ValCitGlyPro-dexamethasone antibody conjugates selectively suppress the activation of human monocytes.

Glucocorticoids (GCs) are effective in treating autoimmune and inflammatory disorders but come with significant side effects, many of which are mediated by non-immunological cells. Therefore, there is rapidly growing interest in using antibody drug conjugate (ADC) technology to deliver GCs specifically to immune cells, thereby minimizing off-target side effects. Herein, we report the study of anti-CD11a, anti-CD38, and anti-TNFα ADCs to deliver dexamethasone to monocytes.

Synthesis and Optimization of 1-Substituted Imidazo[4,5-]quinoline TLR7 Agonists.

TLR7 agonists have significant therapeutic potential in a variety of oncology and autoimmune applications. We recently reported a potent TLR7 selective agonist that could be delivered by antibody-drug conjugate (ADC) technology to elicit potent anticancer activity. Herein we report synthetic chemistry and structure-activity relationship studies to develop TLR7 agonists with improved potency for next-generation ADC efforts.

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.