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

Tofacilitate subcutaneous dosing, biotherapeuticsneed to exhibit properties that enable high-concentration formulationand long-term stability in the formulation buffer. For antibody-drugconjugates (ADCs), the introduction of drug-linkers can lead to increasedhydrophobicity and higher levels of aggregation, which are both detrimentalto the properties required for subcutaneous dosing. Herein we showhow the physicochemical properties of ADCs could be controlled throughthe drug-linker chemistry in combination with prodrug chemistry ofthe payload, and how optimization of these combinations could affordADCs with significantly improved solution stability. Key to achievingthis optimization is the use of an accelerated stress test performedin a minimal formulation buffer.