Antibody–drug conjugates (ADCs) in development target many indications beyond cancer and consist of a multitude of different types of components. Integrated development and manufacturing capabilities are essential to bringing these promising yet complex therapeutics to market.
Moving Beyond Oncology
ADCs are constructs that allow the targeted delivery of a payload molecule — via its linkage — to an engineered antibody that binds to a specific cell type. The first wave of ADCs focused on oncology indications, because the relevant binding sites are more uniquely expressed on cancer cells, but there are tremendous opportunities in other disease areas for both traditional ADCs and their derivatives.
Conjugates are being developed to treat inflammation, pain, Alzheimer’s, Parkinson’s, diabetes and many other diseases and disorders. These new drug candidates may comprise antibodies or other protein components (e.g., Fc fragments, highly engineered protein carriers) conjugated to peptides, nucleic acids, other proteins, polysaccharides or immunomodulators. Their development is driven both by the identification of novel targets and advances in linker payload technologies.
Early Phase Challenges
Drivers of failure for existing ADCs in development involve payload shedding before delivery at the target site and non-specific antibody binding, typically through Fcγ receptors. Abzena works to understand the target, the desired expression levels, the sensitivity to different payload mechanisms, mechanistic interactions — and other key information — using bioanalytical assays to ensure that the right conjugation approach is incoporated from the start.
Development and Manufacturing Hurdles
Because ADCs consist of three distinct components (antibody, payload and linker), their development and manufacture require expertise in biologic production, small molecule synthesis and conjugation technology. While cell line engineering and antibody production are more straightforward, payload preparation may involve 12–25 complex synthetic organic reactions, often needing to establish and maintain multiple chiral centers. Cytotoxic payloads require specialized equipment and facilities to ensure protection of workers and the environment. The conjugation step must be robust and reproducible, generating the product with a consistent payload: antibody ratio. In addition, no single platform approach can be applied — multiple conjugation technologies and approaches, and purification methods are used that often must be tailored to the specific ADC.
Importance of Analytics
Successful ADC design and development is driven by access to a suite of robust analytical methods — in vitro cytotoxicity, characterization, serum stability, mechanistic and functional assays. Together, they underpin the successful design of developable and manufacturable ADCs. In-depth analytical evaluation of antibodies, linkers, payloads and their various combinations is crucial for effective lead candidate selection. Abzena also uses translational assays that correlate well with in vivo PK and efficacy to eliminate ADCs that lack desirable performance properties.
Although each of the three elements of an ADC requires its own manufacturing process and supporting validated analytical methods, their development and implementation must be coordinated. Having capabilities that span all three areas allows Abzena to bring expertise on the manufacturing side into the R&D and early process development stages for rapid process optimization. Our integrated approach, from gene to GMP, allows simultaneous work on various aspects of a project, significantly reducing the whitespace typically present in ADC development programs.
Global project management supported by site-specific project management teams ensures seamless project progression and avoidance of delays and costs associated with the transfer of technology from one company to another. Project teams are staffed with highly experienced personnel that support each project from the early stages to commercial production, adding value to each project throughout its lifetime. Experts involved in the development process also bring their knowledge and understanding to manufacturing campaigns. As a result, teams are able to troubleshoot process-related issues before moving to commercial production — and rapidly find solutions to any issues that arise during manufacturing.
Abzena is also positioned to support ADC production from lab to clinical scale, with a range of specialized equipment and facilities (such as high containment capabilities for cytotoxic payloads and solvent handling and processing for conjugation processes). Single-use systems are employed (where feasible) at manufacturing scale to eliminate the need for cleaning validation between projects. Much of our equipment is directly scalable, from process development to manufacturing, minimizing the change for unexpected issues during scale-up.