Stable antibody formulation

Patent metadata

Field	Value
Publication number	US-12337199-B2
Application number	US-202117155432-A
Country	US
Kind code	B2
Filing date	Jan 22, 2021
Priority date	Jan 24, 2020
Publication date	Jun 24, 2025
Grant date	Jun 24, 2025

Abstract

The present disclosure provides stable pharmaceutical formulations comprising a human antibody that specifically binds to Ebola Virus (EBOV). In certain embodiments, the formulations contain, in addition to an anti-EBOV antibody, a buffer, an amino acid, a non-ionic surfactant, and a stabilizer. The pharmaceutical formulations of the present disclosure exhibit a substantial degree of antibody stability upon stress, for example, agitation during transport, and storage, for example, storage at temperatures greater than 40° C.

First claim

What is claimed is:

1. A stable liquid pharmaceutical formulation comprising:
(a) sucrose at a concentration from 10%±2% to 20%±4% w/v;
(b) a buffer comprising histidine at a concentration from 5 mM±1 mM to 20 mM±4 mM;
(c) an organic cosolvent comprising polysorbate at a concentration from 0.01%±0.005% to 0.5%±0.25% w/v; and
(d) at least one antibody which binds specifically to Ebola virus (EBOV) and comprises three heavy chain complementarity determining regions (CDRs) (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in a heavy chain variable region/light chain variable region (HCVR/LCVR) amino acid sequence pair selected from the group consisting of (i) SEQ ID NOs: 2/10, (ii) SEQ ID NOs: 20/28, and (iii) SEQ ID NOs: 38/46;
wherein the formulation comprises the following: (i), (ii), (iii), (i)+(ii), (i)+(iii), (ii)+(iii), or (i)+(ii)+(iii), at a total antibody concentration from 5 mg/mL±0.75 mg/mL to 250 mg/mL±37.5 mg/mL; and
wherein the formulation has a pH of 6.0±0.3; and
wherein the formulation maintains ADCC potency of at least about 90% in an ADCC bioassay and/or demonstrates that at least 90% of the antibody is the native species after storage at a temperature from about 40° C. to about 45° C. for no less than 20 days.

2. The pharmaceutical formulation of claim 1 , wherein the total antibody concentration is 50 mg/mL±7.5 mg/mL.

3. The pharmaceutical formulation of claim 1 , wherein the total antibody concentration is 100 mg/mL±15.0 mg/mL.

4. The pharmaceutical formulation of claim 1 , wherein the polysorbate is polysorbate 80.

5. The pharmaceutical formulation of claim 1 , comprising:
(a) from 10%±2% to 15%±3% w/v sucrose,
(b) from 5 mM±1 mM to 20 mM±4 mM histidine buffer,
(c) from 0.01%±0.005% to 0.5%±0.25% w/v polysorbate 80, and
(d) (i)+(ii)+(iii) in an amount of 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3.

6. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3;
wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10.

7. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3;
wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28.

8. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3;
wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

9. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3;
wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28.

10. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3;
wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

11. The pharmaceutical formulation of claim 1 comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3;
wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

12. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 50 mg/mL±7.5 mg/mL total antibody,
at pH 6.0±0.3;
wherein a first antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10, a second antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28, and a third antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

13. The pharmaceutical formulation of claim 1 , comprising:
(a) from 10%±2% to 15%±3% w/v sucrose,
(b) from 5 mM±1 mM to 20 mM±4 mM histidine buffer,
(c) from 0.01%±0.005% to 0.5%±0.25% w/v polysorbate 80, and
(d) (i)+(ii)+(iii) in an amount of 100 mg/mL±15 mg/mL total antibody,
at pH 6.0±0.3.

14. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 100 mg/mL±15 mg/mL total antibody,
at pH 6.0±0.3;
wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (i) SEQ ID NOs: 2/10.

15. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 100 mg/mL±15 mg/mL total antibody,
at pH 6.0±0.3;
wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (ii) SEQ ID NOs: 20/28.

16. The pharmaceutical formulation of claim 1 , comprising:
(a) 10%±2% w/v sucrose,
(b) 10 mM±2 mM histidine buffer,
(c) 0.1%±0.05% w/v polysorbate 80, and
(d) 100 mg/mL±15 mg/mL total antibody,
at pH 6.0±0.3;
wherein the antibody comprises three heavy chain CDRs (HCDR1, HCDR2 and HCDR3) and three light chain CDRs (LCDR1, LCDR2 and LCDR3) contained in the HCVR/LCVR amino acid sequence pair of (iii) SEQ ID NOs: 38/46.

17. The pharmaceutical formulation of cl

Assignees

• Regeneron Pharma

Inventors

• Cao Yuan
• Liu Dingjiang
• Xu Long

Classifications

• A61K47/26

  Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin · CPC title

• A61K47/22

  Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones · CPC title

• A61K39/42

  viral · CPC title

• A61P31/12 Primary

  Antivirals · CPC title

• C07K2317/94

  Stability, e.g. half-life, pH, temperature or enzyme-resistance · CPC title