NF-κB inducing kinase is a therapeutic target for systemic lupus erythematosus

Hans D. Brightbill, Eric Suto, Nicole Blaquiere, Nandhini Ramamoorthi, Swathi Sujatha-Bhaskar, Emily B. Gogol, Georgette M. Castanedo, Benjamin T. Jackson, Youngsu C. Kwon, Susan Haller, Justin Lesch, Karin Bents, Christine Everett, Pawan Bir Kohli, Sandra Linge, Laura Christian, Kathy Barrett, Allan Jaochico, Leonid M. Berezhkovskiy, Peter W. Fan, Zora Modrusan, Kelli Veliz, Michael J. Townsend, Jason DeVoss, Adam R. Johnson, Robert Godemann, Wyne P. Lee, Cary D. Austin, Brent S. McKenzie, Jason A. Hackney, James J. Crawford, Steven T. Staben, Moulay H. Alaoui Ismaili, Lawren C. Wu and Nico Ghilardi ()
Additional contact information
Hans D. Brightbill: Genentech
Eric Suto: Genentech
Nicole Blaquiere: Genentech
Nandhini Ramamoorthi: Genentech
Swathi Sujatha-Bhaskar: Genentech
Emily B. Gogol: Genentech
Georgette M. Castanedo: Genentech
Benjamin T. Jackson: Genentech
Youngsu C. Kwon: Genentech
Susan Haller: Genentech
Justin Lesch: Genentech
Karin Bents: Evotec, Inc.
Christine Everett: Genentech
Pawan Bir Kohli: Genentech
Sandra Linge: Evotec, Inc.
Laura Christian: Genentech
Kathy Barrett: Genentech
Allan Jaochico: Genentech
Leonid M. Berezhkovskiy: Genentech
Peter W. Fan: Genentech
Zora Modrusan: Genentech
Kelli Veliz: Genentech
Michael J. Townsend: Genentech
Jason DeVoss: Genentech
Adam R. Johnson: Genentech
Robert Godemann: Evotec, Inc.
Wyne P. Lee: Genentech
Cary D. Austin: Genentech
Brent S. McKenzie: Genentech
Jason A. Hackney: Genentech
James J. Crawford: Genentech
Steven T. Staben: Genentech
Moulay H. Alaoui Ismaili: Genentech
Lawren C. Wu: Genentech
Nico Ghilardi: Genentech

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract NF-κB-inducing kinase (NIK) mediates non-canonical NF-κB signaling downstream of multiple TNF family members, including BAFF, TWEAK, CD40, and OX40, which are implicated in the pathogenesis of systemic lupus erythematosus (SLE). Here, we show that experimental lupus in NZB/W F1 mice can be treated with a highly selective and potent NIK small molecule inhibitor. Both in vitro as well as in vivo, NIK inhibition recapitulates the pharmacological effects of BAFF blockade, which is clinically efficacious in SLE. Furthermore, NIK inhibition also affects T cell parameters in the spleen and proinflammatory gene expression in the kidney, which may be attributable to inhibition of OX40 and TWEAK signaling, respectively. As a consequence, NIK inhibition results in improved survival, reduced renal pathology, and lower proteinuria scores. Collectively, our data suggest that NIK inhibition is a potential therapeutic approach for SLE.

Date: 2018
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DOI: 10.1038/s41467-017-02672-0

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