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.