Treatment of asthma with anti-tslp antibody

Abstract

The present disclosure, relates, in general, to methods of treating asthma, including severe asthma and eosinophilic asthma, using an antibody specific for thymic stromal lymphopoietin (TSLP).

1 . (canceled) 
     
     
         2 . A method for treating asthma in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant in a dose of 70 mg to 280 mg at an interval of every two weeks or 4 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises
 a. a light chain variable domain selected from the group consisting of:   i. a sequence of amino acids at least 80% identical to SEQ ID NO:12;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11; and   b. a heavy chain variable domain selected from the group consisting of:   i. a sequence of amino acids that is at least 80% identical to SEQ ID NO:10;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:9;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b), wherein the antibody specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.   
     
     
         3 . The method of  claim 47  wherein the antibody or antibody variant is administered every 4 weeks. 
     
     
         4 . The method of  claim 47  wherein the antibody or antibody variant is administered at a dose of 70 mg. 
     
     
         5 . The method of  claim 47  wherein the antibody or antibody variant is administered at a dose of 210 mg. 
     
     
         6 . The method of  claim 47  wherein the antibody or antibody variant is administered at a dose of 280 mg. 
     
     
         7 - 8 . (canceled) 
     
     
         9 . The method of  claim 47 , wherein the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year or more. 
     
     
         10 . The method of  claim 47 , wherein said anti-TSLP antibody or antibody variant thereof is bivalent and selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody. 
     
     
         11 . The method of claim  8 , wherein said anti-TSLP antibody variant is selected from the group consisting of a diabody, a triabody, a tetrabody, a Fab fragment, single domain antibody, scFv, wherein the dose is adjusted such that the binding sites to be equimolar to the those dosed by bivalent antibodies. 
     
     
         12 . The method of  claim 47 , wherein the antibody is an IgG2 antibody. 
     
     
         13 . The method of  claim 47 , wherein the antibody or antibody variant is a human antibody. 
     
     
         14 . The method of  claim 47  wherein, the antibody or antibody variant further comprises a pharmaceutically acceptable carrier or excipient. 
     
     
         15 - 17 . (canceled) 
     
     
         18 . The method of  claim 47 , wherein the subject is an adult. 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 47 , wherein the administration decreases eosinophils in blood, sputum, broncheoalveolar fluid, or lungs of the subject. 
     
     
         21 . The method of  claim 47 , wherein the administration shifts cell counts in the subject from a Th2 high population to a Th2 low population. 
     
     
         22 - 28 . (canceled) 
     
     
         29 . The method of  claim 47  wherein the antibody is tezepelumab. 
     
     
         30 . The method of  claim 29  wherein the antibody is an IgG2 antibody, and has the full length heavy and light chain sequences set out in SEQ ID NOs: 105 and 106, respectively. 
     
     
         31 - 32 . (canceled) 
     
     
         33 . A method of reducing the frequency of asthma exacerbation in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant in a dose of 70 mg to 280 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises
 a. a light chain variable domain selected from the group consisting of:   i. a sequence of amino acids at least 80% identical to SEQ ID NO:12;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11; and   b. a heavy chain variable domain selected from the group consisting of:   i. a sequence of amino acids that is at least 80% identical to SEQ ID NO:10;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:9;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).   
     
     
         34 . The method of  claim 33  wherein the antibody or antibody variant is administered every 4 weeks. 
     
     
         35 . The method of  claim 33  wherein the antibody or antibody variant is administered at a dose of 70 mg, 210 mg or 280 mg. 
     
     
         36 - 37 . (canceled) 
     
     
         38 . The method of  claim 33  wherein the antibody or antibody variant is administered for a period of at least 4 months, 6 months, 9 months, 1 year or more. 
     
     
         39 . The method of  claim 33 , wherein said anti-TSLP antibody or antibody variant is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a monoclonal antibody, a recombinant antibody, an antigen-binding antibody fragment, a single chain antibody, a monomeric antibody, a diabody, a triabody, a tetrabody, a Fab fragment, an IgG1 antibody, an IgG2 antibody, an IgG3 antibody, and an IgG4 antibody. 
     
     
         40 - 42 . (canceled) 
     
     
         43 . The method of  claim 33  wherein the administration delays the time to an asthma exacerbation compared to a subject not receiving the anti-TSLP antibody. 
     
     
         44 . The method  claim 33  wherein the administration reduces frequency of or levels of co-administered therapy in the subject. 
     
     
         45 - 46 . (canceled) 
     
     
         47 . A method of treating chronic obstructive pulmonary disease (COPD) comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant in a dose of 70 mg to 280 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises
 a. alight chain variable domain comprising:   i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3;   ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4;   iii. alight chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and   b. a heavy chain variable domain comprising:   i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6;   ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and   iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.   
     
     
         48 . A method of treating chronic obstructive pulmonary disease (COPD) in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant in a dose of 70 mg to 280 mg at an interval of every 2 weeks or every 4 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises
 a. a light chain variable domain selected from the group consisting of:   i. a sequence of amino acids at least 80% identical to SEQ ID NO:12;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11; and   b. a heavy chain variable domain selected from the group consisting of:   i. a sequence of amino acids that is at least 80% identical to SEQ ID NO:10;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:9;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).   
     
     
         49 . The method of  claim 47  wherein the administration is subcutaneous or intravenous. 
     
     
         50 . A method for reducing ACQ-6 score in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant in a dose of 70 mg to 280 mg at an interval of every 4 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises
 a. alight chain variable domain comprising:   i. a light chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:3;   ii. a light chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:4;   iii. alight chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:5; and   b. a heavy chain variable domain comprising:   i. a heavy chain CDR1 sequence comprising the amino acid sequence set forth in SEQ ID NO:6;   ii. a heavy chain CDR2 sequence comprising the amino acid sequence set forth in SEQ ID NO:7, and   iii. a heavy chain CDR3 sequence comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antigen binding protein specifically binds to a TSLP polypeptide as set forth in amino acids 29-159 of SEQ ID NO:2.   
     
     
         51 . A method for reducing ACQ-6 score in a subject comprising administering a therapeutically effective amount of an anti-TSLP antibody or antibody variant in a dose of 70 mg to 280 mg at an interval of every 4_2 weeks, wherein both binding sites of the antibody have identical binding to TSLP, and the antibody comprises
 a. a light chain variable domain selected from the group consisting of:   i. a sequence of amino acids at least 80% identical to SEQ ID NO:12;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:11;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:11; and   b. a heavy chain variable domain selected from the group consisting of:   i. a sequence of amino acids that is at least 80% identical to SEQ ID NO:10;   ii. a sequence of amino acids encoded by a polynucleotide sequence that is at least 80% identical to SEQ ID NO:9;   iii. a sequence of amino acids encoded by a polynucleotide that hybridizes under moderately stringent conditions to the complement of a polynucleotide consisting of SEQ ID NO:9; or c. a light chain variable domain of (a) and a heavy chain variable domain of (b).   
     
     
         52 . The method of  claim 50  wherein the administration is subcutaneous or intravenous. 
     
     
         53 . (canceled) 
     
     
         55 . The method of  claim 33  wherein the anti-TSLP antibody is tezepelumab. 
     
     
         56 . The method of  claim 55  wherein the antibody is an IgG2 antibody, and has the full length heavy and light chain sequences set out in SEQ ID NOs: 105 and 106, respectively. 
     
     
         57 . The method of  claim 33  wherein the antibody variant has substantially similar pK characteristics as tezepelumab in humans. 
     
     
         58 - 76 . (canceled)