Treatment of ophthalmologic diseases

Abstract

The current invention relates to the use of antibodies which bind to VEGF and ANG2 for the treatment of ophthalmologic diseases.

1 . A method of treating a patient suffering from an ocular vascular disease the method comprising administering to the patient an effective amount of a bispecific antibody which binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2),
 wherein the bispecific antibody is administered intravitreally every 8 weeks or less frequently.   
     
     
         2 . A method of treating a patient suffering from an ocular vascular disease the method comprising administering to the patient an effective amount of a bispecific antibody which binds to human vascular endothelial growth factor (VEGF) and to human angiopoietin-2 (ANG-2), wherein the patient gains 12 or more letters of Best Corrected Visual Acuity (BCVA) measured using Early Treatment Diabetic Retinopathy Study (ETDRS) like charts, compared to the patient's BCVA letter score prior to the dosing of the bispecific VEGF/ANG2 antibody. 
     
     
         3 . The method according to  claim 2 , wherein the bispecific antibody is administered intravitreally every 8 weeks or less frequently. 
     
     
         4 . The method according to any one of  claims 1  to  3 , wherein the gain of letters in the BCVA/ETDRS letter score is measured at 4 weeks, and/or at 8 weeks, and/or at 12 weeks, and/or at 16 weeks, and/or at 20 weeks, and/or at 24 weeks after treatment start, respectively. 
     
     
         5 . The method according to any one of  claims 1  to  3 , wherein the gain of letters in the BCVA/ETDRS letter score is measured at 45 weeks, and/or at 46 weeks, and/or at 47 weeks, and/or at 48 weeks, and/or at 49 weeks, and/or at 50 weeks, and/or at 51 weeks, and/or at 52 weeks, and/or at 53 weeks, and/or at 54 weeks, and/or at 55 weeks, and/or at 56 weeks, and/or at 57 weeks, and/or at 58 weeks, and/or at 59 weeks, and/or at 60 weeks after treatment start, respectively. 
     
     
         6 . The method according to any one of  claims 1  to  5 , wherein the bispecific antibody is used to prolong the time to retreatment and/or to prolong the time to loss of visual acuity and, wherein the retreatment with the bispecific antibody is administered in case of a disease activity which is determined as
 Central Subfield Thickness (CST) increase by ≥50 μm; and/or 
 Best Corrected Visual Acuity (BCVA/ETDRS) decrease by ≥5 letters. 
 
     
     
         7 . The method according to any one of  claims 1  to  6 , wherein the bispecific antibody is administered following a treatment initiation of 3 to 7 monthly administrations. 
     
     
         8 . The method according to any one of  claims 1  to  7 , wherein the ocular vascular disease is selected from the group of: wet age-related macular degeneration (wet AMD), neovascular AMD, diabetic macular edema (DME), cystoid macular edema (CME), non-proliferative diabetic retinopathy (NPDR), proliferative diabetic retinopathy (PDR), macular edema secondary to central retinal vein occlusion, secondary to hemiretinal vein occlusion or secondary to branch vein occlusion, retinitis, conjunctivitis, uveitis, choroiditis, choroidal neovascularization (CNV) secondary to ocular inflammation including secondary to ocular histoplasmosis or presumed histoplasmosis or choroiditis; myopic choroidal neovascularization (mCNV), choroidal neovascularization secondary to trauma, retinopathy of prematurity and rubeosis iridis/rubeotic glaucoma. 
     
     
         9 . The method according to of  claim 8 , wherein the ocular vascular disease is DME. 
     
     
         10 . The method according to  claim 8 , wherein the ocular vascular disease is wet AMD or neovascular AMD. 
     
     
         11 . The method according to any one of  claims 1  to  10 , wherein the a bispecific antibody which binds to VEGF and to human ANG-2 is a VEGF antagonist/inhibitor and an ANG2 antagonist/inhibitor or inhibits binding of VEGF to its receptor VEGFR and inhibits binding of ANG2 to its receptor TIE2. 
     
     
         12 . The method according to any one of  claims 1  to  11 , wherein the bispecific antibody is administered every 10 to 12 weeks. 
     
     
         13 . The method according to any one of  claims 1  to  11 , wherein the bispecific antibody is administered every 11 to 13 weeks 
     
     
         14 . The method according to any one of  claims 1  to  11 , wherein the bispecific antibody is administered every 12 to 14 weeks. 
     
     
         15 . The method according to any one of  claims 1  to  11 , wherein the bispecific antibody is administered every 13 to 15 weeks. 
     
     
         16 . The method according to any one of  claims 1  to  11 , wherein the bispecific antibody is administered every 14 to 16 weeks. 
     
     
         17 . The method according to any one of  claims 1  to  16 , wherein the bispecific antibody which binds to human VEGF and to human ANG2 is a bispecific, bivalent anti-VEGF/ANG2 antibody comprising a first antigen-binding site that specifically binds to human VEGF and a second antigen-binding site that specifically binds to human ANG-2, wherein
 i) said first antigen-binding site specifically binding to VEGF comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 1, a CDR2H region of SEQ ID NO: 2, and a CDR1H region of SEQ ID NO:3, and in the light chain variable domain a CDR3L region of SEQ ID NO: 4, a CDR2L region of SEQ ID NO:5, and a CDR1L region of SEQ ID NO:6; and 
 ii) said second antigen-binding site specifically binding to ANG-2 comprises in the heavy chain variable domain a CDR3H region of SEQ ID NO: 9, a CDR2H region of, SEQ ID NO: 10, and a CDR1H region of SEQ ID NO: 11, and in the light chain variable domain a CDR3L region of SEQ ID NO: 12, a CDR2L region of SEQ ID NO: 13, and a CDR1L region of SEQ ID NO: 14, and wherein 
 iii) the bispecific antibody comprises a constant heavy chain region of human IgG1 subclass comprising the mutations I253A, H310A, and H435A and the mutations L234A, L235A and P329G (numberings according to EU Index of Kabat). 
 
     
     
         18 . The method according to  claim 17 , wherein
 i) said first antigen-binding site specifically binding to VEGF comprises as heavy chain variable domain VH an amino acid sequence of SEQ ID NO: 7, and as light chain variable domain VL an amino acid sequence of SEQ ID NO: 8, and   ii) said second antigen-binding site specifically binding to ANG-2 comprises as heavy chain variable domain VH an amino acid sequence of SEQ ID NO: 15, and as light chain variable domain VL an amino acid sequence of SEQ ID NO: 16.   
     
     
         19 . The method according to  claim 18 , wherein the bispecific antibody which binds to human VEGF and human ANG2 comprises the amino acid sequences of SEQ ID NO: 17, of SEQ ID NO: 18, of SEQ ID NO: 19, and of SEQ ID NO: 20. 
     
     
         20 . The method according to any one of  claims 17  to  19 , wherein the bispecific antibody is administered in a dose of about 5 to 7 mg. 
     
     
         21 . The method according to any one of  claims 17  to  19 , wherein the bispecific antibody is administered in a dose of about 6 mg. 
     
     
         22 . The method according to  claim 20  or  21 , wherein the bispecific antibody is administered at a concentration of about 30 mg/ml. 
     
     
         23 . The method according to  claim 20  or  21 , wherein the bispecific antibody is administered at a concentration of about 120 mg/ml. 
     
     
         24 . The method according to any one of the  claims 1  to  23  wherein patients suffering from an ocular vascular disease have not been previously treated with anti-VEGF treatment (e.g monotherapy). 
     
     
         25 . The method according to any one of  claims 1  to  23  wherein patients suffering from an ocular vascular disease have been previously treated with anti-VEGF treatment (e.g monotherapy). 
     
     
         26 . The method according to any one of the preceding claims wherein the ocular vascular disease is DME and the treatment of patients suffering from DME includes a fixed every 8th week (Q8W) dosing schedule following treatment initiation. 
     
     
         27 . The method according to any one of the preceding claims wherein the ocular vascular disease is DME and the treatment of patients suffering from DME includes a fixed Q12W dosing schedule following treatment initiation. 
     
     
         28 . The method according to  claim 27  wherein, following the treatment initiation, first one dose cycle of Q8W follows before the fixed Q12W dosing schedule. 
     
     
         29 . The method according to any one of the preceding claims wherein the ocular vascular disease is DME and the treatment of patients suffering from DME includes following treatment initiation a dosing schedule that extends the administration interval in stable absence of disease, or shortens the interval if there is disease activity. 
     
     
         30 . The method according to  claim 29  wherein such dosing schedule includes that the patient receives Q8W or Q12W or Q16W dosing, dependent on their disease state. 
     
     
         31 . The method according to  claim 28  or  29 , wherein the stable absence of disease is determined as
 Central Subfield Thickness (CST) increased by <50 μm; and/or 
 Best Corrected Visual Acuity (BCVA/ETDRS) decreased by <5 letters and the disease activity is determined as 
 Central Subfield Thickness (CST) increased by ≥50 μm; and/or 
 Best Corrected Visual Acuity (BCVA/ETDRS) decreased by ≥5 letters. 
 
     
     
         32 . The method according to  claim 28  or  29 , wherein the stable absence of disease is determined as
 Central Subfield Thickness (CST) is below about 300 μm (In one embodiment below 325 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Spectralis™ device; in one embodiment below 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Cirrus' device; in one embodiment below 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Topcon™ device; in one embodiment below 295 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Optovue™ device), 
 and the disease activity is determined as 
 Central Subfield Thickness (CST) is above about 300 μm (In one embodiment above 325 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Spectralis™ device; in one embodiment above 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Cirrus™ device; in one embodiment above 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Topcon™ device; in one embodiment above 295 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Optovue™ device). 
 
     
     
         33 . The method according to any one of the preceding claims wherein the treatment of patients suffering from AMD includes following treatment initiation a dosing schedule that extends the administration interval in stable absence of disease, or shortens the interval if there is disease activity. 
     
     
         34 . The method according to  claim 33  wherein such dosing schedule includes that the patient receives Q8W or Q12W or Q16W dosing, dependent on their disease state. 
     
     
         35 . The method according to  claim 33  or  34 , wherein the stable absence of disease is determined as
 Central Subfield Thickness (CST) increased by <50 μm; and/or 
 Best Corrected Visual Acuity (BCVA/ETDRS) decreased by <5 letters 
 and the disease activity is determined as 
 Central Subfield Thickness (CST) increased by ≥50 μm; and/or 
 Best Corrected Visual Acuity (BCVA/ETDRS) decreased by ≥5 letters. 
 
     
     
         36 . The method according to  claim 33  or  34 , wherein the stable absence of disease is determined as
 Central Subfield Thickness (CST) is below about 300 μm (In one embodiment below 325 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Spectralis™ device; in one embodiment below 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Cirrus™ device; in one embodiment below 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Topcon™ device; in one embodiment below 295 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Optovue™ device), 
 and the disease activity is determined as 
 Central Subfield Thickness (CST) is above about 300 μm (In one embodiment above 325 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Spectralis™ device; in one embodiment above 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Cirrus™ device; in one embodiment above 315 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Topcon™ device; in one embodiment above 295 μm measured by spectral domain optical coherence tomography (SD-OCT) with a Optovue™ device).