Granted Patent
B2
US 12,404,344 · App. 17/893,515 · Granted Sep 2, 2025
Low-viscosity, high concentration evolocumab formulations and methods of making the same
Inventors:
Christopher James Sloey (Newbury Park, CA); Sekhar Kanapuram (Thousand Oaks, CA); Huanchun Cui (Aesch, CH); Chio Mui Chan (Hillsboro, OR); Elaheh Binabaji (Los Angeles, CA)
Assignee:
AMGEN INC.
C07K16/40C07K1/34C07K16/065A61K9/0019A61K39/3955A61K39/39591A61K47/183C07K1/16C07K1/36C07K16/22C07K2317/565C07K2317/76C07K2317/90
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Abstract
Provided herein are formulations of PCSK9-binding polypeptides, such as those comprising evolocumab, that comprise N-acetyl arginine and have reduced viscosities when compared to formulations lacking N-acetyl arginine. Provided herein are also methods of formulating such compositions that are advantageous in that they conserve certain components. Such formulations comprising PCSK9-binding polypeptides can be administered to patients to treat and/or prevent PCSK9-related diseases, conditions, and disorders.
Claims (31)
1. A method of formulating a therapeutic polypeptide, comprising
a. a first concentration step, wherein the polypeptide in a first solution is concentrated;
b. a first solution exchange step, wherein the concentrated polypeptide in the first solution is exchanged into a second solution comprising N-acetyl arginine using diafiltration;
c. a second concentration step, wherein the polypeptide in the second solution is concentrated;
d. a second solution exchange step, wherein the polypeptide in the concentrated second solution is exchanged into a third solution comprising N-acetyl arginine using diafiltration; and
e. a third concentration step, wherein the polypeptide in the third solution is concentrated;
wherein the therapeutic polypeptide comprises (A) an antibody:
heavy chain having an amino acid sequence of SEQ ID NO:1 and an antibody light chain having an amino acid sequence of SEQ ID NO:2; or
(B) an antibody heavy chain comprising the following complementarity determining regions (CDRs): a heavy chain CDR1 that is a CDR1 in SEQ ID NOs:14 or 16; a heavy chain CDR2 that is a CDR2 in SEQ ID NOs:14 or 16; a heavy chain CDR3 that is a CDR3 in SEQ ID NOs:14 or 16, and
an antibody light chain comprising the following CDRs: a light chain CDR1 that is a CDR1 in SEQ ID NOs:15 or 17; a light chain CDR2 that a CDR2 in SEQ ID NOs:15 or 17; and a light chain CDR3 that a CDR3 in SEQ ID NOs:15 or 17.
2. The method of claim 1 , wherein the therapeutic polypeptide comprises the antibody heavy chain having the amino acid sequence of SEQ ID NO:1 and the antibody light chain having the amino acid sequence of SEQ ID NO:2.
3. The method of claim 1 , wherein the:
a. antibody heavy chain comprises a complementarity determining region (CDR) 1 CDR2, and CDR3 having the amino acid sequence of SEQ ID NOs: 7, 8, and 9, respectively; and
b. the antibody light chain comprises a CDR1, CDR2, and CDR3 having the amino acid sequence of SEQ ID NOs: 4, 5, and 6, respectively.
4. The method of claim 1 , wherein before the third concentration step, the temperature of the solution comprising the polypeptide is increased from 25° C. to 37° C.
5. The method of claim 1 , wherein in the first concentration step, the therapeutic polypeptide concentration is increased from 3-fold to 7-fold.
6. The method of claim 1 , wherein in the second concentration step, the therapeutic polypeptide concentration is increased from 2-fold to 4-fold from the first concentration step.
7. The method of claim 1 , wherein in the third concentration step, the therapeutic polypeptide concentration is increased from 1.5-fold to 2-fold from the second concentration step.
8. The method of claim 1 , wherein the therapeutic polypeptide has a final concentration that is at least 19-fold to 20-fold more concentrated than the initial concentration of the therapeutic polypeptide.
9. The method of claim 1 , wherein the concentration steps comprise fed-batch ultrafiltration.
10. The method of claim 1 , wherein the second or third solution has a pH from 4.8 to 6.9.
11. The method of claim 1 , wherein in the first and second solution exchange steps, a diafiltration membrane is used having at least one characteristic selected from the group consisting of:
a. mesh openings that are greater than 350 μm but less than or equal to 500 μm;
b. an open area that is greater than 32% but less than or equal to 36% of the membrane area;
c. a mesh count of less than 16.2 n/cm but greater than or equal to 12.2 n/cm;
d. a wire diameter that is greater than 270 μm but less than or equal to 340 μm;
e. a basis weight that is greater than 160 g/m 2 but less than or equal to 180 μg/m 2 ;
f. a thickness greater than 515 μm but less than or equal to 610 μm;
g. a membrane load of greater than 1138.1 g/m 2 but less than or equal to 1919.3 g/m 2 ; and
h. a maximum feed pressure of 60 psi.
12. The method of claim 1 , wherein surfactant is added to the third solution after being concentrated.
Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Jan 31, 2023
From: SLOEY, CHRISTOPHER JAMES; KANAPURAM, SEKHAR; CUI, HUANCHUN; CHAN, CHIO MUI; BINABAJI, ELAHEH
To: AMGEN INC.
Reel/Frame 062583/0043 →
Continuity (3)
Provisional Application
62462266
· Feb 22, 2017
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