A Rationally Engineered Hyperactive Actin‐Resistant DNase1‐Fc Fusion Protein Ameliorates Autoimmune Glomerulonephritis

Abstract

Loss of B cell tolerance and generation of autoreactive anti‐nuclear antibodies are hallmarks of systemic lupus erythematosus (SLE) and lupus nephritis. Lupus nephritis is characterized by glomerular and tubulointerstitial inflammation often initiated by the renal glomerular deposition of anti‐nuclear immune complexes which trigger subsequent activation of complement, macrophages/monocytes and other innate inflammatory cells. The mechanism of anti‐nuclear immunoglobulin accumulation and clearance in lupus nephritis pathogenesis remains largely uncharacterized. Here, we show that innate immune activation in the NZB/W F1 mouse model and in human lupus nephritis biopsies rapidly reduces DNase1 expression in renal cortex proximal tubular cells. To overcome the loss of endogenous DNase1, we treated lupus‐prone mice with a hyperactive actin resistant variant of DNase1 with improved catalytic activity against nucleic acid‐IgG immune complexes and acceptable in vivo pharmacokinetics. Hyperactive DNase1‐Fc fusion protein ameliorates nephritis in a murine model of lupus nephritis and reduces immune complex deposition/complement fixation. Taken together, our data suggest that the loss of renal DNase1 through TLR signaling or other innate immune activation impairs clearance of autoreactive anti‐nuclear immune complex deposits in the kidney to promote nephritis progression. Our findings provide a therapeutic rationale for using an engineered DNase1‐Fc as a potential therapeutic approach in lupus nephritis.Support or Funding InformationAll authors are current or previous employees of Genentech, Inc.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.