The persistence of extracellular DNA, one of the central pathogenic mechanisms implicated in SLE, might be the result of a rare mutation in DNASE1L3 enzyme leading to elimination of functional enzyme from the circulation and phenotypically manifesting as monogenic lupus or more commonly due to a pathogenic variant of DNASE1L3 {R206C(rs35677470)} reducing its plasma concentration by 80% or due to the presence of neutralising antibodies against DNASE1L3.

In this study, authors have created a long acting, bioavailable, glycopolished enzyme biologic LBme (Lead biologic, mouse equivalent) with DNASE1L3 activity on DNASE1 backbone resulting in potent DNASE which is resistant to inhibitors of both DNASE1 and DNASE1L3. The efficacy of this biologic was tested in genetic (Dnase1-/-Dnase1l3-/- double knock out mice) and pristane induced mouse models of lupus.

In the double knock out mouse model, the biologic was able to prevent the formation of autoantibodies by weekly dosing as long as dosing was maintained (up to an year) and it also prevented death after disease phenotype acceleration by pristane. In pristane stimulated strains of C57BL/6 WT mice a therapeutic dosing strategy was adopted after the onset of first symptoms, and it prevented death in the treatment arm as compared to vehicle arm.

Human isoform of LBme was demonstrated to degrade extracellular DNA in samples from both healthy controls and SLE patients and the activity was maintained even after adding directly into the whole blood demonstrating no inhibition of biologic should occur in circulation after dosing.