Experiencing the evolution of ADC payloads towards extremely complex molecules from a development and manufacturing perspective – A CDMO opinion
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 AGE OF ADCs
The year 2021 saw the approval of the eleventh Antibody Drug Conjugate (ADC) by the US Food and Drug Administration: Zynlonta. The recent approvals and more than one hundred and fifty of other ADCs currently undergoing clinical trials, demonstrate the great interest and work ongoing in this field (1-3).
Nevertheless, literature and clinical trials results shows that the success for an ADC is a consequence of correct selection of its components: the monoclonal antibody, the cytotoxic drug and the linker (4). In this, the history of Mylotarg is a good example of the difficulties behind the development of an ADC: approved in 2000, withdrawn from market in 2010 and then re-approved in 2017 with a different dose regime.
EVOLUTION OF ADCs
Researchers are pursuing new epitopes to enlarge the applicability of ADCs to new tumor classes, but aside the search for new targets for mAb, for which development strategies and industrial production technologies are well established, a great load of research is currently devoted to the linker - payload part of the ADC (5).