Diagnosis and treatments relating to th2 inhibition

Abstract

Methods of diagnosing and treating disorders related to TH2 inhibition, including but not limited to asthma, are provided. Also provided are methods of selecting or identifying patients for treatment with certain therapeutic agents that are TH2 pathway inhibitors.

1 . A method of identifying an asthma patient or a respiratory disorder patient who is likely to be responsive to treatment with a TH2 Pathway Inhibitor comprising determining whether the patient is Eosinophilic Inflammation Positive (EIP) using an Eosinophilic Inflammation Diagnostic Assay (EIDA), wherein the EIP status indicates that the patient is likely to be responsive to treatment with the TH2 Pathway Inhibitor. 
     
     
         2 . A method of identifying an asthma patient or a respiratory disorder patient who is likely to suffer from severe exacerbations comprising determining whether the patient is Eosinophilic Inflammation Positive (EIP) using an Eosinophilic Inflammation Diagnostic Assay (EIDA), wherein the EIP status indicates that the patient is likely to suffer from an increase in severe exacerbations. 
     
     
         3 . A method of identifying an asthma patient or a respiratory disorder patient who is less likely to be responsive to treatment with a TH2 Pathway Inhibitor comprising determining whether the patient is Eosinophilic Inflammation Negative (EIN) using an Eosinophilic Inflammation Diagnostic Assay (EIDA), wherein the EIN status indicates that the patient is less likely to be responsive to treatment with the TH2 Pathway Inhibitor. 
     
     
         4 . A method of monitoring an asthma patient being treated with a TH2 Pathway inhibitor, comprising determining whether the patient is Eosinophilic Inflammation Positive (EIP) or Eosinophilic Inflammation Negative (EIN) using an Eosinophilic Inflammation Diagnostic Assay (EIDA). 
     
     
         5 . The method of  claim 4 , further comprising determining a treatment regimen for the TH2 Pathway Inhibitor. 
     
     
         6 . The method of  claim 5 , wherein the determination of EIP indicates continuing therapy with the TH2 Pathway Inhibitor and the determination of EIN indicates discontinuing therapy with the TH2 Pathway Inhibitor. 
     
     
         7 . The method according to any one of  claims 1 - 4 , wherein the EIDA comprises the steps of:
 a) determining the amount of Total Periostin in a sample obtained from an asthma patient;   b) comparing the amount of Total Periostin determined in step a) to a reference amount; and   c) stratifying said patient into the category of responder or non-responder based on the comparison obtained in step b).   
     
     
         8 . The method according to  claim 7 , wherein the Total Periostin is serum periostin, which periostin is measured using an immunoassay. 
     
     
         9 . The method according to  claim 8 , wherein the immunoassay is a sandwich immunoassay. 
     
     
         10 . The method according to  claim 9 , wherein the sandwich immunoassay is an E4 Assay or is performed by an Elecsys® analyzer. 
     
     
         11 . The method according to  claim 7 , wherein the reference amount for EIP is 23 ng/ml or greater when using an E4 Assay in step (a). 
     
     
         12 . The method according to  claim 7 , wherein the reference amount for EIP is 50 ng/ml or greater when using an Elecsys® analyzer in step (a). 
     
     
         13 . The method according to  claim 7 , wherein the reference amount for EIN is 21 ng/ml or lower when using an E4 Assay in step (a). 
     
     
         14 . The method according to  claim 7 , wherein the reference amount for EIN is 48 ng/ml or lower when using an Elecsys® analyzer in step (a). 
     
     
         15 . The method according to any one of  claims 1 - 4 , wherein the patient is suffering from moderate to severe asthma. 
     
     
         16 . The method according to any one of  claims 1 - 4 , wherein the asthma or respiratory disorder is uncontrolled on a corticosteroid. 
     
     
         17 . The method according to  claim 16 , wherein the corticosteroid is an inhaled corticosteroid. 
     
     
         18 . The method according to  claim 17 , wherein the inhaled corticosteroid is Qvar®, Pulmicort®, Symbicort®, Aerobid®, Flovent®, Flonase®, Advair® or Azmacort®. 
     
     
         19 . The method according to any one of  claims 1 - 4 , wherein the patient is also being treated with a second controller. 
     
     
         20 . The method according to  claim 19 , wherein the second controller is a long acting bronchial dilator (LABD). 
     
     
         21 . The method according to  claim 20 , wherein the LABD is a long-acting beta-2 agonist (LABA), leukotriene receptor antagonist (LTRA), long-acting muscarinic antagonist (LAMA), theophylline, or oral corticosteroids (OCS). 
     
     
         22 . The method according to  claim 20 , wherein the LABD is Symbicort®, Advair®, Brovana®, Foradil®, Perforomist™ or Serevent®. 
     
     
         23 . The method according to any one of  claims 1 ,  3 , or  4  wherein the TH2 Pathway Inhibitor inhibits the target ITK, BTK, IL-9 (e.g., MEDI-528), IL-5 (e.g., Mepolizumab, CAS No. 196078-29-2; resilizumab), IL-13 (e.g., IMA-026, IMA-638 (also referred to as, anrukinzumab, INN No. 910649-32-0; QAX-576; IL4/IL13 trap), tralokinumab (also referred to as CAT-354, CAS No. 1044515-88-9); AER-001, ABT-308 (also referred to as humanized 13C5.5 antibody), IL-4 (e.g., AER-001, IL4/IL13 trap), OX40L, TSLP, IL-25, IL-33 and IgE (e.g., XOLAIR®, QGE-031; MEDI-4212); and receptors such as: IL-9 receptor, IL-5 receptor (e.g., MEDI-563 (benralizumab, CAS No. 1044511-01-4), IL-4-receptor alpha (e.g., AMG-317, AIR-645), IL-13receptoralpha1 (e.g., R-1671) and IL-13receptoralpha2, OX40, TSLP-R, IL-7Ralpha (a co-receptor for TSLP), IL17RB (receptor for IL-25), ST2 (receptor for IL-33), CCR3, CCR4, CRTH2 (e.g., AMG-853, AP768, AP-761, MLN6095, ACT129968), FcepsilonRI, FcepsilonRII/CD23 (receptors for IgE), Flap (e.g., GSK2190915), Syk kinase (R-343, PF3526299); CCR4 (AMG-761), TLR9 (QAX-935), or is a multi-cytokine inhibitor of CCR3, IL5, IL3, GM-CSF (e.g., TPI ASM8). 
     
     
         24 . The method according to  claim 23 , wherein the TH2 Pathway Inhibitor is an anti-IL13/IL4 pathway inhibitor or an anti IgE binding agent. 
     
     
         25 . The method according to  claim 23 , wherein the TH2 Pathway Inhibitor is an anti-IL-13 antibody. 
     
     
         26 . The method according to  claim 25 , wherein the anti-IL-13 antibody is an antibody comprising a VH comprising SEQ ID NO:9 and VL comprising SEQ ID NO:10, an anti-IL13 antibody comprising HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, and HVRL3, wherein the respective HVRs have the amino acid sequence of SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, and SEQ ID NO.: 16 or lebrikizumab. 
     
     
         27 . The method according to  claim 25 , wherein the anti-IL-13 antibody is a bispecific antibody that also binds IL-4. 
     
     
         28 . The method according to  claim 23 , wherein the TH2 Pathway Inhibitor is an anti-IgE antibody. 
     
     
         29 . The method according to  claim 28 , wherein the anti-IgE antibody is (i) the XOLAIR® antibody, (ii) anti-M1′ antibody comprising a variable heavy chain and a variable light chain, wherein the variable heavy chain is SEQ ID NO:24 and the variable light chain is SEQ ID NO:25 or (iii) an anti-M1′ antibody comprising a variable heavy chain and a variable light chain, wherein the variable heavy chain further comprises an HVR-H1, HVR-H2 and HVR-H3, and the variable light chain further comprises and HVR-L1, HVR, L2 and HVR-L3 and: (a) the HVR-H1 is residues 26-35 of SEQ ID NO:24, [GFTFSDYGIA]; (b) the HVR-H2 is residues 49-66 of SEQ ID NO:24, [AFISDLAYTIYYADTVTG]; (c) the HVR-H3 is residues 97-106 of SEQ ID NO:24, [ARDNWDAMDY]; (d) the HVR-L1 is residues 24-39 of SEQ ID NO:25, [RSSQSLVHNNANTYLH]; (e) the HVR-L2 is residues 55-61 of SEQ ID NO:25, [KVSNRFS]; (f) the HVR-L3 is residues 94-102 of SEQ ID NO:25 [SQNTLVPWT]. 
     
     
         30 - 51 . (canceled) 
     
     
         52 . A kit for measuring the Total Periostin in a biological sample obtained from an asthma patient or a patient suffering from a respiratory disorder, wherein the kit comprises either (1) a first nucleic acid molecule that hybridizes to a second nucleic acid molecule, wherein the second nucleic acid molecule encodes Total Periostin or a portion thereof, or (2) the kit comprises an antibody that binds to Total Periostin. 
     
     
         53 . (canceled) 
     
     
         54 . A kit for diagnosing an asthma subtype in a patient comprising:
 (1) determining the levels of Total Periostin in a serum sample obtained from the patient and optionally the protein expressions levels in the serum sample for one or more proteins selected from TARC and MCP-4; and   (2) instructions for measuring the expression levels of the Total Periostin and optionally one or more proteins selected from TARC and MCP-4 in the serum sample, wherein the elevated expression levels of any one, combination or all of said proteins is indicative of the asthma subtype.   
     
     
         55 . The kit according to  claim 54 , wherein the kit further comprises a package insert for determining whether an asthma patient or respiratory disorder patient is EIP or EIN. 
     
     
         56 . The kit according to  claim 55 , wherein the kit further comprises a package insert for determining whether an asthma patient is likely to respond to a TH2 Pathway Inhibitor. 
     
     
         57 . (canceled) 
     
     
         58 . The kit according to  claim 52  or  claim 54 , further comprising an empty container to hold a biological sample. 
     
     
         59 . The kit according to  claim 52  or  claim 54 , wherein the kit comprises two anti-periostin antibodies for use in an immunoassay for determining Total Periostin levels. 
     
     
         60 . A method of treating an asthma or a respiratory disorder comprising administering an anti-IL-13 antibody comprising HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, and HVRL3, wherein the respective HVRs have the amino acid sequence of SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, and SEQ ID NO.: 16 to a patient suffering from asthma or a respiratory disorder in a 125-500 mg flat dose every 2-8 weeks. 
     
     
         61 . The method according to  claim 60 , wherein the patient is suffering from moderate to severe asthma. 
     
     
         62 . The method according to  claim 60  or  61 , wherein the asthma or respiratory disorder is uncontrolled on a corticosteroid. 
     
     
         63 . The method according to  claim 62 , wherein the asthma or respiratory disorder is uncontrolled on an inhaled corticosteroid. 
     
     
         64 . The method according to  claim 62 , wherein the asthma or respiratory disorder is uncontrolled on a total daily dose of at least 500 mcg fluticasone propionate (FP). 
     
     
         65 . The method according to  claim 63 , wherein the corticosteroid is an inhaled corticosteroid is Qvar®, Pulmicort®, Symbicort®, Aerobid®, Flovent®, Flonase®, Advair®, Azmacort®. 
     
     
         66 . The method according to  claim 62 , wherein the patient is being treated with a second controller. 
     
     
         67 . The method according to  claim 60 , wherein the patient is continuing to be treated with a corticosteroid, optionally an inhaled corticosteroid, during the treatment with the anti-IL13 antibody. 
     
     
         68 . The method according to  claim 67 , wherein the patient is continuing to be treated with a second controller during the treatment with the anti-IL-13 antibody. 
     
     
         69 . The method according to  claim 68 , wherein the second controller is a long acting bronchial dilator. 
     
     
         70 . The method according to  claim 69 , wherein the long acting bronchial dilator is a LABA, LTRA, LAMA, theophylline, or OCS. 
     
     
         71 . The method according to  claim 70 , wherein the patient has been determined to be EIP. 
     
     
         72 . The method according to  claim 70 , wherein the patient has been determined to be EIP using the kit according to  claim 52  or  claim 54 . 
     
     
         73 . The method according to  claim 70 , wherein the patient has been determined to be EIP using the method of  claim 1  or  claim 2 . 
     
     
         74 . The method according to  claim 60 , wherein the patient is administered a flat dose of 125 mg or 250 mg every four weeks. 
     
     
         75 . The method according to  claim 74 , wherein the patient is 18 years or older. 
     
     
         76 . The method according to  claim 74 , wherein the patient is 12-17 years old or 12 years old and older. 
     
     
         77 . The method according to  claim 74 , wherein the patient is 6-11 years old or 6 years old and older. 
     
     
         78 . The method according to  claim 60 , wherein the anti-IL-13 antibody is administered subcutaneously. 
     
     
         79 . The method according to  claim 78 , wherein the anti-IL-13 antibody is administered using a prefilled syringe or autoinjector device. 
     
     
         80 . The method according to  claim 60 , wherein the asthma patient to be treated is 18 years old or older and has serum periostin at ≧50 ng/mL and is uncontrolled on an inhaled corticosteroid and a second controller medication. 
     
     
         81 . The method according to  claim 78 , wherein the serum periostin is measured using the method of  claim 1  or  claim 2 . 
     
     
         82 . The method according to  claim 78 , wherein the serum periostin is measured using the kit of  claim 52  or  claim 54 . 
     
     
         83 . The method according to  claim 60 , wherein the anti-IL-13 antibody is an antibody comprising a VH comprising SEQ ID NO:9 and a VL comprising SEQ ID NO:10. 
     
     
         84 . The method according to  claim 60 , wherein the anti-IL-13 antibody is lebrikizumab. 
     
     
         85 . The method according to  claim 76 , wherein the asthma patient is 12 years old and above and uncontrolled on an inhaled corticosteroid and a second controller medication. 
     
     
         86 . A method of treating asthma or a respiratory disease comprising administering a therapeutically effective amount of lebrikizumab to the patient, wherein the treatment results in a relative improvement in FEV1 of greater than 5% compared to before treatment with lebrikizumab. 
     
     
         87 . The method according to  claim 86 , wherein the relative improvement in FEV1 is greater than 8% compared to before treatment with lebrikizumab. 
     
     
         88 . A method of treating asthma or a respiratory disease comprising administering a therapeutically effective amount of lebrikizumab to the patient, wherein the treatment results in a reduction in severe exacerbations. 
     
     
         89 . A method of treating of a patient suffering from asthma or a respiratory disease comprising administering a TH2 Pathway Inhibitor to the patient diagnosed as EIP. 
     
     
         90 . The method according to  claim 89  further comprising the step of diagnosing the patient as EIP using a Total Periostin Assay. 
     
     
         91 . The method according to  claim 90 , further comprising the step of retreating the patient with the TH2 Pathway Inhibitor if the patient is determined to be EIP. 
     
     
         92 . The method according to any one of  claims 89 - 91 , wherein serum from the patient is used to determine whether the patient is EIP. 
     
     
         93 . The method according to any one of  claims 89 - 91 , wherein the EIP status is diagnosed using an EIDA in which the assay comprises the steps of:
 a) determining the amount of Total Periostin in a sample obtained from the patient;   b) comparing the amount of Total Periostin determined in step a) to a reference amount; and   c) stratifying said patient into the category of responder or non-responder based on the comparison obtained in step (b).   
     
     
         94 . The method according to  claim 93 , wherein the Total Periostin is serum periostin, which periostin is a measured using an immunoassay. 
     
     
         95 . The method according to  claim 94 , wherein the immunoassay is a sandwich immunoassay. 
     
     
         96 . The method according to  claim 95 , wherein the sandwich immunoassay is performed by an Elecsys® analyzer. 
     
     
         97 . The method according to  claim 93 , wherein the reference amount is 23 ng/ml or greater when using the E4 Assay in step (a). 
     
     
         98 . The method according to  claim 93 , wherein the reference amount is 50 ng/ml or greater when using the Elecsys® periostin assay in step a. 
     
     
         99 . The method according to  claim 89 , wherein the patient is suffering from moderate to severe asthma. 
     
     
         100 . The method according to  claim 89 , wherein the asthma or respiratory disorder is uncontrolled on a corticosteroid. 
     
     
         101 . The method according to  claim 100 , wherein the corticosteroid is an inhaled corticosteroid. 
     
     
         102 . The method according to  claim 101 , wherein the inhaled corticosteroid is Qvar®, Pulmicort®, Symbicort®, Aerobid®, Flovent®, Flonase®, Advair® or Azmacort®. 
     
     
         103 . The method according to  claim 89 , wherein the patient is also being treated with a second controller. 
     
     
         104 . The method according to  claim 103 , wherein the second controller is a long acting bronchial dilator (LABD). 
     
     
         105 . The method according to  claim 104 , wherein the LABD is a LABA, LTRA, LAMA, theophylline, or OCS. 
     
     
         106 . The method according to  claim 104 , wherein the LABD is Symbicort®, Advair®, Brovana®, Foradil®, Perforomist™ or Serevent®. 
     
     
         107 . The method according to  claim 88 , wherein the TH2 Pathway Inhibitor inhibits the target ITK, BTK, IL-9 (e.g., MEDI-528), IL-5 (e.g., Mepolizumab, CAS No. 196078-29-2; resilizumab), IL-13 (e.g., IMA-026, IMA-638 (also referred to as, anrukinzumab, INN No. 910649-32-0; QAX-576; IL4/IL13 trap), tralokinumab (also referred to as CAT-354, CAS No. 1044515-88-9); AER-001, ABT-308 (also referred to as humanized 13C5.5 antibody), IL-4 (e.g., AER-001, IL4/IL13 trap), OX40L, TSLP, IL-25, IL-33 and IgE (e.g., XOLAIR, QGE-031; MEDI-4212); and receptors such as: IL-9 receptor, IL-5 receptor (e.g., MEDI-563 (benralizumab, CAS No. 1044511-01-4), IL-4-receptor alpha (e.g., AMG-317, AIR-645), IL-13receptoralpha1 (e.g., R-1671) and IL-13receptoralpha2, OX40, TSLP-R, IL-7Ralpha (a co-receptor for TSLP), IL17RB (receptor for IL-25), ST2 (receptor for IL-33), CCR3, CCR4, CRTH2 (e.g., AMG-853, AP768, AP-761, MLN6095, ACT129968), FcepsilonRI, FcepsilonRII/CD23 (receptors for IgE), Flap (e.g., GSK2190915), Syk kinase (R-343, PF3526299); CCR4 (AMG-761), TLR9 (QAX-935) or is a multi-cytokine inhibitor of CCR3, IL5, IL3, GM-CSF (e.g., TPI ASM8). 
     
     
         108 . The method according to  claim 88 , wherein the TH2 Pathway is an anti-IL13/IL4 pathway inhibitor or an anti IgE binding agent. 
     
     
         109 . The method according to  claim 108 , wherein the anti-IL-13/IL4 pathway inhibitor is an anti-anti-IL-13 antibody. 
     
     
         110 . The method according to  claim 109 , wherein the anti-IL-13 antibody is an antibody comprising a VH comprising SEQ ID NO:9 and VL comprising SEQ ID NO:10, an anti-IL13 antibody comprising HVRH1, HVRH2, HVRH3, HVRL1, HVRL2, and HVRL3, wherein the respective HVRs have the amino acid sequence of SEQ ID NO.: 11, SEQ ID NO.: 12, SEQ ID NO.: 13, SEQ ID NO.: 14, SEQ ID NO.: 15, and SEQ ID NO.: 16 or lebrikizumab. 
     
     
         111 . The method according to  claim 109 , wherein the anti-IL-13 antibody is a bispecific antibody that also binds IL-4. 
     
     
         112 . The method according to  claim 108 , wherein the TH2 Pathway Inhibitor is an anti-IgE antibody. 
     
     
         113 . The method according to  claim 112 , wherein the anti-IgE antibody is (i) the XOLAIR® antibody, (ii) anti-M1′ antibody comprising a variable heavy chain and a variable light chain, wherein the variable heavy chain is SEQ ID NO:24 and the variable light chain is SEQ ID NO:25 or (iii) an anti-M1′ antibody comprising a variable heavy chain and a variable light chain, wherein the variable heavy chain further comprises an HVR-H1, HVR-H2 and HVR-H3, and the variable light chain further comprises and HVR-L1, HVR, L2 and HVR-L3 and: (a) the HVR-H1 is residues 26-35 of SEQ ID NO:24, [GFTFSDYGIA]; (b) the HVR-H2 is residues 49-66 of SEQ ID NO:24, [AFISDLAYTIYYADTVTG]; (c) the HVR-H3 is residues 97-106 of SEQ ID NO:24, [ARDNWDAMDY]; (d) the HVR-L1 is residues 24-39 of SEQ ID NO:25, [RSSQSLVHNNANTYLH]; (e) the HVR-L2 is residues 55-61 of SEQ ID NO:25, [KVSNRFS]; (f) the HVR-L3 is residues 94-102 of SEQ ID NO:25 [SQNTLVPWT]. 
     
     
         114 . A method for evaluating adverse events in a patient associated with treatment of asthma with lebrikizumab comprising the steps of monitoring the number and/or severity of events that are exacerbations, community-acquired pneumonia, anaphylaxis, musculoskeletal pains, musculoskeletal disorders, connective tissue pains or connective tissue disorders. 
     
     
         115 . The method according to  claim 114 , wherein the musculoskeletal or connective tissue disorder is arthralgia, back pain, pain in extremity, myalgia, neck pain, arthritis, bone development abnormalities, bursitis, costochondritis, exostosis, flank pain, musculoskeletal chest pain, musculoskeletal pain, pain in jaw or tendinitis. 
     
     
         116 . An anti-periostin antibody comprising the HVR sequences of SEQ ID NO:1 and the HVR sequences of SEQ ID NO:2. 
     
     
         117 . The antibody according to  claim 116 , wherein the antibody comprises the sequences of SEQ ID NO:1 and SEQ ID NO:2. 
     
     
         118 . An anti-periostin antibody comprising the HVR sequences of SEQ ID NO:3 and the HVR sequences of SEQ ID NO:4. 
     
     
         119 . The antibody according to  claim 118 , wherein the antibody comprises the sequences of SEQ ID NO:3 and SEQ ID NO:4. 
     
     
         120 . (canceled) 
     
     
         121 . The kit of  claim 52  comprising an antibody that binds to Total Periostin, wherein the antibody comprises the HVR sequences of SEQ ID NO:1 and the HVR sequences of SEQ ID NO:2 and wherein the kit further comprises a second antibody, wherein the second antibody comprises the HVR sequences of SEQ ID NO:3 and the HVR sequences of SEQ ID NO:4.