Issue: January / February 2022

Antibody drug conjugates have evolved enormously from their first inception. The linker, while devoid of pharmaceutical activity, has been recognized to play a major role in the safety and efficacy of the whole ADC system. Therefore, great efforts have been spent to improve the pharmacological and biological properties of this fundamental part of ADC. Nevertheless, this has come at the expense of molecular complexity of the linker-toxin, which are now very large molecules, with tens of defined stereocenters, very flexible structures and highly hydrophilic functional groups. The technical issues, and the demanding timeframes of innovators to get to the BLA, require a modern approach for the chemical process development, very different that for small molecules. Quality by Design to prioritize the issues to address, extensive use of preparative HPLC as main control strategy, tangential flow filtration and lyophilization for recovery are the keys to the successful development and production of the most recent linker-payloads.

The pharmaceutical sector, uniquely carries out extensive testing of their products on human subjects. This testing provides data that allows toxicologists to develop safe limits for occupational exposure. However, ultra-high potent pharmaceuticals, with exposure limits below 10 ng/m3 provide challenges by pushing the containment technology and the verification of this technology to the limits of what is achievable.