Multivalent linkers: A growing trend in antibody-drug conjugate development

Over the last 25 years, antibody-drug conjugates (ADCs) have evolved from a novelty to a well-established and clinically validated tool for cancer treatment. Most ADCs are prepared by conjugating one payload per site via linear linkers. However, when conjugation is performed at a single position or a higher drug-to-antibody ratio (DAR) is desired, it becomes necessary to conjugate multiple drug moieties per site. This requires the use of multivalent linkers, which can be either low-molecular-weight branched structures or polymers. Several ADCs based on these linkers have reached clinical trials, and branched linkers are now being actively explored for preparing highly promising dual-payload conjugates. In this review, we comprehensively examine various multivalent linker architectures and explore the interplay between linker-payload design, conjugation strategies, and ADC properties and activity. We also evaluate the unique challenges associated with multivalent ADC linkers, such as increased local hydrophobicity and hindered payload release, as well as strategies for overcoming these hurdles. Further, we provide a future outlook for multivalent linker technologies, considering current trends in the rapidly evolving field of ADC development.