Antibody-drug conjugates (ADCs), also known as armed antibodies, are positioned to be a significant source of next-generation oncolytic therapies. There has been explosive growth in ADC R&D, especially since the development and subsequent marketing approval of Mylotarg (gemtuzumab ozogamicin; withdrawn from market in 2010), Adcetris (brentuximab vedotin), and Kadcyla (ado-trastuzumab emtansine). Estimates place the global ADC market at $10 billion annually after 2024 with seven to 10 new commercial ADC launches projected in the next decade.

ADCs marry the selective targeting properties of antibodies with the potency of highly cytotoxic small molecules. The antibody targets and adheres to a selected antigenic cell-surface receptor, ideally only expressed on the target cancer cell. Once an ADC binds to its target cell, the cell internalizes the ADC through endocytosis, and the cytotoxic payload is then released in the lysosomal cellular compartment to provide precise, selective delivery to cancerous cells.

The development of ADCs brings many challenges, however. Multiple disciplines across drug development must engage to successfully discover, develop, evaluate and eventually manufacture a therapeutically relevant ADC. To illustrate, large macromolecular ADCs have a complex architecture whose assembly, manufacture, and analysis presents challenges for organizations without significant experience in biological conjugation, optimization, and the development of the payload-linker (PL; a component used for antibody attachment and subsequent release of the small molecule payload).

For many companies, outsourcing this component of ADC development may make sense. In this article, we will focus on the complexities of developing ADCs with an emphasis on the nature of the PL.

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Antibody-Drug Conjugates: Catalysts for Chemistry - Genetic Engineering & Biotechnology News