US2023183348A1PendingUtilityA1
Stable antibody formulation

Assignee: REGENERON PHARMAPriority: Apr 6, 2017Filed: Feb 1, 2023Published: Jun 15, 2023
Est. expiryApr 6, 2037(~10.7 yrs left)· nominal 20-yr term from priority
Inventors:Qingyan Hu Dingjiang Liu
A61K 47/26A61K 47/183A61K 9/0019C07K 16/2818C07K 2317/94A61K 39/39591A61K 9/08A61K 47/22C07K 16/28
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References
Claims
Abstract

The present invention provides stable pharmaceutical formulations comprising a human antibody that specifically binds to human programmed death-1 protein (PD-1). In certain embodiments, the formulations contain, in addition to an anti-PD-1 antibody, a buffer, an amino acid, a non-ionic surfactant, and a sugar. The pharmaceutical formulations of the present invention exhibit a substantial degree of antibody stability upon stress and storage.
Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A liquid pharmaceutical formulation comprising:
 (a) an antibody which binds specifically to human programmed death-1 (PD-1), wherein the antibody comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) contained in a heavy chain variable region (HCVR) of SEQ ID NO: 1 and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a light chain variable region (LCVR) of SEQ ID NO: 2;   (b) a buffer comprising histidine;   (c) an organic solvent comprising polysorbate;   (d) a stabilizer comprising a sugar; and   (e) a viscosity modifier comprising an amino acid;   wherein the formulation has a pH of 6.0±0.3.   
     
     
         2 . The pharmaceutical formulation of  claim 1 , wherein the antibody concentration is from 5 mg/mL±0.75 mg/mL to 250 mg/mL±37.5 mg/mL. 
     
     
         3 . The pharmaceutical formulation of  claim 2 , wherein the antibody concentration is 25 mg/mL±3.75 mg/mL. 
     
     
         4 . The pharmaceutical formulation of  claim 2 , wherein the antibody concentration is 50 mg/mL±7.5 mg/mL. 
     
     
         5 . The pharmaceutical formulation of  claim 2 , wherein the antibody concentration is 150 mg/mL±22.5 mg/mL. 
     
     
         6 . The pharmaceutical formulation of  claim 2 , wherein the antibody concentration is 175 mg/mL±26.25 mg/mL. 
     
     
         7 . The pharmaceutical formulation of any one of  claims 1 - 6 , wherein the histidine buffer concentration is from 5 mM±1 mM to 20 mM±4 mM. 
     
     
         8 . The pharmaceutical formulation of  claim 7 , wherein the histidine buffer concentration is 10 mM±2 mM. 
     
     
         9 . The pharmaceutical formulation of  claim 7  or  8 , wherein the histidine buffer comprises L-histidine and L-histidine monohydrochloride monohydrate. 
     
     
         10 . The pharmaceutical formulation of  claim 9 , wherein the L-histidine concentration is 4.8 mM±0.96 mM and the L-histidine monohydrochloride monohydrate concentration is 5.2 mM±1.04 mM. 
     
     
         11 . The pharmaceutical formulation of any one of  claims 1 - 10 , wherein the polysorbate concentration is from 0.01%±0.005% to 0.5%±0.25% w/v. 
     
     
         12 . The pharmaceutical formulation of  claim 11 , wherein the polysorbate concentration is 0.1%±0.05% w/v. 
     
     
         13 . The pharmaceutical formulation of  claim 11 , wherein the polysorbate concentration is 0.2%±0.1% w/v. 
     
     
         14 . The pharmaceutical formulation of any one of  claims 11 - 13 , wherein the organic solvent is polysorbate 80. 
     
     
         15 . The pharmaceutical formulation of any one of  claims 1 - 14 , wherein the stabilizer is sucrose and the sucrose concentration is from 0% to 20%±4% w/v. 
     
     
         16 . The pharmaceutical formulation of  claim 15 , wherein the sucrose concentration is from 1%±0.2% to 10%±2% w/v. 
     
     
         17 . The pharmaceutical formulation of  claim 16 , wherein the sucrose concentration is 5%±1% w/v. 
     
     
         18 . The pharmaceutical formulation of  claim 17 , wherein the viscosity modifier is proline. 
     
     
         19 . The pharmaceutical formulation of  claim 18 , wherein the proline concentration is from 0 to 5%±1% w/v. 
     
     
         20 . The pharmaceutical formulation of  claim 19 , wherein the proline concentration is 1.5%±0.3% w/v. 
     
     
         21 . The pharmaceutical formulation of  claim 18  comprising:
 (a) 175 mg/mL±26.25 mg/mL antibody, 
 (b) of from 5 mM±1 mM to 20 mM±4 mM histidine buffer, 
 (c) of from 0.1%±0.05% to 0.5%±0.25% w/v polysorbate, 
 (d) of from 1%±0.2% to 10%±2% w/v sucrose, and 
 (e) of from 1%±0.2% to 5%±1% w/v proline; 
 at pH 6.0±0.3. 
 
     
     
         22 . The pharmaceutical formulation of  claim 21  comprising:
 (a) 175 mg/mL±26.25 mg/mL antibody, 
 (b) 10 mM±2 mM histidine buffer, 
 (c) 0.2%±0.1% w/v polysorbate 
 (d) 5%±1% w/v sucrose, and 
 (e) 1.5%±0.3% w/v proline; 
 at pH 6.0±0.3. 
 
     
     
         23 . The pharmaceutical formulation of  claim 22  comprising:
 (a) 175 mg/mL±26.25 mg/mL antibody, 
 (b) 4.8 mM±0.96 mM L-histidine, 
 (c) 5.2 mM±1.04 mM L-histidine monohydrochloride monohydrate, 
 (d) 0.2%±0.1% w/v polysorbate, 
 (e) 5%±1% w/v sucrose, and 
 (f) 1.5%±0.3% w/v proline; 
 at pH 6.0±0.3. 
 
     
     
         24 . The pharmaceutical formulation of  claim 18  comprising:
 (a) 150 mg/mL±22.5 mg/mL antibody, 
 (b) of from 5 mM±1 mM to 20 mM±4 mM histidine buffer, 
 (c) of from 0.1%±0.05% to 0.5%±0.25% w/v polysorbate, 
 (d) of from 1%±0.2% to 10%±2% w/v sucrose, and 
 (e) of from 1%±0.2% to 5%±1% w/v proline; 
 at pH 6.0±0.3. 
 
     
     
         25 . The pharmaceutical formulation of  claim 24  comprising:
 (a) 150 mg/mL±22.5 mg/mL antibody, 
 (b) 10 mM±2 mM histidine buffer, 
 (c) 0.2%±0.1% w/v polysorbate, 
 (d) 5%±1% w/v sucrose, and 
 (e) 1.5%±0.3% w/v proline, 
 at pH 6.0±0.3. 
 
     
     
         26 . The pharmaceutical formulation of  claim 25  comprising:
 (a) 150 mg/mL±22.5 mg/mL antibody, 
 (b) 4.8 mM±0.96 mM L-histidine, 
 (c) 5.2 mM±1.04 mM) L-histidine monohydrochloride monohydrate, 
 (d) 0.2%±0.1% w/v polysorbate, 
 (e) 5%±1% w/v sucrose, and 
 (f) 1.5%±0.3% w/v proline; 
 at pH 6.0±0.3. 
 
     
     
         27 . The pharmaceutical formulation of  claim 18  comprising:
 (a) 50 mg/mL±7.5 mg/mL antibody, 
 (b) of from 5 mM±1 mM to 20 mM±4 mM histidine buffer, 
 (c) of from 0.1%±0.05% to 0.5%±0.25% w/v polysorbate, 
 (d) of from 1%±0.2% to 10%±2% w/v sucrose, and 
 (e) of from 1%±0.2% to 5%±1% w/v proline, 
 at pH 6.0±0.3. 
 
     
     
         28 . The pharmaceutical formulation of  claim 27  comprising:
 (a) 50 mg/mL±7.5 mg/mL antibody, 
 (b) 10 mM±2 mM histidine buffer, 
 (c) 0.2%±0.1% w/v polysorbate, 
 (d) 5%±1% w/v sucrose, and 
 (e) 1.5%±0.3% w/v proline, 
 at pH 6.0±0.3. 
 
     
     
         29 . The pharmaceutical formulation of  claim 28  comprising:
 (a) 50 mg/mL±7.5 mg/mL antibody, 
 (b) 4.8 mM±0.96 mM L-histidine, 
 (c) 5.2 mM±1.04 mM L-histidine monohydrochloride monohydrate, 
 (d) 0.2%±0.1% w/v polysorbate, 
 (e) 5%±1% w/v sucrose, and 
 (f) 1.5%±0.3% w/v proline; 
 at pH 6.0±0.3. 
 
     
     
         30 . The pharmaceutical formulation of  claim 18  comprising:
 (a) 25 mg/mL±3.75 mg/mL antibody, 
 (b) of from 5 mM±1 mM to 20 mM±4 mM histidine buffer, 
 (c) of from 0.1%±0.05% to 0.5%±0.25% w/v polysorbate 
 (d) of from 1%±0.2% to 10%±2% w/v sucrose, and 
 (e) of from 1%±0.2% to 5%±1% w/v proline, 
 at pH 6.0±0.3. 
 
     
     
         31 . The pharmaceutical formulation of  claim 30  comprising:
 (a) 25 mg/mL±3.75 mg/mL antibody, 
 (b) 10 mM±2 mM histidine buffer, 
 (c) 0.2%±0.1% w/v polysorbate, 
 (d) 5%±1% w/v sucrose, and 
 (e) 1.5%±0.3% w/v proline, 
 at pH 6.0±0.3. 
 
     
     
         32 . The pharmaceutical formulation of  claim 31  comprising:
 (a) 25 mg/mL±3.75 mg/mL antibody, 
 (b) 4.8 mM±0.96 mM L-histidine, 
 (c) 5.2 mM±1.04 mM L-histidine monohydrochloride monohydrate, 
 (d) 0.2%±0.1% w/v polysorbate, 
 (e) 5%±1% w/v sucrose, and 
 (f) 1.5%±0.3% w/v proline; 
 at pH 6.0±0.3. 
 
     
     
         33 . The pharmaceutical formulation of any one of  claims 1 - 32 , wherein the formulation has viscosity less than 20 cP. 
     
     
         34 . The pharmaceutical formulation of any one of  claims 1 - 33 , wherein at least 90% of the antibody has native conformation after 28 days at 45° C. 
     
     
         35 . The pharmaceutical formulation of any one of  claims 1 - 34 , wherein at least 35% of the antibody is the main charge variant of the antibody after 28 days at 45° C. 
     
     
         36 . The pharmaceutical formulation of any one of  claims 1 - 35 , wherein at least 94% of the antibody has native conformation after three months at 25° C. 
     
     
         37 . The pharmaceutical formulation of any one of  claims 1 - 36 , wherein at least 44% of the antibody is the main charge variant of the antibody after three months at 25° C. 
     
     
         38 . The pharmaceutical formulation of any one of  claims 1 - 37 , wherein at least 96% of the antibody has native conformation after 12 months at 5° C. 
     
     
         39 . The pharmaceutical formulation of any one of  claims 1 - 38 , wherein at least 45% of the antibody is the main charge variant of the antibody after 12 months at 5° C. 
     
     
         40 . The pharmaceutical formulation of any one of  claims 1 - 39 , wherein at least 96% of the antibody has native conformation after 12 months at −20° C., −30° C., &amp;/or −80° C. 
     
     
         41 . The pharmaceutical formulation of any one of  claims 1 - 40 , wherein at least 40% of the antibody is the main charge variant of the antibody after 12 months at −20° C., −30° C., &amp;/or −80° C. 
     
     
         42 . A pharmaceutical formulation comprising:
 (a) 175 mg/mL±26.25 mg/mL of an antibody that binds specifically to PD-1, wherein the antibody comprises a HCVR of SEQ ID NO: 1 and a LCVR of SEQ ID NO: 2,   (b) 10 mM±2 mM histidine buffer, pH 6.0±0.3,   (c) 0.2%±0.1% w/v polysorbate 80,   (d) 5%±1% w/v sucrose; and   (e) 1.5%±0.3% w/v proline; wherein:   
       (i) ≥90% of the antibodies have a molecular weight of 143 kDa±1 kDa; 
       (ii) the pharmaceutical formulation has a viscosity of less than 20 cP; and 
       (iii) at least 97% or more of the antibodies have native conformation upon storage at −80° C., −30° C. &amp;/or −20° C. for 6 months. 
     
     
         43 . The pharmaceutical formulation of  claim 42  consisting of: (a) 175 mg/mL±26.25 mg/mL of the antibody, (b) 4.8 mM±0.96 mM L-histidine (c) 5.2 mM±1.04 mM L-histidine monohydrochloride monohydrate, (d) 0.2%±0.1% w/v polysorbate 80, (e) 5%±1% w/v sucrose; and (f) 1.5%±0.3% w/v proline, in water at pH 6.0±0.3. 
     
     
         44 . A pharmaceutical formulation comprising:
 (a) 150 mg/mL±22.5 mg/mL of an antibody that binds specifically to PD-1, wherein the antibody comprises an HCVR of SEQ ID NO: 1 and an LCVR of SEQ ID NO: 2,   (b) 10 mM±2 mM histidine buffer, pH 6±0.3,   (c) 0.2%±0.1% w/v polysorbate 80,   (d) 5%±1% w/v sucrose; and   (e) 1.5%±0.3% w/v proline; wherein:   
       (i) ≥90% of the antibodies have a molecular weight of 143 kDa±1 kDa; 
       (ii) the pharmaceutical formulation has a viscosity of less than 15 cP; and 
       (iii) at least 97% or more of the antibodies have native conformation upon storage at −80° C., −30° C. or −20° C. for 6 months. 
     
     
         45 . The pharmaceutical formulation of  claim 44  consisting of: (a) 150 mg/mL±22.5 mg/mL of the antibody, (b) 4.8 mM±0.96 mM L-histidine, (c) 5.2 mM±1.04 mM L-histidine monohydrochloride monohydrate, (d) 0.2%±0.1% w/v polysorbate 80, (e) 5%±1% w/v sucrose; and (f) 1.5%±0.3% w/v proline, in water at pH 6.0±0.3. 
     
     
         46 . A pharmaceutical formulation comprising:
 (a) 50 mg/mL±7.5 mg/mL of an antibody that binds specifically to PD-1, wherein the antibody comprises an HCVR of SEQ ID NO: 1 and an LCVR of SEQ ID NO: 2,   (b) 10 mM±2 mM histidine buffer, pH 6±0.3,   (c) 0.2%±0.1% w/v polysorbate 80,   (d) 1.5%±0.3% w/v proline, and   (e) 5%±1% w/v sucrose; wherein:   
       (i) ≥90% of the antibodies have a molecular weight of 143 kDa±1 kDa; 
       (ii) more than 96% of the antibodies have native conformation upon storage for 12 months at 5° C.; and 
       (iii) the pharmaceutical formulation has a viscosity less than 15 cP. 
     
     
         47 . The pharmaceutical formulation of  claim 46  consisting of: (a) 50 mg/mL mL±7.5 mg/mL of the antibody, (b) 4.8 mM±0.96 mM L-histidine, (c) 5.2 mM±1.04 mM L-histidine monohydrochloride monohydrate, (d) 0.2%±0.1% w/v polysorbate 80, (e) 5%±1% w/v sucrose; and (f) 1.5%±0.3% w/v proline, in water at pH 6.0±0.3. 
     
     
         48 . A pharmaceutical formulation comprising:
 (a) 25 mg/mL±3.75 mg/mL of an antibody that binds specifically to PD-1, wherein the antibody comprises an HCVR of SEQ ID NO: 1 and an LCVR of SEQ ID NO: 2,   (b) 10 mM±2 mM histidine buffer, pH 6.0±0.3,   (c) 0.2%±0.1% w/v polysorbate 80,   (d) 5%±1% w/v sucrose; and   (e) 1.5%±0.3% w/v proline; wherein:   
       (a) ≥90% of the antibodies have a molecular weight of 143 kDa±1 kDa; 
       (b) the pharmaceutical formulation has a viscosity of less than 10 cP; and 
       (c) at least 96% of the antibodies have native conformation upon storage for 12 months at 5° C. 
     
     
         49 . The pharmaceutical formulation of  claim 48  consisting of: (a) 25 mg/mL±3.75 mg/mL of the antibody, (b) 4.8 mM±0.96 mM L-histidine, (c) 5.2 mM±1.04 mM L-histidine monohydrochloride monohydrate, (d) 0.2% w/v±0.1% polysorbate 80, (e) 5% w/v±1% sucrose; and (f) 1.5% w/v±0.3% proline, in water at pH 6.0±0.3. 
     
     
         50 . The pharmaceutical formulation of any one of  claims 1 - 49 , wherein the antibody comprises a HCDR1 of SEQ ID NO: 3, a HCDR2 of SEQ ID NO: 4, a HCDR3 of SEQ ID NO: 5, a LCDR1 of SEQ ID NO: 6, a LCDR2 of SEQ ID NO: 7, and a LCDR3 of SEQ ID NO: 8. 
     
     
         51 . The pharmaceutical formulation of  claim 50 , wherein the antibody comprises a HCVR of SEQ ID NO: 1 and a LCVR of SEQ ID NO: 2. 
     
     
         52 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 1. 
     
     
         53 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a LCVR having 90% sequence identity to SEQ ID NO: 2. 
     
     
         54 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a HCVR having 90% sequence identity to SEQ ID NO: 1 and a LCVR having 90% sequence identity to SEQ ID NO: 2. 
     
     
         55 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a heavy chain and light chain, wherein the heavy chain comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 9 and 11. 
     
     
         56 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a heavy chain and light chain, wherein the heavy chain comprises an amino acid sequence of SEQ ID NO: 9. 
     
     
         57 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a heavy chain and light chain, wherein the heavy chain comprises an amino acid sequence of SEQ ID NO: 11. 
     
     
         58 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a heavy chain and light chain, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 10. 
     
     
         59 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a heavy chain/light chain comprising amino acid sequences selected from the group consisting of SEQ ID NOs: 9/10 and 11/10. 
     
     
         60 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a heavy chain/light chain comprising amino acid sequences of SEQ ID NOs: 9/10. 
     
     
         61 . The pharmaceutical formulation of any one of  claims 1 - 51 , wherein the antibody comprises a heavy chain/light chain comprising amino acid sequences of SEQ ID NOs: 11/10. 
     
     
         62 . A pharmaceutical formulation of any one of  claims 1 - 61 , wherein said formulation is contained in a container. 
     
     
         63 . The pharmaceutical formulation of  claim 62 , wherein the container is a vial. 
     
     
         64 . The pharmaceutical formulation of  claim 63 , wherein the vial is 10 mL Type 1 clear glass vial. 
     
     
         65 . The pharmaceutical formulation of  claim 62 , wherein the container is a syringe. 
     
     
         66 . The pharmaceutical formulation of  claim 65 , wherein the syringe is low-tungsten glass. 
     
     
         67 . The pharmaceutical formulation of  claim 62 , wherein the container is a prefilled syringe. 
     
     
         68 . The pharmaceutical formulation of  claim 62  contained in an autoinjector. 
     
     
         69 . A kit comprising a pharmaceutical formulation of any one of  claims 1 - 61 , a container, and instructions. 
     
     
         70 . The kit of  claim 69 , wherein the container is a glass vial. 
     
     
         71 . The kit of  claim 69 , wherein the container is a prefilled syringe. 
     
     
         72 . The kit of  claim 69 , wherein the container is an autoinjector.
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