From R&D to Clinical Supplies

In the development of new antibody drug conjugates (ADCs), the activities performed by discovery groups typically focus on the rapid and comprehensive screening of many conjugates to find the ones with the desired efficacy and safety profiles. These conjugates are typically prepared in a combinatorial approach whereby various monoclonal antibodies (mAbs) for a specific target, linkers, and payloads are combined. These efforts usually rely on efficient screening methodologies and high-throughput tools, such as solid phase conjugation and purification arrays. The development of robust and consistent processes suitable to produce the selected candidate for clinical trials is typically not a priority for discovery. Many of the ADCs in the clinic today are based on one of two conjugation technologies and associated linker-payloads (LP). The traditional cysteine conjugation technology utilizes an auristatin as a payload with a cleavable or noncleavable linker. The other technology is based on conjugating a maytansinoid or calicheamicin based payload to lysine residues on the mAb. Selecting a single conjugation chemistry and one linker-payload for all ADCs, where only the mAb is changing based on the target, allows the building of platform processes and methods. This leads to efficient process and analytical methods development and a reduction in the work required to develop processes suitable for the production of GMP clinical trial material. However, a growing number of ADCs are being developed to further reduce toxicity and improve efficacy utilizing novel linkers and payloads as well as new conjugation technologies. These payloads include DNA damaging cytotoxins such as DNA alkylating or cross-linking agents and cytotoxic payloads derived from natural products with a novel mechanism of action. New conjugation chemistries include site-specific technologies based on non-native amino acids, inserting unpaired cysteine residues and enzymatically mediated conjugation methods. As a result, developing processes for each new conjugation technology and a combination of new linker and payload may require significant resources for process and methods development as well as scale-up. Therefore, aligning discovery and development (analytical and process development) efforts for clinical trial material production becomes important. To facilitate the technology transfer from Discovery to Process Development, a systematic approach of early engagement and evaluation of the mAb, linker–payload, and ADC should be established. This includes the harmonization of analytical methods and processes used for production of ADCs for preclinical screening experiments, including exploratory toxicology studies. This paper will review methodologies for technology transfer from Discovery to Development, approaches to process and methods development for a diverse portfolio of ADC technologies, as well as process scale-up and specification setting. Case studies for different conjugation chemistries and linker–payloads will be reviewed, including conventional cysteine, lysine, and site-specific technologies.