AO-176 MOA
AO-176 Differentiated Mechanisms of Action
AO-176 has a highly differentiated mechanism of action versus other anti-CD47 approaches that simply block the SIRPα / CD47 interaction, the “Don’t eat me” mechanism for macrophages. In addition to blocking the SIRPα / CD47 interaction, AO-176 employs mechanisms such as direct tumor cell killing through Programmed Cell Death Type III and induction of Damage Associated Molecular Patterns (DAMPs) resulting in Immunogenic Cell Death. These mechanisms can be uniquely employed due to AO-176’s preferential binding to Tumor Cells vs. Normal Cells through contextual binding to the CD47 receptor only in the presence of integrin β1, as well as AO-176’s better binding and activity in low pH such as the tumor microenvironment.
AO-176 binds to CD47 contextually in the presence of integrin β1, resulting in preferential binding to tumor vs. normal cells. For clarity AO-176 does not bind integrin β1, rather it binds CD47, when complexed to integrin β1. Both integrin β1 and CD47 are expressed higher on tumor vs. normal cells and integrin β1 is not expressed on red blood cells which are negligibly bound by AO-176. Other monoclonal antibodies bind CD47 indiscriminately, resulting in antibody sink and conditions such as anemia and hemagglutination. In addition to integrin β1 contextual binding, AO-176 was engineered to bind better at acidic pH found in tumor microenvironments.
AO-176 blocks the SIRPα / CD47 interaction, known as the “Don’t eat me” mechanism, allowing macrophages to engulf and eliminate cancer cells.
AO-176 was designed to employ additional mechanisms such as direct killing through Programmed Cell Death Type III and induction of Damage Associated Molecular Patterns (DAMPs) resulting in Immunogenic Cell Death.