ADH-503

A new study has shown that immunotherapeutic responses in pancreatic ductal adenocarcinoma (PDAC) can be improved by agonism of integrin mol. expressed on cell surface of myeloid cell subsets.CD11b (integrin αM) is expressed on most myeloid cells and plays important part in myeloid cell migration and function, but to achieve CD11b blockade requires antagonist doses not tolerable in humans.To overcome this limitation, small mol., allosteric agonist of CD11b were developed.This agonist(ADH-503) results in a partially active CD11b conformation upon binding and suppresses myeloid cell infiltration by increasing adhesion to endothelium.Using various mouse models and ex vivo assays, effect of treatment with ADH-503 on immune responses and potential for immunotherapeutic synergy were assessed.CD11b agonism rapidly repolarizes TAMs to support antitumor immunity without compensatory mechanisms seen from other myeloid-targeting agents.The combination of CD11b-agonists with checkpoint immunotherapy leads to tumor regression, long-term survival and immunol. memory in PDAC models that are otherwise resistant to immunotherapy.This work identifies CD11b agonism as an alternative approach for reprograming innate immunity in PDAC.These studies have led to the development of ADH-503 for planned testing in human patients, although more studies are also needed to understand if the novel mechanisms of action observed in animals are similar in humans.

Agonism of CD11b overcomes myeloid cell–induced immunosuppression to render pancreatic cancer models responsive to checkpoint immunotherapy.