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

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.

Strategies for UF/DF-Based Impurity Removal in the Post-conjugation Purification of Antibody–Drug Conjugates

“…Spiking studies with small-molecule impurities are also routinely employed by the majority (also, 83%) of companies, which represents a consideration for ADCs that differentiates from mAb development. As discussed in the preceding paper from the WG, fate-and-purge studies can be a valuable tool to bolster the scientific justification of a small-molecule impurity control strategy for ADCs, by providing experimental data to substantiate (or refute) paper-based assessments of the effectiveness of impurity removal by UF/DF. A quarter of respondents (25%) indicated that they perform membrane reuse studies during ADC UF/DF process characterization, consistent with the earlier result above showing that membrane reuse is not common in the clinical supply space,…”

“…9 The preceding paper from the WG presented results and analysis from a wide-ranging survey of IQ Consortium member companies, covering this topic along with a number of other aspects of drug-linker and ADC development. 10 One of the survey questions asked companies how many operations, and of which type, they typically use to purify the crude ADC following the conjugation step. All responding companies stated that they used ultrafiltration/diafiltration (UF/DF), and for the majority of companies (73%) this was the only purification method employed.…”

“…A key area of focus for the WG has been to define control strategy principles for small-molecule impurities arising from both the chemical synthesis of the drug-linker and the subsequent conjugation reaction with the mAb, as this topic for ADCs is not explicitly covered in existing regulatory guidelines for small molecules and biologic drugs . The preceding paper from the WG presented results and analysis from a wide-ranging survey of IQ Consortium member companies, covering this topic along with a number of other aspects of drug-linker and ADC development . One of the survey questions asked companies how many operations, and of which type, they typically use to purify the crude ADC following the conjugation step.…”

Considerations for Starting Material Designation for Drug-Linkers in Antibody–Drug Conjugates

“…This current paper is the third in a new series of publications from the WG. The preceding two papers presented the following: (1) results from a survey of IQ Consortium member companies on numerous aspects of drug-linker development and (2) a deeper dive into post-conjugation purification operations …”

“…7 This current paper is the third in a new series of publications from the WG. The preceding two papers presented the following: (1) results from a survey of IQ Consortium member companies on numerous aspects of druglinker development 8 and (2) a deeper dive into postconjugation purification operations. 9 The survey asked member companies about designation and justification of drug-linker starting materials (SMs), and the results revealed little consistency among companies.…”