US2019046642A1PendingUtilityA1

Il-6 antagonist formulations and uses thereof

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Assignee: ELEVEN BIOTHERAPEUTICS INCPriority: Feb 23, 2016Filed: Feb 23, 2017Published: Feb 14, 2019
Est. expiryFeb 23, 2036(~9.6 yrs left)· nominal 20-yr term from priority
Inventors:Grigorios Zarbis-PapastoitsisPatricia Lowden
A61P 9/00A61P 35/00A61P 43/00A61P 27/14A61P 27/02A61K 39/3955A61K 9/0019C07K 16/248A61K 9/0048A61K 47/22A61K 39/39591A61K 45/06A61K 47/10A61K 47/183C07K 2317/94A61K 47/26A61K 47/02
32
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Claims

Abstract

Featured herein are pharmaceutical compositions and formulations containing an interleukin-6 (IL-6) antagonist, e.g., an IL-6 antibody molecule, designed for administration for a subject. The pharmaceutical compositions and formulations provided herein are suitable for use in manufacture of medicaments or methods of treating subjects with IL-6 associated diseases, e.g., ocular diseases associated with elevated levels of IL-6.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A pharmaceutical formulation comprising
 1-100 mg/mL of an anti-IL-6 antibody or fragment thereof;   10-50 mM histidine;   0.01%-0.1% polysorbate-20 (Tween-20), polysorbate-80 (Tween-80), or poloxamer 188;   1-150 mM sodium chloride; and   1-10% sorbitol;   and wherein the pH of the formulation is between 5.5 and 7.5.   
     
     
         2 . The formulation of  claim 1 , wherein the formulation comprises 5-50 mg/ml of an anti-IL-6 antibody for fragment thereof. 
     
     
         3 . The formulation of  claim 2  or  3 , wherein the formulation comprises 5 mg/ml of an anti-IL-6 antibody for fragment thereof. 
     
     
         4 . The formulation of  claim 2  or  3 , wherein the formulation comprises 50 mg/ml of an anti-IL-6 antibody for fragment thereof. 
     
     
         5 . The formulation of any of  claims 1 - 4 , wherein the IL-6 antibody or fragment thereof comprises a VH CDR1 comprising the sequence of SEQ ID NO:19, a VH CDR2 comprising the sequence of SEQ ID NO:20, and a VH CDR3 comprising the sequence of SEQ ID NO:21. 
     
     
         6 . The formulation of any of  claims 1 - 5 , wherein the IL-6 antibody or fragment thereof further comprises a VL CDR1 comprising the sequence of SEQ ID NO:22, a VL CDR2 comprising the sequence of SEQ ID NO:23, and a VL CDR3 comprising the sequence of SEQ ID NO:24. 
     
     
         7 . The formulation of any of  claims 1 - 6 , wherein the IL-6 antibody or fragment thereof comprises:
 (i) a constant region sequence comprising SEQ ID NO: 28 or 29, or   (ii) a constant region sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:28 or.   
     
     
         8 . The formulation of any of  claims 1 - 7 , wherein the IL-6 antibody or fragment thereof comprises:
 (i) a heavy chain variable region sequence comprising SEQ ID NO:17, or   (ii) a heavy chain variable region sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:17.   
     
     
         9 . The formulation of any of  claims 1 - 8 , wherein the IL-6 antibody or fragment thereof comprises:
 (i) a heavy chain sequence comprising SEQ ID NO:13, or   (ii) a heavy chain sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:13.   
     
     
         10 . The formulation of any of  claims 1 - 9 , wherein the IL-6 antibody or fragment thereof further comprises:
 (i) a light chain variable region sequence comprising SEQ ID NO:18, or   (ii) a light chain variable region sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:18.   
     
     
         11 . The formulation of any of  claims 1 - 10 , wherein the IL-6 antibody or fragment thereof comprises
 i) a light chain sequence comprising SEQ ID NO:14, or   ii) a light chain sequence that is at least 90, 91, 92, 93, 94, 95, 96, 97, 98, or 99% identical to SEQ ID NO:14.   
     
     
         12 . The formulation of any of  claims 1 - 11 , wherein the IL-6 antibody or fragment thereof comprises a heavy chain variable region comprising SEQ ID NO:17 and a light chain variable region comprising SEQ ID NO:18. 
     
     
         13 . The formulation of any of  claims 1 - 12 , wherein the IL-6 antibody or fragment thereof comprises a heavy chain sequence comprising SEQ ID NO:13 and a light chain sequence comprising SEQ ID NO:14. 
     
     
         14 . The formulation of any of  claims 1 - 13 , wherein the formulation comprises 10-30 mM histidine buffer. 
     
     
         15 . The formulation of any of  claims 1 - 14 , wherein the formulation comprises 20 mM histidine buffer. 
     
     
         16 . The formulation of any of  claims 1 - 15 , wherein the formulation comprises 0.01%-0.05% polysorbate-20 (Tween-20), polysorbate-80 (Tween-80), or poloxamer 188. 
     
     
         17 . The formulation of any of  claims 1 - 16 , wherein the formulation comprises 0.03% polysorbate-20 (Tween-20), polysorbate-80 (Tween-80), or poloxamer 188. 
     
     
         18 . The formulation of any of  claims 1 - 17 , wherein the formulation comprises 10-50 mM sodium chloride. 
     
     
         19 . The formulation of any of  claims 1 - 18 , wherein the formulation comprises 10-30 mM sodium chloride. 
     
     
         20 . The formulation of any of  claims 1 - 19 , wherein the formulation comprises 20 mM sodium chloride. 
     
     
         21 . The formulation of any of  claims 1 - 20 , wherein the formulation comprises 2-6% sorbitol. 
     
     
         22 . The formulation of any of  claims 1 - 21 , wherein the formulation comprises 4% sorbitol. 
     
     
         23 . The formulation of any of  claims 1 - 22 , wherein the formulation is at a pH between 6.0 and 7.0. 
     
     
         24 . The formulation of any of  claims 1 - 23 , wherein the formulation is at a pH between 6.2 and 6.8. 
     
     
         25 . The formulation of any of  claims 1 - 24 , wherein the formulation is at about pH 6.5. 
     
     
         26 . A pharmaceutical formulation comprising
 5-50 mg/mL of an anti-IL-6 antibody or fragment thereof, e.g., 5 mg/ml or 50 mg/ml;   20 mM histidine;   0.03% polysorbate-20 (Tween-20), polysorbate-80 (Tween-80), or poloxamer 188;   20 mM sodium chloride; and   4% sorbitol;   and wherein the pH of the formulation is 6.5.   
     
     
         27 . The formulation of  claim 26 , wherein the formulation comprises 5 mg/ml of an anti-IL-6 antibody or fragment thereof. 
     
     
         28 . The formulation of  claim 26 , wherein the formulation comprises 50 mg/ml of an anti-IL-6 antibody or fragment thereof. 
     
     
         29 . The formulation of any of  claims 26 - 28 , wherein the anti-IL-6 antibody or fragment thereof comprises:
 i) a VH CDR1 comprising the sequence of SEQ ID NO:19, a VH CDR2 comprising the sequence of SEQ ID NO:20, and a VH CDR3 comprising the sequence of SEQ ID NO:21; and   ii) a VL CDR1 comprising the sequence of SEQ ID NO:22, a VL CDR2 comprising the sequence of SEQ ID NO:23, and a VL CDR3 comprising the sequence of SEQ ID NO:24.   
     
     
         30 . The formulation of any of  claims 26 - 29 , wherein the IL-6 antibody or fragment thereof comprises a heavy chain variable region comprising SEQ ID NO:17 and a light chain variable region comprising SEQ ID NO:18. 
     
     
         31 . The formulation of any of  claims 26 - 30 , wherein the IL-6 antibody or fragment thereof comprises a heavy chain sequence comprising SEQ ID NO:13 and a light chain sequence comprising SEQ ID NO:14. 
     
     
         32 . The formulation of any of  claims 1 - 31 , wherein the anti-IL-6 antibody is an IgG2 antibody. 
     
     
         33 . The formulation of any of  claims 1 - 32 , wherein the IL-6 antibody is a full-length antibody. 
     
     
         34 . The formulation of any of  claims 1 - 33 , wherein at least 95%, e.g., 96%, 97%, 98%, or 99%, of the antibody present in the formulation is in isoform A or A/B, collectively. 
     
     
         35 . The formulation of any of  claims 1 - 34 , wherein at least 85%, e.g., 86%, 87%, 88%, 89%, or 90%, of the antibody present in the formulation is in isoform A. 
     
     
         36 . The formulation of any of  claims 1 - 35 , wherein less than 1%, e.g., 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, or 0.1%, of the antibody present in the formulation is in isoform B. 
     
     
         37 . The formulation of any of  claims 1 - 36 , wherein the formulation is substantially free, e.g., less than 5%, 4%, 3%, 2%, or 1%, of the antibody in isoform B. 
     
     
         38 . The formulation of any of  claims 34 - 37 , wherein the percentage of antibody present in isoform A, A/B, and/or B is determined by HPLC, e.g., RP-HPLC, or peptide mapping, e.g., under non-reducing conditions followed by mass spectrometry analysis. 
     
     
         39 . The formulation of any of  claims 1 - 38 , further comprising one or more of a chelating agent, a preserving agent, or an antioxidant. 
     
     
         40 . The formulation of any of  claims 1 - 39 , further comprising a second therapeutic agent. 
     
     
         41 . The formulation of any of  claims 1 - 40 , wherein the formulation is suitable for administration to the eye. 
     
     
         42 . The formulation of any of  claims 1 - 41 , wherein the formulation is suitable for administration intravitreally, intraocularly, or subconjunctivally. 
     
     
         43 . The formulation of any of  claims 1 - 42 , wherein the formulation is stable at a temperature of −65° C. or less for at least 1 or 2 years. 
     
     
         44 . The formulation of any of  claims 1 - 42 , wherein the formulation is stable at a temperature between 2 to 8° C. for at least 6 months. 
     
     
         45 . Use of a formulation of any of  claims 1 - 44  for treating a subject having an IL-6 associated disease. 
     
     
         46 . The use of  claim 45 , wherein the IL-6 associated disease is selected from the group consisting of diabetic macular edema (DME), diabetic retinopathy, dry eye (e.g., dry eye disease or dry eye syndrome), allergic conjunctivitis, uveitis, age-related macular degeneration (AMD) (e.g., wet AMD or dry AMD), proliferative diabetic retinopathy (PDR), Rhegmatogenous retinal detachment (RRD), retinal vein occlusion (RVO), neuromyelitis optica (NMO), myopic choroidal neovascularization, an ocular cancer, corneal transplant, corneal abrasion, or physical injury to the eye. 
     
     
         47 . The use of  claim 45  or  46 , wherein the IL-6 associated disease is diabetic macular edema (DME). 
     
     
         48 . The use of any of  claims 46 - 47 , wherein the formulation is administered to the eye of the subject. 
     
     
         49 . The use of any of  claims 46 - 48 , wherein the formulation is administrated intravitreally. 
     
     
         50 . A container or device comprising the formulation of any of  claims 1 - 44 . 
     
     
         51 . The container of  claim 50 , wherein the volume of the formulation is at least 0.1, 0.5, 1, 2, or 5 ml. 
     
     
         52 . The container of any  claim 50  or  51 , wherein the container is an multidose container. 
     
     
         53 . A drug delivery device comprising a formulation of any one of  claims 1  to  44 . 
     
     
         54 . A kit comprising a container or device comprising the formulation of any one of  claims 1  to  44 , and optionally, instructions for use. 
     
     
         55 . A method of treating a subject having an IL-6 associated disease, e.g., a disease associated with elevated IL-6 expression, comprising administering to the subject the pharmaceutical formulation of any of  claims 1 - 44 . 
     
     
         56 . The method of  claim 55 , wherein the formulation is administered to the eye. 
     
     
         57 . The method of  claim 56 , wherein the formulation is administered intravitreally, e.g., by intravitreal injection. 
     
     
         58 . The method of any of  claims 55 - 57 , wherein the IL-6 associated disease is selected from the group consisting of diabetic macular edema (DME), diabetic retinopathy, dry eye (e.g., dry eye disease or dry eye syndrome), allergic conjunctivitis, uveitis, age-related macular degeneration (AMD) (e.g., wet or dry AMD), proliferative diabetic retinopathy (PDR), Rhegmatogenous retinal detachment (RRD), retinal vein occlusion (RVO), neuromyelitis optica (NMO), myopic choroidal neovascularization, an ocular cancer, corneal transplant, corneal abrasion, or physical injury to the eye. 
     
     
         59 . The method of any of  claims 55 - 58 , wherein the IL-6 associated disease is diabetic macular edema (DME). 
     
     
         60 . The method of any of  claims 55 - 59 , further comprising administering to the subject a second therapeutic agent. 
     
     
         61 . The method of  claim 60 , wherein the second therapeutic agent is an anti-VEGF agent, a steroid, e.g., a corticosteroid, or an anti-PDGF agent. 
     
     
         62 . The method of any of  claims 55 - 51 , wherein the subject has previously been treated with an anti-VEGF agent, a steroid, or an anti-PDGF agent. 
     
     
         63 . The method of  claim 52 , wherein the subject did not respond to treatment with an anti-VEGF agent, a steroid, or an anti-PDGF agent. 
     
     
         64 . The method of any of  claims 55 - 63 , wherein the subject is a mammal. 
     
     
         65 . The method of any of  claims 55 - 64 , wherein the subject is a human.

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