive for thyroid stimulating activity at a concentration of 2 μg/ml in the cyclic AMP thyroid cell assay. 3. The binding partner according to claim 1, wherein the monoclonal antibody is a recombinant antibody. 4. The binding partner according to claim 1, wherein the antigen binding fragment comprises a Fab fragment, Fv fragment, F(ab')2 fragment, or scFv. 5. The binding partner according to claim 1, wherein the monoclonal antibody comprises a VH domain comprising amino acid residues 9 to 120 of SEQ ID NO:67 and a VL domain comprising amino acid residues 9 to 107 of SEQ ID NO:68. 6. The binding partner according to claim 1, wherein the monoclonal antibody comprises a VH domain comprising amino acid residues 9 to 120 of SEQ ID NO:69 and a VL domain comprising amino acid residues 9 to 107 of SEQ ID NO:70. 7. The binding partner according to claim 1, wherein the monoclonal antibody comprises a VH domain comprising amino acid residues 9 to 120 of SEQ ID NO:71 and a VL domain comprising amino acid residues 9 to 107 of SEQ ID NO:72. 8. The binding partner according to claim 1, wherein the monoclonal antibody comprises: a VH domain wherein CDR1 comprises amino acid residues 31 to 35 of SEQ ID NO: 67, CDR2 comprises amino acid residues 50 to 66 of SEQ ID NO:67, and CDR3 comprises amino acid residues 99 to 109 of SEQ ID NO:67; anda VL domain wherein CDR1 comprises amino acid residues 24 to 34 of SEQ ID NO:68, CDR2 comprises amino acid residues 50 to 56 of SEQ ID NO:68, and CDR3 comprises amino acid residues 89 to 97 of SEQ ID NO: 68. 9. The binding partner according to claim 1, wherein the monoclonal antibody comprises: a VH domain wherein CDR 1 comprises amino acid residues 31 to 35 of SEQ ID NO:69, CDR 2 comprises amino acid residues 50 to 66 of SEQ ID NO:69, and CDR 3 comprises amino acid residues 99 to 109 of SEQ ID NO:69, anda VL domain wherein CDR1 comprises amino acid residues 24 to 34 of SEQ ID NO:70, CDR2 comprises amino acid residues 50 to 56 of SEQ ID NO:70, and CDR3 comprises amino acid residues 89 to 97 of SEQ ID NO: 70. 10. The binding partner according to claim 1, wherein the monoclonal antibody comprises: a VH domain wherein CDR1 comprises amino acid residues 31 to 35 of SEQ ID NO: 71, CDR2 comprises amino acid residues 50 to 66 of SEQ ID NO:71, and CDR 3 comprises amino acid residues 99 to 109 of SEQ ID NO:71, anda VL domain wherein CDR1 comprises amino acid residues 24 to 34 of SEQ ID NO:72, CDR2 comprises amino acid residues 50 to 56 of SEQ ID NO:72, and CDR3 comprises amino acid residues 89 to 97 of SEQ ID NO: 72. 11. A pharmaceutical composition comprising a binding partner according to claim 1 and one or more pharmaceutically acceptable carriers, diluents or excipients therefor. 12. The composition according to claim 11, further comprising recombinant human TSH. 13. A kit for screening for autoantibodies to a TSH receptor in a sample of body fluid obtained from a subject suspected of suffering from, susceptible to, having or recovering from autoimmune disease associated with an immune reaction to a TSH receptor, said kit comprising: (a) a soluble or solubilized TSH receptor comprising the amino acid sequence of amino acid residues 47 to 61 of SEQ ID NO:17 or SEQ ID NO:22; and(b) one or more binding partners, wherein the binding partner comprising an isolated monoclonal antibody or antigen binding fragment thereof that:binds to an epitope on the TSH receptor wherein the TSH receptor is from a species selected from a group consisting of porcine, bovine, feline, canine, mouse, rat and ovine;has a binding affinity for the TSH receptor of at least about 108 molar−1;is positive for thyroid stimulating activity at a concentration of 20 μg/ml in a cyclic AMP thyroid cell assay and wherein the binding partner is classified as positive if the thyroid stimulating activity of the binding partner is greater than 180 percent in the cyclic AMP thyroid cell assay, said percent thyroid stimulating activity comprising 100×(ratio of cyclic AMP produced in the thyroid cell assay in the presence of said binding partner to cyclic AMP produced in the thyroid cell assay in the presence of sera pooled from healthy blood donors); andinhibits TSH binding, the binding partner inhibiting binding of TSH to the TSH receptor in a coated tube binding assay by 61% to 83.3% at a concentration of 2 μg/ml to 20 μg/ml wherein the TSH receptor is immobilized on a surface of the tube and wherein the monoclonal antibody comprises the VH domain as shown in SEQ ID NO:67 paired with the VL domain as shown in SEQ ID NO:68; or the VH domain as shown in SEQ ID NO:69 paired with the VL domain as shown in SEQ ID NO:70; or the VH domain as shown in SEQ ID NO:71 paired with the VL domain as shown in SEQ ID NO:72. 14. The kit according to claim 13, wherein the one or more binding partners comprises a detectable label. 15. The kit according to claim 13, wherein the kit further comprises a tube for contacting the sample of body fluid from the subject and the TSH receptor so as to permit the TSH receptor to interact with either autoantibodies to a TSH receptor present in the sample, or the one or more binding partners. 16. The kit according to claim 13, wherein the kit further a labelled binding partner for TSH receptor autoantibodies, a competitor capable of competing with autoantibodies to a TSH receptor in the interaction thereof with a TSH receptor, or a detectable label. 17. A binding partner for a TSH receptor, the binding partner comprising an isolated monoclonal antibody or antigen binding fragment thereof that: has a binding affinity for the TSH receptor of at least about 108 molar−1;inhibits TSH binding, the binding partner inhibiting binding of TSH to the TSH receptor in a coated tube binding assay by 61% to 83.3% at a concentration of 2 μg/ml to 20 μg/ml wherein the TSH receptor is immobilized on a surface of the tube; andhas heavy chain variable region CDRs contained within a heavy chain variable domain having an amino acid sequence selected from the group consisting SEQ ID NOs: 67, 69, and 71. 18. A binding partner for a TSH receptor of claim 17, the binding partner comprising an isolated monoclonal antibody or antigen binding fragment thereof further comprising light chain variable region CDRs contained within a light chain variable domain having an amino acid selected from the group consisting of SEQ ID NOs 68, 70, and 72. 19. A binding partner for a TSH receptor, the binding partner comprising an isolated monoclonal antibody or antigen binding fragment thereof that: binds to an epitope on the TSH receptor;has a binding affinity for the TSH receptor of at least about 108 molar−1;is positive for thyroid stimulating activity at a concentration of 20 μg/ml in a cyclic AMP thyroid cell assay, wherein the binding partner is classified as positive if the thyroid stimulating activity of the binding partner is greater than 180 percent in the cyclic AMP thyroid cell assay, said percent thyroid stimulating activity comprising 100×(ratio of cyclic AMP produced in the thyroid cell assay in the presence of said binding partner to cyclic AMP produced in the thyroid cell assay in the presence of sera pooled from healthy blood donors); andinhibits TSH binding, the binding partner inhibiting binding of TSH to the TSH receptor in a coated tube binding assay by 61% to 83.3% at a concentration of 2 μg/ml to 20 μg/ml wherein the TSH receptor is immobilized on a surface of the tube and wherein the monoclonal antibody comprises a VH domain comprising amino acid residues 9 to 120 of SEQ ID NO:67 and a VL domain comprising amino acid residues 9 to 107 of SEQ ID NO:68; a VH domain comprising amino acid residues 9 to 120 of SEQ ID NO:69 and a VL domain comprising amino acid residues 9 to 107 of SEQ ID NO:70 or a VH domain comprising amino acid residues 9 to 120 of SEQ ID NO:71 and a VL domain comprising amino acid residues 9 to 107 of SEQ ID NO:72. 20. A binding partner for a TSH receptor, the binding partner comprising a monoclonal antibody or fragment thereof comprising a Fab domain for a TSH receptor, wherein the antibody is capable of binding to a TSH receptor so as to stimulate the TSH receptor, which comprises: an antibody heavy chain (HC) selected from the group consisting of: a HC comprising (SEQ ID NO:67), (SEQ ID NO:69) or (SEQ ID NO:71); and/oran antibody light chain (LC) selected from the group consisting of: a LC comprising (SEQ ID NO:68), (SEQ ID NO:70) or (SEQ ID NO:72). 21. The binding partner comprising a monoclonal antibody or fragment thereof of claim 20, wherein the binding partner comprising a monoclonal antibody or fragment thereof comprises at least one HC comprising (SEQ ID NO:67), (SEQ ID NO:69) or (SEQ ID NO:71) and at least one LC comprising (SEQ ID NO:68), (SEQ ID NO:70) or (SEQ ID NO:72). 22. An antibody or fragment according to claim 20, wherein the HC and LC are paired, and wherein the HC in (SEQ ID NO:67) is paired with an antibody LC in (SEQ ID NO:68) to provide an antibody binding site, comprising both these heavy and light chains for a TSH receptor, or wherein an antibody HC as shown in (SEQ ID NO:69) is paired with an antibody LC in (SEQ ID NO:70) to provide an antibody binding site comprising both these heavy and light chains for a TSH receptor, or wherein an antibody HC in (SEQ ID NO:71)is paired with an antibody LC in (SEQ ID NO:72) to provide an antibody binding site comprising both heavy and light chains for a TSH receptor.
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