Drug-Linkers in Antibody–Drug Conjugates: Perspective on Current Industry Practices
Paul G. Bulger, David A. Conlon, Russell D. Cink, Lara Fernandez‐Cerezo, Qunying Zhang, Srinath Thirumalairajan, Thomas Raglione, Ruiting Liang, Jinsheng Zhou, Arun Chalgeri
Abstract
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.