Evaluation of an ester-linked immunosuppressive payload: A case study in understanding the stability and cleavability of ester-containing ADC linkers.

In spite of their value in prodrug applications, the use of esters in antibody-drug-conjugate (ADC) payloads and linkers has generally been avoided due to the ubiquitous and promiscuous nature of human esterases. ADCs generally have a long circulating half life (3-7 days) that makes them susceptible to esterase-mediated metabolism. Moreover, it is largely unclear whether lysosomal and cytosolic esterases cleave ester-containing linkers upon ADC internalization. Due to our interest in the targeted delivery of immune-modulators, our team has recently prepared a series of ester-linked dexamethasone ADCs. Herein, we report our studies of the functional activity of these ADCs, with a particular focus on their catabolism in various biological milieu. We found that esters are selectively but inefficiently cleaved upon cellular uptake, likely by cytosolic esterases. Lysosomal catabolism studies indicate that, in spite of the strong proteolytic activity, very little cleavage of ester-containing linkers occurs in the lysosome. However, ADCs bearing the ester-linked payloads are active in various immune-suppressive assays, suggesting that cytosolic cleavage is taking place. This was confirmed through LCMS quantitation of the payload following cell lysis. Finally, the stability of the ester linkage was evaluated in mouse and human plasma. We found, similar to other reports, there is a significant site-dependence on the cleavage. Esters attached at highly exposed sites, such as 443C, were rapidly cleaved in plasma while esters at more hindered sites, such at 334C, were not. Together, these results help to unravel the complexities of ester-incorporation into ADC linkers and pave a path forward for their utility in ADC applications.

Promoting quality improvement and achieving measurable change: the lead states initiative.

Along with the development of a national voluntary accreditation program for public health departments that holds quality improvement as its core goal, the application of quality improvement in public health has been gaining momentum. The 16 states participating in the Multi-State Learning Collaborative: Lead States in Public Health Quality Improvement (MLC) represent best practices in these activities. The MLC brings together partnerships in 16 US states to prepare for accreditation and implement quality-improvement practices. The grantee states are managing quality-improvement teams of local and state health department representatives and other partners. These teams, called mini-collaboratives, are working collectively to implement quality-improvement techniques to make measurable change on identified public health issues, or target areas. The work of the MLC seems to show that state and local-health departments and their key partners have the leadership, will and interest to apply quality improvement tools, and methods to solving public health problems and to raising the standard of public health practice. This article describes the history, current status, and lessons learned from the work of the MLC.