Discovery and Optimization of a STING Agonist Platform for Application in Antibody Drug Conjugates

While STING agonists have proven to be effective preclinically
as anti-tumor agents, these promising results have yet to be translated
in the clinic. A STING agonist antibody–drug conjugate (ADC)
could overcome current limitations by improving tumor accessibility,
allowing for systemic administration as well as tumor-localized activation
of STING for greater anti-tumor activity and better tolerability.
In line with this effort, a STING agonist ADC platform was identified
through systematic optimization of the payload, linker, and scaffold
based on multiple factors including potency and specificity in both
in vitro and in vivo evaluations. The platform employs a potent non-cyclic
dinucleotide STING agonist, a cleavable ester-based linker, and a
hydrophilic PEG8-bisglucamine scaffold. A tumor-targeted ADC built
with the resulting STING agonist platform induced robust and durable
anti-tumor activity and demonstrated high stability and favorable
pharmacokinetics in nonclinical species.