Low ph pharmaceutical composition comprising t cell engaging antibody constructs

Abstract

The present invention provides a low pH pharmaceutical composition comprising (a) an antibody construct including a first domain for binding a target cell surface antigen, a second domain for binding a second antigen, and a third domain having a specific Fc morphology; (b) at least one buffer; (c) at least one sugar; and (d) at least one surfactant; wherein the pH of the pharmaceutical composition is in the range of 3.5 to 6.

Claims

1. A liquid pharmaceutical composition comprising: (a) an antibody construct comprising at least three domains, wherein: • The first domain binds a target cell surface antigen selected from DLL3 and CD19, comprising an amino acid sequence selected from SEQ ID NO:202 and 1409, and having an isoelectric point (pI) in the range of 4 to 9.5; • The second domain binds a second antigen, which is an extracellular antigenic determinant of the CD3 human and / or macaque CD3ε chain; and has a pI of 8 to 10; and • The third domain comprises two polypeptide monomers, each polypeptide monomer comprising a hinge, a CH2 domain and a CH3 domain, wherein the two polypeptide monomers are fused to each other via a peptide linker; (b) at least one buffer, wherein the at least one buffer is an acid selected from the group consisting of: acetate, glutamate, citrate, succinate, tartrate, maleate, and phosphate or combinations thereof; (c) At least one sugar selected from the group consisting of sucrose, trehalose and mannitol or combinations thereof; (d) at least one surfactant, wherein the at least one surfactant is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80 and poloxamer 188 or a combination thereof; wherein the pharmaceutical composition does not contain sodium chloride, and wherein the pH of the pharmaceutical composition is in the range of 4.0 to 5.

0.

2. The liquid pharmaceutical composition of claim 1, wherein the antibody construct is a single-chain antibody construct.

3. The liquid pharmaceutical composition of claim 1 or 2, wherein the third domain comprises, in the order of amino group to carboxyl group: hinge-CH2 domain-CH3 domain-linker-hinge-CH2 domain-CH3 domain.

4. A liquid pharmaceutical composition as claimed in claim 1 or 2, wherein each of the polypeptide monomers of the third domain has a sequence selected from the group consisting of SEQ ID NO: 17-24.

5. A liquid pharmaceutical composition as claimed in claim 1 or 2, wherein the CH2 domain comprises an intradomain cysteine ​​disulfide bridge.

6. A liquid pharmaceutical composition as claimed in claim 1 or 2, wherein the antibody construct comprises, in the order of amino to carboxyl,: (a) the first domain; (b) a peptide linker having an amino acid sequence selected from the group consisting of: SEQ ID NO: 1-3; (c) the second domain; (d) a peptide linker having an amino acid sequence selected from the group consisting of: SEQ ID NO: 1, 2, 3, 9, 10, 11 and 12; (e) the first polypeptide monomer of the third domain; (f) a peptide linker having an amino acid sequence selected from the group consisting of: SEQ ID NO: 5, 6, 7 and 8; and (g) the second polypeptide monomer of the third domain.

7. The liquid pharmaceutical composition of claim 1 or 2, wherein the antibody construct comprises an amino acid sequence selected from SEQ ID NO:205 and 1411.

8. The liquid pharmaceutical composition of claim 1 or 2, wherein the at least one buffer is present in a concentration range of 5 to 200 mM.

9. The liquid pharmaceutical composition of claim 1 or 2, wherein the at least one sugar is present at a concentration in the range of 1% to 15% (m / V).

10. The liquid pharmaceutical composition of claim 1 or 2, wherein the at least one surfactant is present at a concentration in the range of 0.004% to 0.5% (m / V).

11. The liquid pharmaceutical composition of claim 1 or 2 has an osmotic pressure in the range of 150 to 500 mOsm.

12. The liquid pharmaceutical composition of claim 1 or 2 further comprises an excipient selected from the group consisting of one or more polyols and one or more amino acids.

13. The liquid pharmaceutical composition of claim 12, wherein the one or more excipients are present in a concentration range of 0.1% to 15% (w / V).

14. A liquid pharmaceutical composition as claimed in claim 1 or 2, wherein the composition comprises (a) an antibody construct as claimed in any one of claims 1 to 13; (b) 10 mM glutamate or acetate; (c) 9% (m / V) sucrose or 6% (m / V) sucrose and 6% (m / V) hydroxypropyl-β-cyclodextrin; (d) 0.01% (m / V) polysorbate 80, and wherein the pH of the liquid pharmaceutical composition is 4.

2.

15. The liquid pharmaceutical composition of claim 1 or 2, wherein the antibody construct is present in a concentration range of 0.1 to 8 mg / ml.

16. A solid pharmaceutical composition which can be prepared by freeze-drying a liquid pharmaceutical composition as claimed in any one of claims 1 to 15.

17. A liquid pharmaceutical composition which can be prepared by reconstituted a solid pharmaceutical composition of claim 16 using a pharmaceutically acceptable liquid.

18. Use of a liquid pharmaceutical composition as claimed in any one of claims 1 to 17 for the preparation of a medicament for the treatment of proliferative diseases.

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