Background/Purpose:

Spleen tyrosine kinase (SYK) mediates immunoreceptor signaling in hematopoietic cells important in the initiation and progression of systemic lupus erythematosus (SLE), including those from the B cell receptor (BCR) and Fc receptors (FcR) in B cells, monocytes, and dendritic cells¹. SLE is a heterogeneous autoimmune disease characterized by immune system hyperactivation leading to the production of autobodies and immune attack on multiple organs including skin, kidney, and others. SYK inhibition is expected to reduce adaptive as well as innate immune cell activation, and immune complex signaling, which are all key drivers in SLE pathology. This work characterizes the disease modifying activity and mechanism of action of SYK inhibition in two spontaneous in vivo murine models of lupus: the MRL/lpr and NZB/W F1 models and estimates the required target engagement needed for efficacy in SLE. In vitro studies focused on GS-9876, a novel, highly selective, once-daily SYK inhibitor that Gilead Sciences is developing for the chronic treatment of rheumatoid arthritis and SLE. In vivo studies were performed with SYKi-A, a structurally similar analog that exhibits better mouse pharmacokinetics. In vitro properties of SYKi-A are similar to those of GS‑9876.

Methods:

SYK inhibition was characterized in biochemical and cellular assays demonstrating potency and selectivity. To determine the disease-modifying activity of SYK inhibition, SYKi-A was tested in the MRL/lpr and NZB/W F1 models of lupus. Efficacy was determined by measuring anti-dsDNA titers, proteinuria, renal histopathology, and survival. Splenic cell populations were analyzed by flow cytometry to measure changes in lymphocyte subsets and activation status following SYK inhibition. An in vitro murine whole blood pSYK assay and PK was used to estimate target engagement and correlate with efficacy.

Results:

SYK inhibitors potently inhibited BCR-induced B cell signaling and activation, BCR and CD40 co-stimulation-induced B cell proliferation, and immune-complex stimulated cytokine production in human macrophages. In the murine models of SLE, SYKi-A decreased anti-dsDNA antibody titers, prevented the progression of proteinuria, reduced B cell activation, altered B cell subsets, and reduced T cell activation. In the NZB/W F1 model, there was a significant reduction of renal SYK immunolabeling, decreased renal inflammation, and improved glomerular morphology concurrent with decreased proteinuria, and increased survival. Average SYK target coverage of >50% was required for significant changes in disease activity.

Conclusion:

Building on previously reported studies^2,3, these results further support the role of SYK in SLE pathogenesis, provide important information about target coverage needed for efficacy in the murine model, and identify the therapeutic potential for SYK inhibition by GS-9876 in human SLE.

1. Mitchell, SA, et al. J Med Chem 2014;57;3856−3873; 2. Bahjat et al, Arth & Rheum 2008;58(5); 1433-1444; 3. Deng et al. Arth & Rheum 2010;62(7); 2086-2092

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/inhibition-of-spleen-tyrosine-kinase-improves-renal-pathology-and-reduces-lymphocyte-activation-in-the-mrllpr-and-nzbnzw-murine-models-of-systemic-lupus-erythematosus/