George J Kahaly 1 , Marius Nicolae Stan 2 , Lara Frommer 1 , Peter Gergely 3 , Laurence Colin 4 , Ahmed Amer 5 , Imelda Schuhmann 3 , Pascal Espie 3 , James S Rush 3 , Craig Basson 4 , Yanling He 4 Show Affiliations »
Abstract
CONTEXT: The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD) by promoting autoreactive B-cell activation. OBJECTIVE: Evaluate efficacy and safety of a human, blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab, in hyperthyroid patients with GD. DESIGN: Open-label, phase II proof-of-concept study. SETTING: Multicenter. PATIENTS: Fifteen with GD. INTERVENTION: Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. MAIN OUTCOME MEASURES: Thyroid-related hormones and autoantibodies, plasma soluble CD40, free CD40 on B cells, soluble CXCL13, pharmacokinetics, and safety were assessed. RESULTS: The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients. Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P < 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. CONCLUSION: Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients. The potential therapeutic benefit of iscalimab should be further tested. © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
CONTEXT: The CD40 -CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves disease (GD ) by promoting autoreactive B-cell activation. OBJECTIVE: Evaluate efficacy and safety of a human , blocking, nondepleting anti-CD40 monoclonal antibody, iscalimab , in hyperthyroid patients with GD . DESIGN: Open-label, phase II proof-of-concept study. SETTING: Multicenter. PATIENTS : Fifteen with GD . INTERVENTION: Patients received 5 doses of iscalimab at 10 mg/kg intravenously over 12 weeks. MAIN OUTCOME MEASURES: Thyroid-related hormones and autoantibodies, plasma soluble CD40 , free CD40 on B cells, soluble CXCL13 , pharmacokinetics, and safety were assessed. RESULTS: The iscalimab intervention resulted in complete CD40 engagement for up to 20 weeks. A clinical response and biochemical euthyroidism was observed in 7 of 15 (47%) patients . Free and total triiodothyronine and thyroxine normalized in 7 patients who did not receive any rescue medication with antithyroid drugs (ATD), and 2/15 (13.3%) showed normal thyrotropin. Six (40%) patients required ATD. Four of 7 responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab ) significantly declined in all patients (mean 15.3 IU/L vs 4.0 IU/L, 66% reduction; P < 0.001) and TSH-R-Ab levels normalized in 4 (27%). Thyroperoxidase and thyroglobulin autoantibodies significantly decreased in responders. Iscalimab rapidly reduced serum CXCL13 concentrations (P < 0.001). Twelve (80.0%) patients reported at least 1 adverse event (AE). All treatment-related AE were mild or moderate and resolved by end of the study. CONCLUSION: Iscalimab was generally safe and clinically effective in a subgroup of hyperthyroid GD patients . The potential therapeutic benefit of iscalimab should be further tested. © Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
Entities: Chemical
Disease
Gene
Species
Keywords:
Graves hyperthyroidism; anti-CD40; iscalimab; monoclonal antibody
Year: 2020
PMID： 31512728 DOI： 10.1210/clinem/dgz013
Source DB: PubMed Journal: J Clin Endocrinol Metab ISSN： 0021-972X Impact factor: 5.958