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US-12617853-B2 - Low pH pharmaceutical composition comprising T cell engaging antibody constructs

US12617853B2US 12617853 B2US12617853 B2US 12617853B2US-12617853-B2

Abstract

The present disclosure provides a low pH pharmaceutical composition comprising (a) an antibody constructs comprising a first domain binding to a target cell surface antigen, a second domain binding to a second antigen and preferably a third domain, which is a specific Fc modality, (b) at least one buffer agent, (c) at least one saccharide, and (d) at least one surfactant; and wherein the pH of the pharmaceutical composition is in the range of 3.5 to 6.

Inventors

  • Arnold McAuley
  • Pavan GHATTYVENKATAKRISHNA
  • Jeff Abel
  • Joon Huh
  • Cornelius Pompe
  • Sekhar Kanapuram
  • Michael Treuheit
  • Bharadwaj Jagannathan

Assignees

  • AMGEN RESEARCH (MUNCIH) GMBH
  • AMGEN INC.

Dates

Publication Date
20260505
Application Date
20180202

Claims (17)

  1. 1 . A liquid pharmaceutical composition comprising (a) an antibody construct comprising at least: a first domain comprising an Fv fragment having the VL and VH domains of a single arm of an antibody which binds to a target cell surface antigen, wherein the target cell surface antigen is a tumor antigen selected from MSLN, DLL3, FLT3, BCMA, PSMA, CD33, and CD19, and wherein the first domain has an isoelectric point (pl) in the range of 4 to 9.5; a second domain comprising an Fv fragment having the VL and VH domains of a single arm of an antibody which binds to an extracellular epitope of CD3 of the human and/or Macaca CD3 epsilon (CD3ε) chain, wherein the VL domain comprises an amino acid sequence comprising at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 13 and the VH domain comprises an amino acid sequence comprising at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 14, and wherein the second domain has a pl in the range of 8.5 to 9.5; and a third domain comprising two polypeptide monomers, each monomer comprising a hinge, a CH2 domain and a CH3 domain, wherein each of said polypeptide monomers of the third domain comprises an amino acid sequence that is at least 90% identical to a sequence selected from the group consisting of: SEQ ID NOs: 17-24, wherein said two polypeptide monomers are fused to each other via a peptide linker, and wherein the third domain has a pl in the range of 5.5 to 7.5; (b) at least one buffer agent selected from the group consisting of: acetate, glutamate, citrate, succinate, tartrate, maleate, and phosphate, or any combination thereof, wherein the at least one buffer agent is present at a concentration in the range of 5 to 100 mM; (c) at least one saccharide selected from the group consisting of: sucrose, trehalose, mannitol, and sorbitol, wherein the at least one saccharide is present at a concentration in the range of 1 to 15% m/V; and (d) at least one surfactant selected from the group consisting of: polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and poloxamer 188, wherein the at least one surfactant is present at a concentration in the range of 0.004 to 0.5% m/V; wherein the composition does not comprise sodium chloride, and wherein the pH of the pharmaceutical composition is in the range of 4.0 to 5.0.
  2. 2 . The composition of claim 1 , wherein the antibody construct is a single chain antibody construct.
  3. 3 . The composition of claim 1 , wherein each of said polypeptide monomers of the third domain comprises the amino acid sequence of any one of SEQ ID NOs: 17-24.
  4. 4 . The composition of claim 1 , wherein the antibody construct comprises in an amino to carboxyl order: (a) the first domain; (b) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-3; (c) the second domain; (d) a peptide linker having an amino acid sequence selected from the group consisting of SEQ ID NOs: 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 NOs: 5, 6, 7 and 8; and (g) the second polypeptide monomer of the third domain.
  5. 5 . The composition of claim 1 , wherein the pH of the composition is 4.2.
  6. 6 . The composition of claim 1 , having an osmolarity in the range of 150 to 500 mOsm.
  7. 7 . The composition of claim 1 , further comprising an excipient selected from the group consisting of: one or more polyols; and one or more amino acids.
  8. 8 . The composition of claim 7 , wherein the excipient is present in the concentration range of 0.1 to 15% m/V.
  9. 9 . The composition of claim 1 , wherein the buffer agent is 10 mM acetate or glutamate, wherein the saccharide is 9% m/V sucrose, wherein the surfactant is 0.01% m/V polysorbate 80, and wherein the pH of the liquid pharmaceutical composition is 4.2.
  10. 10 . The composition of claim 1 , wherein the antibody construct is present at a concentration in the range of 0.1 to 8 mg/ml.
  11. 11 . A solid pharmaceutical composition, obtained by lyophilizing the composition of claim 1 .
  12. 12 . A method for therapeutically treating or ameliorating a proliferative disease, an immunological disease or a viral disease comprising administering an effective amount of the composition of claim 1 to a subject in need thereof.
  13. 13 . The method of claim 12 , wherein the composition is administrated parenterally.
  14. 14 . The method of claim 12 , wherein the composition is administered (i) 1, 2, 3, 4, 5, 6 or 7 times per week, (ii) 1, 2, 3, 4, 5 or 6 times every two weeks, (iii) 1 or 2 times per month, (iv) 1 or 2 times every two months, or (v) 1 time per week.
  15. 15 . The pharmaceutical composition of claim 1 , wherein the second domain comprises a single chain antibody fragment (scFv) comprising an amino acid sequence comprising at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 15.
  16. 16 . A liquid pharmaceutical composition comprising (a) an antibody construct comprising at least: a first domain comprising an amino acid sequence selected from SEQ ID NOs: 202 and 1409, and wherein the first domain has an isoelectric point (pl) in the range of 4 to 9.5; a second domain comprising an Fv fragment having the VL and VH domains of a single arm of an antibody which binds to an extracellular epitope of CD3 of the human and/or Macaca CD3 epsilon (CD3c) chain, wherein the VL domain comprises an amino acid sequence comprising at least 90% sequence identity to the amino acid sequence of SEQ ID NO: 13 and the VH domain comprises an amino acid sequence comprising at least 85% sequence identity to the amino acid sequence of SEQ ID NO: 14, and wherein the second domain has a pl in the range of 8.5 to 9.5; and a third domain comprising two polypeptide monomers, each monomer comprising a hinge, a CH2 domain and a CH3 domain, wherein each of said polypeptide monomers of the third domain comprises an amino acid sequence that is at least 90% identical to a sequence selected from the group consisting of: SEQ ID NOs: 17-24, wherein said two polypeptide monomers are fused to each other via a peptide linker, and wherein the third domain has a pl in the range of 5.5 to 7.5; (b) at least one buffer agent selected from the group consisting of: acetate, glutamate, citrate, succinate, tartrate, maleate, and phosphate, or any combination thereof, wherein the at least one buffer agent is present at a concentration in the range of 5 to 100 mM; (c) at least one saccharide selected from the group consisting of: sucrose, trehalose, mannitol, and sorbitol, wherein the at least one saccharide is present at a concentration in the range of 1 to 15% m/V; and (d) at least one surfactant selected from the group consisting of: polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and poloxamer 188, wherein the at least one surfactant is present at a concentration in the range of 0.004 to 0.5% m/V; wherein the composition does not comprise sodium chloride, and wherein the pH of the pharmaceutical composition is in the range of 4.0 to 5.0.
  17. 17 . A liquid pharmaceutical composition comprising (a) an antibody construct comprising an amino acid sequence selected from SEQ ID NOs: 205 and 1411; (b) at least one buffer agent selected from the group consisting of: acetate, glutamate, citrate, succinate, tartrate, maleate, and phosphate, or any combination thereof, wherein the at least one buffer agent is present at a concentration in the range of 5 to 100 mM; (c) at least one saccharide selected from the group consisting of: sucrose, trehalose, mannitol, and sorbitol, wherein the at least one saccharide is present at a concentration in the range of 1 to 15% m/V; and (d) at least one surfactant selected from the group consisting of: polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and poloxamer 188, wherein the at least one surfactant is present at a concentration in the range of 0.004 to 0.5% m/V; wherein the composition does not comprise sodium chloride, and wherein the pH of the pharmaceutical composition is in the range of 4.0 to 5.0.

Description

BACKGROUND Protein-based pharmaceuticals are among the fastest growing therapeutic agents in (pre)clinical development and as commercial products. In comparison with small chemical drugs, protein pharmaceuticals have high specificity and activity at relatively low concentrations, and typically provide for therapy of high impact diseases such as various cancers, auto-immune diseases, and metabolic disorders (Roberts, Trends Biotechnol. 2014 July; 32(7):372-80, Wang, Int J Pharm. 1999 Aug. 20; 185(2):129-88). Protein-based pharmaceuticals, such as recombinant proteins, can now be obtained in high purity when first manufactured due to advances in commercial scale purification processes. However, proteins are only marginally stable and are highly susceptible to degradation, both chemical and physical. Chemical degradation refers to modifications involving covalent bonds, such as deamidation, oxidation, cleavage or formation of new disulfide bridges, hydrolysis, isomerization, or deglycosylation. Physical degradation includes protein unfolding, undesirable adsorption to surfaces, and aggregation. Dealing with these physical and chemical instabilities is one of the most challenging tasks in the development of protein pharmaceuticals (Chi et al., Pharm Res, Vol. 20, No. 9, September 2003, pp. 1325-1336, Roberts, Trends Biotechnol. 2014 July; 32(7):372-80). Interesting protein-based pharmaceuticals include bispecific molecules such as BiTE®×(bispecific T cell engager) antibody constructs which are recombinant protein constructs made from two flexibly linked antibody derived binding domains. One binding domain of BiTE® antibody constructs is specific for a selected tumor-associated surface antigen on target cells; the second binding domain is specific for CD3, a subunit of the T cell receptor complex on T cells. By their particular design BiTE® antibody constructs are uniquely suited to transiently connect T cells with target cells and, at the same time, potently activate the inherent cytolytic potential of T cells against target cells. An important further development of the first generation of BiTE® antibody constructs (see WO 99/54440 and WO 2005/040220) developed into the clinic as AMG 103 and AMG 110 was the provision of bispecific antibody constructs binding to a context independent epitope at the N-terminus of the CD3E chain (WO 2008/119567). BiTE® antibody constructs binding to this elected epitope do not only show cross-species specificity for human and Callithrix jacchus, Saguinus oedipus or Saimiri sciureus CD3ε chain, but also, due to recognizing this specific epitope instead of previously described epitopes for CD3 binders in bispecific T cell engaging molecules, do not unspecifically activate T cells to the same degree as observed for the previous generation of T cell engaging antibodies. This reduction in T cell activation was connected with less or reduced T cell redistribution in patients, which was identified as a risk for side effects. Antibody constructs as described in WO 2008/119567 are likely to suffer from rapid clearance from the body; thus, whilst they are able to reach most parts of the body rapidly, and are quick to produce and easier to handle, their in vivo applications may be limited by their brief persistence in vivo. Prolonged administration by continuous intravenous infusion was used to achieve therapeutic effects because of the short in vivo half life of this small, single chain molecule. However, such continuous intravenous infusions are classified as inconvenient for the patients and, thus, in case of more convenient alternative treatment approaches, hamper the election of the compound demonstrated to be more efficient in the treatment of the respective disease. Hence, Applicant has introduced bispecific therapeutics that retain similar therapeutic efficacy that have a format which is straightforward to produce, and that have favorable pharmacokinetic properties, including a longer half-life. An increased half-life is generally useful in in vivo applications of immunoglobulins, especially antibodies and most especially antibody fragments of small size. Approaches described in the art to achieve such effect comprise the fusion of the small bispecific antibody construct to larger proteins, which preferably do not interfere with the therapeutic effect of the BiTE® antibody construct. Examples for such further developments of bispecific T cell engagers comprise bispecifc Fc-molecules e.g. described in US 2014/0302037, US 2014/0308285, WO 2014/144722, WO 2014/151910 and WO 2015/048272. Protein aggregation represents a major event of physical instability of proteins and occurs due to the inherent tendency to minimize the thermodynamically unfavorable interaction between the solvent and hydrophobic protein residues. It is particularly problematic because it is encountered routinely during refolding, purification, sterilization, shipping, and storage processes. Aggregation can occur even