IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0488074
(2002-08-21)
|
등록번호 |
US-8298769
(2012-10-30)
|
우선권정보 |
GB-0120649.9 (2001-08-23); GB-0215212.2 (2002-07-01) |
국제출원번호 |
PCT/GB02/03831
(2002-08-21)
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§371/§102 date |
20040617
(20040617)
|
국제공개번호 |
WO03/018632
(2003-03-06)
|
발명자
/ 주소 |
- Smith, Bernard Rees
- Furmaniak, Jadwiga
- Sanders, Jane Fina
|
출원인 / 주소 |
|
대리인 / 주소 |
|
인용정보 |
피인용 횟수 :
1 인용 특허 :
17 |
초록
The present invention is concerned with epitope regions of thyrotrophin (TSH) receptor, uses thereof and antibodies thereto.
대표청구항
▼
1. A method of screening a sample of body fluid for TSH receptor autoantibodies wherein said sample is 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 method comprising: (a) contacting
1. A method of screening a sample of body fluid for TSH receptor autoantibodies wherein said sample is 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 method comprising: (a) contacting said sample with a polypeptide comprising a full length TSH receptor, so as to permit said polypeptide to bind with TSH receptor autoantibodies present in said sample;(b) contacting said sample with one or more monoclonal antibodies that binds TSH receptor and competes with said autoantibodies for binding to said polypeptide, wherein said one or more monoclonal antibodies is positive for thyroid stimulating activity at a concentration of 20 μg/ml in a cyclic AMP thyroid cell assay and positive for inhibition of TSH binding to TSH receptor at a concentration of 20 μg/ml, said one or more monoclonal antibodies being classified as positive for thyroid stimulating activity if the thyroid stimulating activity is greater than 180 percent in the cyclic AMP thyroid cell assay wherein said percent thyroid stimulation activity comprises 100×(ratio of cyclic AMP produced in the thyroid cell assay in the presence of said monoclonal antibody to cyclic AMP produced in the thyroid cell assay in the presence of sera pooled from healthy blood donors) and said one or more monoclonal antibodies being classified as positive for inhibition of TSH binding to TSH receptor if the inhibition of TSH binding to TSH receptor is greater than 10%; and(c) detecting binding of said polypeptide with said autoantibodies thereby providing an indication of the presence of said autoantibodies in said sample. 2. A method of screening a sample of body fluid for TSH receptor autoantibodies wherein said sample is 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 method comprising: (a) providing said sample of body fluid from said subject;(b) contacting said sample with (i) a full length TSH receptor, and(ii) at least one monoclonal antibody that binds the TSH receptor in (i) and is positive for thyroid stimulating activity at a concentration of 20 μg/ml in a cyclic AMP thyroid cell assay and positive for inhibition of TSH binding to TSH receptor at a concentration of 20 μg/ml, said one or more monoclonal antibodies being classified as positive for thyroid stimulating activity if the thyroid stimulating activity of said one or more monoclonal antibodies is greater than 180 percent in the cyclic AMP thyroid cell assay wherein said percent thyroid stimulation activity comprises 100×(ratio of cyclic AMP produced in the thyroid cell assay in the presence of said monoclonal antibody to cyclic AMP produced in the thyroid cell assay in the presence of sera pooled from healthy blood donors) and said one or more monoclonal antibodies being classified as positive for inhibition of TSH binding to TSH receptor if the inhibition of TSH binding to TSH receptor is greater than 10%,so as to permit said TSH receptor to bind with either autoantibodies to a TSH receptor present in said sample, or said monoclonal antibody; and(c) detecting the binding of said TSH receptor with said autoantibodies present in said sample, thereby providing an indication of the presence of said autoantibodies to a TSH receptor in said sample. 3. A method of screening a sample of body fluid for autoantibodies to a TSH receptor wherein said sample is 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 method comprising: (a) contacting said sample with (i) a full length TSH receptor; and(ii) one or more monoclonal antibodies for a TSH receptor that are capable of binding to the TSH receptor so as to stimulate the TSH receptor wherein said monoclonal antibodies: (1) are positive for TSH stimulating activity at a concentration of 20 μg/ml in a cyclic AMP thyroid cell assay, said one or more monoclonal antibodies being classified as positive if the thyroid stimulating activity of said one or more monoclonal antibodies is greater than 180 percent in the cyclic AMP thyroid cell assay wherein said percent thyroid stimulation activity comprises 100×(ratio of cyclic AMP produced in the thyroid cell assay in the presence of said monoclonal antibody to cyclic AMP produced in the thyroid cell assay in the presence of sera pooled from healthy blood donors); and(2) are positive for inhibition of TSH binding to TSH receptor at a concentration of 20 μg/ml, said one or more monoclonal antibodies being classified as positive for inhibition of TSH binding to TSH receptor if the inhibition of TSH binding to TSH receptor is greater than 10%;so as to permit said TSH receptor to bind with either autoantibodies to a TSH receptor present in said sample, or said one or more monoclonal antibodies for the TSH receptor; and(b) detecting binding of said TSH receptor with said autoantibodies present in said sample, thereby providing an indication of the presence of said autoantibodies to a TSH receptor in said sample. 4. A method according to claim 3, which comprises providing labeling means for said one or more antibodies for a TSH receptor, which antibody is capable of binding to a TSH receptor so as to stimulate the TSH receptor, which antibody does not comprise TSH or naturally produced autoantibodies to the TSH receptor. 5. A method according to claim 3, wherein said one or more monoclonal antibodies includes a monoclonal antibody comprising: (a) 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;(b) 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(c) 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. 6. A method according to claim 3, wherein said one or more monoclonal antibodies for a TSH receptor have a binding affinity for TSH receptor of at least about 108 molar−1. 7. A method according to claim 3, wherein said one or more monoclonal antibodies includes a monoclonal antibody comprising 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. 8. A method according to claim 3, wherein said one or more monoclonal antibodies includes a monoclonal antibody comprising: i) 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; and a 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;ii) 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, and a 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; oriii) 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, and a 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. 9. A method of screening a sample of body fluid for TSH receptor autoantibodies wherein said sample is 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 method comprising: (a) contacting said sample with (i) a full length TSH receptor, and(ii) one or more monoclonal antibodies to a TSH receptor that are capable of binding to the TSH receptor so as to stimulate the TSH receptor, wherein said monoclonal antibodies: (1) are positive for TSH stimulating activity at a concentration of 20 μg/ml in a cyclic AMP thyroid cell assay, said one or more monoclonal antibodies being classified as positive if the thyroid stimulating activity of said one or more monoclonal antibodies is greater than 180 percent in the cyclic AMP thyroid cell assay wherein said percent thyroid stimulation activity comprises 100×(ratio of cyclic AMP produced in the thyroid cell assay in the presence of said monoclonal antibody to cyclic AMP produced in the thyroid cell assay in the presence of sera pooled from healthy blood donors); and(2) are positive for inhibition of TSH binding to TSH receptor at a concentration of 20 μg/ml, said one or more monoclonal antibodies being classified as positive for inhibition of TSH binding to TSH receptor if the inhibition of TSH binding to TSH receptor is greater than 10%;so as to permit said TSH receptor to bind with either autoantibodies to a TSH receptor present in said sample, or said one or more monoclonal antibodies; and(b) detecting binding of said TSH receptor with said autoantibodies present in said sample, thereby providing an indication of the presence of said autoantibodies to a TSH receptor in said sample;wherein said one or more monoclonal antibodies are directly or indirectly immobilised to a surface either prior to, or after step (a). 10. A method according to claim 9, wherein said-antibody is capable of binding to a TSH receptor so as to stimulate the TSH receptor, which antibody does not comprise TSH or naturally produced autoantibodies to the TSH receptor. 11. A method according to claim 9, which comprises providing labeling means for said TSH receptor, said one or more epitopes thereof or said polypeptide. 12. A method according to claim 9, wherein said one or more monoclonal antibodies includes a monoclonal antibody comprising: (a) 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;(b) 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(c) 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. 13. A method according to claim 9, wherein said one or more monoclonal antibodies for a TSH receptor have a binding affinity for TSH receptor of at least about 108 molar−1. 14. A method according to claim 9, wherein said one or more monoclonal antibodies includes a monoclonal antibody comprising 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. 15. A method according to claim 9, wherein said one or more monoclonal antibodies includes a monoclonal antibody comprising: i) 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; and a 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;ii) 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, and a 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; or iii) 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.
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