scholarly journals A Novel Anti-Cd40 Monoclonal Antibody, Iscalimab, for Control of Graves’ Hyperthyroidism – A Proof-Of-Concept Trial

2019 ◽  
Author(s):  
G J Kahaly ◽  
M N Stan ◽  
L Frommer ◽  
P Gergely ◽  
L Colin ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Activation ◽  
Therapeutic Benefit ◽  
Proof Of Concept ◽  
B Cell Activation ◽  
Open Label ◽  
Open Label Phase ◽  
Thyroglobulin Autoantibodies ◽  
Potential Therapeutic Benefit ◽  
Hyperthyroid Patients

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting 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 five 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 seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P<0.001) and TSH-R-Ab levels normalized in four (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 one 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.

scholarly journals A Novel Anti-Cd40 Monoclonal Antibody, Iscalimab, for Control of Graves’ Hyperthyroidism – A Proof-Of-Concept Trial

2019 ◽  
Author(s):  
G J Kahaly ◽  
M N Stan ◽  
L Frommer ◽  
P Gergely ◽  
L Colin ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Activation ◽  
Therapeutic Benefit ◽  
Proof Of Concept ◽  
B Cell Activation ◽  
Open Label ◽  
Open Label Phase ◽  
Thyroglobulin Autoantibodies ◽  
Potential Therapeutic Benefit ◽  
Hyperthyroid Patients

Abstract Context The CD40-CD154 co-stimulatory pathway plays an important role in the pathogenesis of Graves’ disease (GD) by promoting auto-reactive B cell activation. Objective Evaluate efficacy and safety of a human, blocking, non-depleting 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 five 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 seven of 15 (47%) patients. Free and total T3 and T4 normalized in seven patients who did not receive any rescue medication with anti-thyroid drugs (ATD), and 2/15 (13.3%) showed normal TSH. Six (40%) patients required ATD. Four of seven responders relapsed after treatment completion. Serum concentrations of thyrotropin receptor autoantibodies (TSH-R-Ab) significantly declined in all patients (mean 15.3 IU/L versus 4.0 IU/L, 66% reduction, P<0.001) and TSH-R-Ab levels normalized in four (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 one 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.

A Novel Anti-CD40 Monoclonal Antibody, Iscalimab, for Control of Graves Hyperthyroidism—A Proof-of-Concept Trial

2019 ◽  
Vol 105 (3) ◽  
pp. 696-704 ◽  
Author(s):  
George J Kahaly ◽  
Marius Nicolae Stan ◽  
Lara Frommer ◽  
Peter Gergely ◽  
Laurence Colin ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cell Activation ◽  
Therapeutic Benefit ◽  
Antithyroid Drugs ◽  
Proof Of Concept ◽  
B Cell Activation ◽  
Open Label ◽  
Total Triiodothyronine ◽  
Open Label Phase ◽  
Thyroglobulin Autoantibodies

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 &lt; 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 &lt; 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.

scholarly journals A randomized, multicentre, open-label phase II proof-of-concept trial investigating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19: the Donated Antibodies Working against nCoV (DAWn-Plasma) trial

Trials ◽  
2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Timothy Devos ◽  
Tatjana Geukens ◽  
Alexander Schauwvlieghe ◽  
Kevin K. Ariën ◽  
Cyril Barbezange ◽  
...  
Keyword(s):  
Treatment Group ◽  
Phase Ii ◽  
Clinical Efficacy ◽  
Active Treatment ◽  
Standard Of Care ◽  
Active Treatment Group ◽  
Proof Of Concept ◽  
Efficacy And Safety ◽  
Open Label ◽  
Open Label Phase

Abstract Background The COVID-19 pandemic has imposed an enormous burden on health care systems around the world. In the past, the administration of convalescent plasma of patients having recovered from SARS and severe influenza to patients actively having the disease showed promising effects on mortality and appeared safe. Whether or not this also holds true for the novel SARS-CoV-2 virus is currently unknown. Methods DAWn-Plasma is a multicentre nation-wide, randomized, open-label, phase II proof-of-concept clinical trial, evaluating the clinical efficacy and safety of the addition of convalescent plasma to the standard of care in patients hospitalized with COVID-19 in Belgium. Patients hospitalized with a confirmed diagnosis of COVID-19 are eligible when they are symptomatic (i.e. clinical or radiological signs) and have been diagnosed with COVID-19 in the 72 h before study inclusion through a PCR (nasal/nasopharyngeal swab or bronchoalveolar lavage) or a chest-CT scan showing features compatible with COVID-19 in the absence of an alternative diagnosis. Patients are randomized in a 2:1 ratio to either standard of care and convalescent plasma (active treatment group) or standard of care only. The active treatment group receives 2 units of 200 to 250 mL of convalescent plasma within 12 h after randomization, with a second administration of 2 units 24 to 36 h after ending the first administration. The trial aims to include 483 patients and will recruit from 25 centres across Belgium. The primary endpoint is the proportion of patients that require mechanical ventilation or have died at day 15. The main secondary endpoints are clinical status on day 15 and day 30 after randomization, as defined by the WHO Progression 10-point ordinal scale, and safety of the administration of convalescent plasma. Discussion This trial will either provide support or discourage the use of convalescent plasma as an early intervention for the treatment of hospitalized patients with COVID-19 infection. Trial registration ClinicalTrials.govNCT04429854. Registered on 12 June 2020 - Retrospectively registered.

Phase 1 open-label, multiple ascending dose trial of AGEN1884, an anti-CTLA-4 monoclonal antibody, in advanced solid malignancies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3075-3075
Author(s):  
Breelyn A. Wilky ◽  
Priya Kumthekar ◽  
Robert Wesolowski ◽  
Jimmy J. Hwang ◽  
Jeffrey J. Raizer ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Open Label ◽  
Inhibitory Protein ◽  
Dose Trial ◽  
Dose Levels

3075 Background: AGEN1884 is a fully human IgG1 monoclonal antibody targeting the co-inhibitory protein cytotoxic T lymphocyte-associated protein 4 (CTLA-4). CTLA-4 blockade has been shown to augment T cell activation and proliferation, resulting in immune infiltration of the tumor and subsequent regression. Objectives: Assess the safety, maximum tolerated dose (MTD), and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of AGEN1884 in patients (pts) with advanced and refractory malignancies using a “3+3” trial design. Methods: Eleven pts have been enrolled and treated to date. AGEN1884 was administered intravenously q3w for 4 doses and then q12w. Three (0.1, 0.3 and 1 mg/kg) of six (3, 6 and 10 mg/kg) planned dose levels have been completed. Results: Five pts were accrued at 0.1 mg/kg dose level (2 were not DLT evaluable) and three pts each at doses of 0.3 mg/kg and 1 mg/kg. Median age was 56 years (range 26–70), ECOG 0–2, with a median of 4 (range 1–8) prior therapies. No DLT events have been observed thus far. Data from 5 pts were available for PK evaluation. Half-life of AGEN1884 post first dose was 8.8 and 9.6 days for 0.3 mg/kg and 0.1 mg/kg dose levels, respectively, as measured by ELISA. As of Jan 31, 2017, pts across cohorts were followed for a median of 6 weeks (range 0-28). Six pts (54.5%) have come off study due to disease progression, while 5 (45.5 %) remain on study. One confirmed partial response (80% reduction) by RECIST criteria was seen at 0.1 mg/kg in a patient with angiosarcoma. Conclusions: AGEN1884 is safe at 0.1 and 0.3 mg/kg dose levels. Dose escalation is ongoing and updated safety and PK data will be presented. Clinical trial information: NCT02694822.

An open-label phase 1 clinical trial of the anti-α4β7 monoclonal antibody vedolizumab in HIV-infected individuals

2019 ◽  
Vol 11 (509) ◽  
pp. eaax3447 ◽  
Author(s):  
Michael C. Sneller ◽  
Katherine E. Clarridge ◽  
Catherine Seamon ◽  
Victoria Shi ◽  
Marek D. Zorawski ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Monoclonal Antibody ◽  
Hiv Infection ◽  
Phase 1 ◽  
Single Subject ◽  
Lymphoid Tissues ◽  
Plasma Viremia ◽  
Open Label ◽  
Phase 1 Clinical Trial ◽  
Open Label Phase

Despite the substantial clinical benefits of antiretroviral therapy (ART), complete eradication of HIV has not been possible. The gastrointestinal tract and associated lymphoid tissues may play an important role in the pathogenesis of HIV infection. The integrin α4β7 facilitates homing of T lymphocytes to the gut by binding to the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on venules in gut-associated lymphoid tissue. CD4+ T cells with increased expression of α4β7 are susceptible to HIV infection and may be key players in subsequent virus dissemination. Data from nonhuman primate models infected with simian immunodeficiency virus (SIV) have suggested that blockade of the α4β7/MAdCAM-1 interaction may be effective at preventing SIV infection and may have beneficial effects in animals with established viral infection. To explore whether these findings could be reproduced in HIV-infected individuals after interruption of ART, we conducted an open-label phase 1 clinical trial of vedolizumab, a monoclonal antibody against α4β7 integrin. Vedolizumab infusions in 20 HIV-infected individuals were well tolerated with no serious adverse events related to the study drug. After interruption of ART, the median time to meeting protocol criteria to restart therapy was 13 weeks. The median duration of plasma viremia of <400 copies/ml was 5.4 weeks. Only a single subject in the trial experienced prolonged suppression of plasma viremia after interruption of ART. These results suggest that blockade of α4β7 may not be an effective strategy for inducing virological remission in HIV-infected individuals after ART interruption.

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