Stabilized aqueous antibody compositions
Inventors
Jezek, Jan • Casy, Guy • Derham, Barry Kingston • Royle, Nikki
Assignees
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Publication Number
US-10532098-B2
Publication Date
2020-01-14
Expiration Date
Abstract
The present invention provides an aqueous solution comprising an antibody protein at a concentration of at least about 10 mg/mL and an oligomer of ethyleneimine, wherein the number of repeating units of ethyleneimine (n) in the oligomer is in the range n=2-12.
Core Innovation
The invention concerns an aqueous solution comprising an antibody protein at a concentration of at least about 10 mg/mL and an oligomer of ethyleneimine having a number of repeating units (n) in the range consisting of 2 to 12. The aqueous solution is substantially free of a buffer with a pKa within 1 unit of the pH of the solution.
The antibody protein is selected from trastuzumab, rituximab, infliximab, a fusion protein comprising an active protein domain fused to one or more immunoglobulin Fc fragments, and certolizumab pegol. The ethyleneimine oligomer may be linear or branched and may include PEG/mPEG-derivatized oligomers and oligomers with bridging groups.
Representative embodiments describe aqueous formulations together with antibody proteins including rituximab and certolizumab pegol, and effects on protein aggregation and stability are assessed. Aggregation control is evaluated by SEC using HMWS species and by visual precipitation, with reduced aggregation rates and improved visual clarity reported for selected ethyleneimine oligomers relative to controls and reference formulations.
Claims Coverage
The independent claim set is centered on one independent claim. The claim coverage requires an aqueous solution with a high antibody concentration together with an ethyleneimine oligomer of defined repeating units (n = 2 to 12), and further constrains the solution by requiring that it is substantially free of a buffer whose pKa is within 1 unit of the solution pH. Dependent claims further refine the formulation by specifying particular antibody proteins and narrowing the identity and derivatization of the ethyleneimine oligomer; additional dependent claims broaden scope to packaged pharmaceutical compositions suitable for administration.
High-concentration aqueous antibody with ethyleneimine oligomer
An aqueous solution comprising an antibody protein at a concentration of at least about 10 mg/mL and an oligomer of ethyleneimine, wherein the number of repeating units of ethyleneimine (n) is in the range consisting of 2 to 12.
Buffer pKa separation constraint
The aqueous solution is substantially free of a buffer with a pKa within 1 unit of the pH of the solution.
Selected antibody protein scope
The antibody is trastuzumab, rituximab, infliximab, a fusion protein comprising an active protein domain fused to one or more immunoglobulin Fc fragments, or certolizumab pegol.
Weight ratio constraint of antibody to oligomer
The aqueous solution has a weight ratio (wt/wt) of antibody protein to oligomer of ethyleneimine of at least 10.
Quantitative pH range
The aqueous solution has a pH in the range 5 to 7.5.
Specific ethyleneimine oligomer identity
The aqueous solution uses an ethyleneimine oligomer that is triethylenetetramine.
PEG or mPEG derivatized ethyleneimine oligomer
The ethyleneimine oligomer is derivatized with one or more PEG or mPEG groups.
Packaged pharmaceutical composition for administration
A packaged pharmaceutical composition suitable for administration includes the aqueous solution of claim 1.
Across the independent claim and its dependents, the inventive core is a high-concentration aqueous antibody solution combined with an ethyleneimine oligomer (n = 2 to 12) while maintaining a buffer pKa separation from the solution pH. Claim coverage then narrows the antibody to specified proteins and fusion proteins and further constrains formulation parameters and oligomer identity, including triethylenetetramine and PEG/mPEG derivatized oligomers, with additional coverage for packaged pharmaceutical compositions suitable for administration.
Stated Advantages
Reduces aggregation, including high molecular weight species (HMWS) and visible aggregates/particulates.
Improves visual clarity for the antibody formulations.
Reduces viscosity increase during storage.
Reduces undesired fragmentation while maintaining favorable toxicity expectations.
Shows ethyleneimine/PEI size-dependent cytotoxicity in HEK293 and Vero cells.
PEGylated derivatives show reduced cytotoxicity compared to non-PEGylated ethyleneimine/PEI.
Documented Applications
Packaged pharmaceutical compositions suitable for administration that include the aqueous solution of the claims.
Formulation and stability testing of rituximab (MabThera) aqueous formulations using oligomers of ethyleneimine, with aggregation control assessed by SEC (%HMWS) and visual precipitation.
Formulation and stability testing of certolizumab pegol (Cimzia) in aqueous backgrounds with ethyleneimine oligomers, with effects on protein aggregation assessed by SEC and visual precipitation.
Cytotoxicity assessment of ethyleneimine/PEI sized species in HEK293 and Vero cells, and comparison of PEGylated derivatives versus non-PEGylated derivatives.
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