Understanding the Critical Role of Linkers in Advancing ADCs

“Since early ADC development efforts in the late 20th century, linker chemistry has advanced dramatically. An appropriate linker between an antibody and cytotoxic drug forms a specific and stable bridge, enabling precise delivery of the payload to tumor cells and subsequently ensuring selective release. Linkers also maintain ADC stability during preparation, storage, and systemic circulation.

“First- and second-generation ADCs used linkers that were unstable in the bloodstream, resulting in limited efficacy, severe side effects, and termination of several clinical trials. To address those challenges, third-generation ADCs incorporate more-stable linkers and leverage advanced conjugation technologies, designed with a well-defined drug:antibody ratio (DAR) (1). Such improvements have enhanced ADC safety and therapeutic performance significantly.

“Considering growing interest in ADCs, understanding how to design and select optimal chemical linkers is essential to developing safe and effective therapies. For ADCs to achieve both selectivity and potency, linkers must exhibit three critical properties:

• high stability in circulation to prevent premature release of cytotoxic payloads
• high water solubility to facilitate bioconjugation and prevent formation of inactive ADC aggregates
• efficient payload release to ensure effective cytotoxic-drug delivery at a tumor site.

“Examining those three factors provides an understanding of the role of linkers in ADC development and further insights into optimizing linker selection, ensuring stability, and contributing to the overall success of these groundbreaking therapies.”

Veranova’s Global VP of Chemical Development Operations, Will Sanders, recently contributed his expertise to a BioProcess International eBook that provides a technology update on the state of Antibody Drug Conjugates (ADCs).

Download the BioProcess International eBook to read the full article.

 

Reference:
(1) Riccardi F, et al. A Comprehensive Overview on Antibody–Drug Conjugates: From the Conceptualization to Cancer Therapy. Front. Pharmacol. 14, 2023: 1274088; https://doi.org/10.3389/fphar.2023.1274088.