Date: Monday, June 3, 2019
Session Time: 4:30pm-6:00pm
Presentation Time: 4:42pm-4:54pm
Location: Ballroom B
*Purpose: We have reported successful use of TCZ for cABMR treatment in HLA-sensitized KTx Pts. CLZ is 3-120 times more potent than TCZ in IL-6/IL-6R signaling inhibition in vitro. A clinical trial to improve cABMR using CLZ in sensitized KTx Pts is now underway. IL-6/sIL-6R complex initiates more pathogenic trans-signaling pathways via interactions with gp130 expressed on various tissues including allografts, and sgp130 is a selective inhibitor of this pathway. Here, we measured sIL-6R & sgp130 levels pre- & post-treatment in CLZ- & TCZ-treated Pts w/ cABMR to determine potential effects on trans-signaling pathway.
*Methods: Plasma samples obtained pre- & at 6-month post-CLZ (25mg SQ, monthly) from 8 Pts and post-TCZ (8mg/kg, monthly) from 11 Pts were submitted for sgp130 & sIL-6R Luminex assays. IL-6 & C-reactive protein (CRP) levels were also tested in CLZ-treated Pts.
*Results: IL-6 levels significantly increased post- vs. pre-CLZ (1541±649 vs. 12±14pg/ml, p=0.001). Near significant reduction of CRP post-CLZ (1.3±1.2 vs. 0.3±0.1µg/ml, p=0.07) in all Pts indicates that high levels of IL-6 detected post-CLZ were mostly CLZ-bound IL-6, and the IL-6/gp130 signaling was efficiently blocked by CLZ. Although the difference was small, sgp130 levels reached near significant differences post- vs. pre-CLZ (292±52 vs. 260±75ng/ml, p=0.07), while there was no significant change post-TCZ (289±51 vs. 270±46ng/ml, p=0.4). In contrast, sIL-6R levels significantly increased post- vs. pre-TCZ (114±69 vs. 59±14ng/ml, p=0.03), while there was no significant change post-CLZ (80±17 vs. 78±14ng/ml, p=0.7).
*Conclusions: Although both drugs block IL-6/IL-6R signaling, CLZ and TCZ may differentially affect IL-6/IL-6R/sgp130 biology, which may result in different risk for progression of cABMR. Significant increase of sIL-6R post-TCZ may contribute to rejection observed after cessation of TCZ, via enhancing trans-signaling. Near significant increases of sgp130 post-CLZ may reduce trans-signaling, potentially reducing pathogenicity to allografts. A larger study with longer follow-up is required for confirming this possibility.
To cite this abstract in AMA style:Shin B, Ge S, Petrosyan A, Ammerman NF, Vo AA, Jordan SC, Toyoda M. Clazakizumab (CLZ, Anti-IL-6 Antibody) and Tocilizumab (TCZ, Anti-IL-6 Receptor [r] Antibody) Treatments Differentially Affect IL-6/IL-6R Signaling by Modulating Soluble IL-6R (sIL-6R) and gp130 (sgp130) in Kidney Transplant Patients (KTx Pts) Treated for Chronic Antibody-Mediated Rejection (cABMR) [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/clazakizumab-clz-anti-il-6-antibody-and-tocilizumab-tcz-anti-il-6-receptor-r-antibody-treatments-differentially-affect-il-6-il-6r-signaling-by-modulating-soluble-il-6r-sil-6r-and-gp130-sgp1/. Accessed March 8, 2021.
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