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Antibody–drug conjugates (ADCs) are becoming increasingly established as a mainstream therapeutic modality for oncology, with more than a dozen compounds already approved for marketing and hundreds of clinical trials ongoing. ADCs are a hybrid construct combining, via chemical conjugation, biologic (monoclonal antibody) and small-molecule (drug-linker) moieties into a single drug substance. They also present significant technical and strategic challenges for chemistry, manufacturing, and controls (CMC). Within the IQ Consortium, a Working Group (WG) on Small Molecule Considerations for ADC Development has been established to assess current biopharmaceutical industry practices specific to the drug-linker moiety and to provide recommendations for future development. This paper presents results and analysis from a survey of IQ member companies covering a variety of drug-linker topics, including control of small-molecule impurities, starting material (SM) designation, considerations for clinical versus commercial stages, and interactions with regulatory agencies. Survey data, perspectives, and forward-looking proposals from the WG are provided. Additionally, this work provides the foundation for a subsequent series of papers from the WG, which will go into more depth on (1) post-conjugation purification operations, (2) a proposal for alignment on SM selection, and (3) post-approval synthesis changes and comparability. The overall goals are to offer visibility and insight into the current state of drug-linker development for ADCs and to provide tools to facilitate discussions between companies and regulatory agencies on future directions.
Bulger et al. (Thu,) studied this question.