Filterable duocarmycin-containing antibody-drug conjugate compositions and related methods
Inventors
VAN DEN HOEF, Carolus Johannes Edgar
Assignees
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Publication Number
US-12178881-B2
Publication Date
2024-12-31
Expiration Date
Abstract
Duocarmycin-based antibody-drug conjugates can be readily separated from non-conjugated duocarmycin linker-drug in a composition that contains a solvent system of water and acetonitrile and that has 30% to 60% acetonitrile.
Core Innovation
The invention relates to duocarmycin-containing antibody-drug conjugate compositions and a method for removing or reducing duocarmycin linker-drug impurities associated with an antibody-drug conjugate. The method comprises combining an aqueous solution or lyophilized product of an antibody-drug conjugate of formula (I), where Ab is an IgG antibody and L-D is a duocarmycin linker-drug, with a duocarmycin linker-drug in non-conjugated form represented by formula (IV).
The method uses a dilution medium comprising water, acetonitrile, and acid to form a filterable composition containing 30% to 60% (v/v) acetonitrile. Filtering is performed across a filter having a molecular weight cutoff within the range of 3 kDa to 50 kDa to form a filtrate, while the acetonitrile content enables filtration-driven separation and limits ADC leakage into the filtrate.
The described method is directed to producing a filtrate that is substantially free of duocarmycin-containing ADC, thereby enabling detection and quantitation of trace free duocarmycin linker-drug without interference from ADC. The workflows support sensitive analytical measurement, chromatographic isolation of duocarmycin linker-drug in non-conjugated form, and ADC batch release/approval based on predetermined linker-drug limits.
Claims Coverage
The independent claim coverage centers on three inventive features: a duocarmycin linker-drug ADC, a water/acetonitrile/acid filterable composition, and filtration through a defined molecular weight cutoff filter. Dependent coverage adds chromatographic isolation and measurement of non-conjugated duocarmycin linker-drug in the filtrate.
Duocarmycin linker-drug ADC of formula (I) with non-conjugated formula (IV)
An antibody-drug conjugate of formula (I) where Ab is an IgG antibody and L-D is a duocarmycin linker-drug, and the duocarmycin linker-drug in non-conjugated form is represented by formula (IV).
Filterable composition using water, acetonitrile, and acid with 30% to 60% (v/v) acetonitrile
A dilution medium that comprises water, acetonitrile, and acid to form a filterable composition wherein the filterable composition comprises 30% to 60% (v/v) of said acetonitrile.
Filtering through a 3 kDa to 50 kDa molecular weight cutoff filter to form a filtrate
Filtering the filterable composition across a filter having a molecular weight cutoff within the range of 3 kDa to 50 kDa to form a filtrate.
Chromatographic isolation and measuring non-conjugated duocarmycin linker-drug in the filtrate
Further separating the filtrate by chromatography to isolate duocarmycin linker-drug in non-conjugated form and measuring any amount of the non-conjugated linker-drug present in the filtrate.
Overall, the claims are directed to combining a duocarmycin linker-drug ADC with a water/acetonitrile/acid filterable composition containing 30% to 60% (v/v) acetonitrile, then filtering through a 3 kDa to 50 kDa molecular weight cutoff filter to produce a filtrate. The dependent coverage also includes chromatographic isolation and measurement of duocarmycin linker-drug in non-conjugated form in the filtrate.
Stated Advantages
Enables sensitive detection and quantitation of trace free duocarmycin linker-drug in the filtrate without interference from ADC.
Produces a filtrate substantially free of duocarmycin-containing ADC.
Provides filtration-driven separation of free duocarmycin linker-drug from the ADC while limiting ADC leakage into the filtrate.
Supports ADC batch release/approval workflows based on predetermined linker-drug limits.
Documented Applications
Quality control and release/approval workflow for ADC batches based on predetermined linker-drug limits.
Analytical measurement of trace free duocarmycin linker-drug, including non-conjugated linker-drug in the filtrate, using chromatographic analysis.
Preparation of a filtrate from a duocarmycin-containing ADC for ADC batch release/approval workflows.
Downstream chromatographic isolation and measurement of duocarmycin linker-drug in non-conjugated form in the filtrate.
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