Optimization of Drug-Linker to Enable Long-term Storage of Antibody–Drug Conjugate for Subcutaneous Dosing

To
facilitate subcutaneous dosing, biotherapeutics
need to exhibit properties that enable high-concentration formulation
and long-term stability in the formulation buffer. For antibody–drug
conjugates (ADCs), the introduction of drug-linkers can lead to increased
hydrophobicity and higher levels of aggregation, which are both detrimental
to the properties required for subcutaneous dosing. Herein we show
how the physicochemical properties of ADCs could be controlled through
the drug-linker chemistry in combination with prodrug chemistry of
the payload, and how optimization of these combinations could afford
ADCs with significantly improved solution stability. Key to achieving
this optimization is the use of an accelerated stress test performed
in a minimal formulation buffer.