Drug-Linkers in Antibody-Drug Conjugates: Perspective on Current Industry Practices

Antibody-drug conjugates (ADCs) are becoming increasinglyestablished as a mainstream therapeutic modality for oncology, withmore than a dozen compounds already approved for marketing and hundredsof 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 forchemistry, manufacturing, and controls (CMC). Within the IQ Consortium,a Working Group (WG) on Small Molecule Considerations for ADC Developmenthas been established to assess current biopharmaceutical industrypractices specific to the drug-linker moiety and to provide recommendationsfor future development. This paper presents results and analysis froma survey of IQ member companies covering a variety of drug-linkertopics, 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 papersfrom the WG, which will go into more depth on (1) post-conjugationpurification operations, (2) a proposal for alignment on SM selection,and (3) post-approval synthesis changes and comparability. The overallgoals are to offer visibility and insight into the current state ofdrug-linker development for ADCs and to provide tools to facilitatediscussions between companies and regulatory agencies on future directions.