MGN1703 - structure of agonist determines cellular responses to TLR9 activation

DNA-based TLR9 agonists are potent activators of immune cell populations and the immune system. In a recent phase II clinical IMPACT trial MGN1703 as maintenance treatment of patients with metastatic colorectal carcinoma improved progression-free survival compared to placebo. Here we compare MGN1703 to ProMune(R) with respect to cytokine secretion patterns and activation of immune cells. We also explore structure-function relationship through exchange and comparison of the CG-motif environments of ProMune(R) and MGN1703. The superior clinical efficacy and toxicity profiles of MGN1703 are most likely due to its covalently closed dumbbell-shaped conformation and lack of PTO-modification. Systematic comparison of MGN1703 with the single-stranded, PTO-modified ProMune(R) in human PBMC cultures shows that -- besides CG-motifs -- also the structure of the agonist determines it's function in TLR9-dependent immune cell activation. However, MGN1703, representing a new class of TLR9 agonists in principle, may likely be detected also by other cellular DNA-sensors.