Protein formulation

• US 9,308,257 B2
• Filed: 11/26/2008
• Issued: 04/12/2016
• Est. Priority Date: 11/28/2007
• Status: Active Grant

• Current Assignee: Medimmune LLC (Astrazeneca PLC)
• Original Assignee: Medimmune LLC (Astrazeneca PLC)
• Inventors: Shah, Ambarish, Hammond, Scott, Sharma, Monika S. Sr.
• Primary Examiner(s): Kim, Yunsoo
• Application Number:
  US12/744,745
• Publication Number:
  US 20100303827A1
• Time in Patent Office: 2,694 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/507 Comprising a combination of two or more separate antibodies
• CPC Class Codes: A61K 39/39591 Stabilisation, fragmentation
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/06 Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/2803 against the immunoglobulin superfamily
• CPC Class Codes: C07K 16/2809 against the T-cell receptor (TcR)-CD3 complex
• CPC Class Codes: C07K 2317/31 multispecific

Abstract

The present invention provides stable lyophilized formulations of bispecific antibodies or fragments thereof.

Claims

1. A liquid pharmaceutical formulation comprising between about 25 μ

g/ml and about 250 μ

g/ml of a single chain bispecific antibody comprising a first and a second binding domain, wherein the first binding domain specifically binds CD3 T cell surface antigen; and

wherein the formulation comprises between about 5 mM and about 125 mM citrate, between about 100 mM and about 300 mM lysine, between about 10% and about 20% trehalose, and between about 0.01% and about 1% Polysorbate 80, and has a pH of between 5.0 and about 8.0.

2. The formulation of claim 1, wherein the first binding domain comprises the amino acid sequence of residues 283-525 of SEQ ID NO:

5.

3. The formulation of claim 1, wherein the second binding domain specifically binds an antigen selected from the group consisting of CD 19, CD20, CD22, EphA2, EphA4, INFR, ICOS, Ep-CAM, CEA, and IL-5 receptor.

4. The formulation of claim 3, wherein the second binding domain comprises the amino acid sequence of residues 28-277 of SEQ ID NO:

5.

5. The formulation of claim 3, wherein the bispecific antibody comprises the amino acid sequence of residues 28-525 of SEQ ID NO:

5.

16. The formulation of claim 1, wherein the formulation comprises about 55 micrograms/ml of a single chain bispecific tandemly arranged antibody or a fragment thereof, about 25 mM citrate, about 200 mM lysine, about 15% trehalose dihydrate and about 0.1% Polysorbate 80, and has a pH of about 7.0.

18. The formulation of claim 1, wherein the formulation comprises between about 10 and about 100 micrograms/ml of a single chain bispecific tandemly arranged antibody or a fragment thereof.

19. The formulation of claim 1, wherein the formulation comprises between about 50 and about 55 micrograms/ml of a single chain bispecific tandemly arranged antibody or a fragment thereof.

20. The formulation of claim 1, wherein the formulation comprises between about 10% and about 15% trehalose dihydrate.

21. The formulation of claim 1, wherein the formulation comprises between about 15% and about 20% trehalose dihydrate.

22. The formulation of claim 1, wherein the bispecific antibody is a a single chain bispecific tandemly arranged antibody or a fragment thereof.

6. A lyophilized pharmaceutical formulation comprising between about 25 μ

g/ml and about 250 μ

g/ml of a single chain bispecific antibody comprising a first and a second binding domain, wherein the first binding domain specifically binds CD3 T cell surface antigen; and

wherein the formulation comprises between about 5 mM and about 125 mM citrate, between about 100 mM and about 300 mM lysine, between about 0.01% and about 1% Polysorbate 80, and has a pH of between 5.0 and about 8.0.

7. The formulation of claim 6, wherein the first binding domain comprises the amino acid sequence of residues 283-525 of SEQ ID NO:

5.

8. The formulation of claim 6, wherein the second binding domain specifically binds an antigen selected from the group consisting of CD 19, CD20, CD22, EphA2, EphA4, INFR, ICOS, Ep-CAM, CEA, and IL-5 receptor.

9. The formulation of claim 8, wherein the second binding domain comprises the amino acid sequence of residues 28-277 of SEQ ID NO:

5.

10. The formulation of claim 8, wherein the bispecific antibody comprises the amino acid sequence of residues 28-525 of SEQ ID NO:

5.

11. A liquid reconstituted pharmaceutical formulation comprising between about 25 μ

g/ml and about 250 μ

g/ml of a single chain bispecific antibody comprising a first and a second binding domain, wherein the first binding domain specifically binds CD3 T cell surface antigen; and

wherein the formulation comprises between about 5 mM and about 125 mM citrate, between about 100 mM and about 300 mM lysine, between about 10% and about 20% trehalose, and between about 0.01% and about 1% Polysorbate 80, and has a pH of between 5.0 and about 8.0.

12. The formulation of claim 11, wherein the first binding domain comprises the amino acid sequence of residues 283-525 of SEQ ID NO:

5.

13. The formulation of claim 11, wherein the second binding domain specifically binds an antigen selected from the group consisting of CD 19, CD20, CD22, EphA2, EphA4, INFR, ICOS, Ep-CAM, CEA, and IL-5 receptor.

14. The formulation of claim 13, wherein the second binding domain comprises the amino acid sequence of residues 28-277 of SEQ ID NO:

5.

15. The formulation of claim 13, wherein the bispecific antibody comprises the amino acid sequence of residues 28-525 of SEQ ID NO:

5.

17. The formulation of claim 11, wherein the formulation comprises about 55 micrograms/ml of a single chain bispecific tandemly arranged antibody, about 25 mM citrate, about 200 mM lysine, about 15% trehalose dihydrate and about 0.1% Polysorbate 80, and has a pH of about 7.0.