Monitoring Inflammatory Cytokine Levels in Kidney Transplant Patients (KTx Pts) with Chronic Antibody Mediated Rejection (cABMR) Treated with Clazakizumab (CLZ, Humanized Anti-IL-6 Monoclonal Antibody)
1Transplant Immunology Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA, 2Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, 3HLA Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA
Meeting: 2019 American Transplant Congress
Abstract number: A179
Keywords: Humanized antibodies, Inflammation, Monitoring, Renal function
Session Information
Date: Saturday, June 1, 2019
Session Name: Poster Session A: Biomarkers, Immune Monitoring and Outcomes
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall C & D
*Purpose: IL-6 is a pro-inflammatory cytokine involved in KTx rejection. A clinical trial to improve cABMR using CLZ in HLA-sensitized KTx Pts is underway. Inhibition of IL-6/IL-6 receptor (R) signaling could reduce inflammatory cytokines induced by IL-6, and improve cABMR. Here, we measured cytokine levels pre- and post-CLZ in Pts w/ cABMR.
*Methods: Archived sera obtained pre- & at Day (D) 90 and D180 post-CLZ (25mg SC, monthly) from 7 KTx Pts w/ cABMR were submitted for IL-6, IL-10, IFNγ, TNFα, IL-17A, IL-2 and IL-1β Luminex assay. Possible interference of CLZ with IL-6 detection was tested in vitro by addition of CLZ (0-200µg/ml) to IL-6 solution (50 and 1000pg/ml). Serum C-reactive protein (CRP) levels and estimated glomerular filtration rate (eGFR) monitored routinely were analyzed.
*Results: There was no interference of CLZ with IL-6 detection by Luminex. IL-6 levels significantly increased at D90 (1400±651, p=0.001) and D180 (1349±651, p=0.001) post- vs. pre-CLZ (11±15). Considering nearly significant reduction of CRP at D180 post- vs. pre-CLZ (0.2±0.1 vs.1.3±1.3µg/ml, p=0.07) in all pts, high levels of IL-6 detected were likely CLZ-bound IL-6, with no signaling capability via the IL-6R. Of 7 Pts, 6 (86%), 4 (57%), 3 (43%), 3 (43%), 2 (29%), 1 (14%) & 1 (14%) showed higher IL-10, IL-6, TNFα, IFNγ, IL-17A, IL-2 & IL-1β levels (pg/mL) pre-CLZ, respectively, than normal, suggesting an ambient state of inflammation. IL-10 significantly decreased at D180 post-CLZ (4.8±7.0 vs. 11.0±8.0, p=0.02), and IL-17A (2.5±5.3 vs. 3.6±7.0, p=0.13), IL-2 (0.8±1.9 vs. 1.1±2.3, p=0.13) and IFNγ (6.3±13.2 vs. 8.2±16.6, p=0.21) tended to decrease, suggesting an overall reduction in inflammation post-CLZ. IL-1β and TNFα levels did not significantly change. eGFR was stable during the 6-month study (45±7 vs. 44±6 mL/min/1.73 M2, p=0.5).
*Conclusions: 1. CLZ does not interfere with IL-6 detection by Luminex. 2. Most Pts w/ cABMR exhibit high levels of IL-6, IL-10, TNFα and IFNγ. 3. CLZ efficiently blocks IL-6/IL-6R signaling, resulting in reduction of cytokine and CRP levels, suggesting improvement of inflammation. This may contribute to stabilized eGFR observed in Pts w/ cABMR. A larger study with longer follow up is required for confirming the findings.
To cite this abstract in AMA style:
Ge S, Petrosyan A, Chu M, Ammerman N, Vo A, Jordan SC, Zhang X, Toyoda M. Monitoring Inflammatory Cytokine Levels in Kidney Transplant Patients (KTx Pts) with Chronic Antibody Mediated Rejection (cABMR) Treated with Clazakizumab (CLZ, Humanized Anti-IL-6 Monoclonal Antibody) [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/monitoring-inflammatory-cytokine-levels-in-kidney-transplant-patients-ktx-pts-with-chronic-antibody-mediated-rejection-cabmr-treated-with-clazakizumab-clz-humanized-anti-il-6-monoclonal-antibody/. Accessed August 4, 2020.« Back to 2019 American Transplant Congress