Abstract
A defining feature of systemic lupus erythematosus (SLE) is loss of tolerance to self-DNA, and deficiency of DNASE1L3, the main enzyme responsible for chromatin degradation in blood, is also associated with SLE. This association can be found in an ultrarare population of pediatric patients with DNASE1L3 deficiency who develop SLE, adult patients with loss-of-function variants of DNASE1L3 who are at a higher risk for SLE, and patients with sporadic SLE who have neutralizing autoantibodies against DNASE1L3. To mitigate the pathogenic effects of inherited and acquired DNASE1L3 deficiencies, we engineered a long-acting enzyme biologic with dual DNASE1/DNASE1L3 activity that is resistant to DNASE1 and DNASE1L3 inhibitors. Notably, we found that the biologic prevented the development of lupus in Dnase1–/–Dnase1L3–/– double-knockout mice and rescued animals from death in pristane-induced lupus. Finally, we confirmed that the human isoform of the enzyme biologic was not recognized by autoantibodies in SLE and efficiently degraded genomic and mitochondrial cell–free DNA, as well as microparticle DNA, in SLE plasma. Our findings suggest that autoimmune diseases characterized by aberrant DNA accumulation, such as SLE, can be effectively treated with a replacement DNASE tailored to bypass pathogenic mechanisms, both genetic and acquired, that restrict DNASE1L3 activity.
Authors
Paul R. Stabach, Dominique Sims, Eduardo Gomez-Bañuelos, Sandra Zehentmeier, Kris Dammen-Brower, Andrew Bernhisel, Sophia Kujawski, Sam G. Lopez, Michelle Petri, Daniel W. Goldman, Ethan R. Lester, Quan Le, Tayyaba Ishaq, Hana Kim, Shivani Srivastava, Deepika Kumar, Joao P. Pereira, Kevin J. Yarema, Fotios Koumpouras, Felipe Andrade, Demetrios T. Braddock
Figure 2
Overview of the design, production, purification, and pharmacodynamics of optimized biologics.
