CD40 Expression and its Association with Low-grade Inflammation in a Greek Population of Type 1 Diabetic Juveniles: Evidence for Differences in CD40 mRNA Isoforms Expressed by Peripheral Blood Mononuclear Cells

Chatzigeorgiou, Antonios; Lembessis, Peter; Mylona-Karagianni, Christina; Tsouvalas, Emmanouil; Diamanti-Kandarakis, Evanthia; Kamper, Elli F.

doi:10.1055/s-0029-1224151

Cited by 22 publications

(14 citation statements)

References 27 publications

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“…Subsequent investigations indicated that thromboembolic liabilities associated with anti-CD154 mAbs were a result of blocking interactions between CD154 and αIIbβ3. [34][35][36][37] This suggests that elevated CD40 receptor expression appears to be associated with a high elimination rate of anti-CD40 mAbs such as iscalimab. 26 These observations suggest that these events are inde- Consistent with preclinical data, iscalimab did not deplete peripheral leukocytes including B cells, and there were minimal effects on total serum IgM and IgG.…”

Section: Discussionmentioning

confidence: 99%

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First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Espié

Koo

et al. 2020

American Journal of Transplantation

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Pascal Espié and YanLing He are co-first authors who have contributed equally to the work. James S. Rush and Peter Gergely have contributed equally to the work.Clinical Trial Registration Number: NCT02089087.Abbreviations: AEs, adverse events; AUC last , area under the plasma concentration-time curve from time zero to the last quantifiable concentration; BLQ, below limit of quantification;Iscalimab is a fully human, CD40 pathway blocking, nondepleting monoclonal antibody being developed as an immunosuppressive agent. We describe a first-in-human, randomized, double-blind, placebo-controlled study investigating the safety, tolerability, pharmacokinetics, and pharmacodynamics of iscalimab in healthy subjects and rheumatoid arthritis patients. Healthy subjects (n = 56) received single doses of intravenous iscalimab (0.03, 0.1, 0.3, 1, or 3 mg/kg), or subcutaneous iscalimab (3 mg/kg), or placebo. Rheumatoid arthritis patients (n = 20) received single doses of intravenous iscalimab (10 or 30 mg/kg) or placebo. Iscalimab exhibited target-mediated drug disposition resulting in dose-dependent and nonlinear pharmacokinetics. Complete (≥90%) CD40 receptor occupancy on whole blood B cells was observed at plasma concentrations >0.3-0.4 µg/mL. In subjects receiving 3 mg/kg iscalimab, antibody responses to keyhole limpet hemocyanin were transiently suppressed. CD40 occupancy by iscalimab prevented ex vivo human rCD154-induced expression of CD69 on B cells in whole blood. All doses were generally safe and well tolerated, with no clinically relevant changes in any safety parameters, including no evidence of thromboembolic events. Iscalimab appears to be a promising blocker of the CD40-CD154 costimulatory pathway with potential use in transplantation and other autoimmune diseases. K E Y W O R D S clinical research/practice, clinical trial, immunosuppressant -fusion proteins and monoclonal antibodies: B cell specific, immunosuppression/immune modulation, translational research/ science S U PP O RTI N G I N FO R M ATI O N Additional supporting information may be found online in the Supporting Information section. How to cite this article: Espié P, He Y, Koo P, et al. First-inhuman clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am J Transplant. 2020;20: 463-473. https ://doi.

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Section: Discussionmentioning

confidence: 99%

“…33 Other data suggest that some patients with autoimmune disease displayed increased CD40 expression in target tissues and elevated serum/plasma soluble CD40 levels. [34][35][36][37] This suggests that elevated CD40 receptor expression appears to be associated with a high elimination rate of anti-CD40 mAbs such as iscalimab.…”

Section: Discussionmentioning

confidence: 99%

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Espié

Koo

et al. 2020

American Journal of Transplantation

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“…PBMCs were lysed according to the method of Chatzigeorgiou et al (2010) in 1% Triton (50 mmol/l Tris, pH 7.4, 150 mmol/l NaCl, 0.02% sodium azide and 1% Triton X-100) supplemented with a protease inhibitor cocktail (Sigma) for 30 min on ice. After centrifugation at 13 000 r.p.m.…”

Section: Preparation Of Cell Lysatesmentioning

confidence: 99%

Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats

Chatzigeorgiou¹,

Kandaraki²,

Piperi³

et al. 2013

Journal of Endocrinology

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The levels of advanced glycation end products (AGEs) are increased under conditions of impaired glucose metabolism and/or oxidative stress, promoting insulin resistance and other endocrine abnormalities. AGEs play a major role in the pathogenesis of several diseases such as diabetes, atherosclerosis, polycystic ovary syndrome and Alzheimer's disease, contributing to progressive ageing. Receptor-based clearance of AGEs by the receptor for AGE (RAGE) and/or the macrophage scavenger receptor A (SR-A) is considered as a main factor for the regulation of the concentration of AGEs under these conditions. This study aimed to investigate the expression of RAGE (AGER) and SR-A (MSR1) under high/low-dietary AGE conditions in vivo and their potential contribution to the metabolic and sex hormonal profile of female rats. Female Wistar rats were fed a low-AGE or high-AGE diet for 3 months. Serum samples were collected at baseline and at the completion of the 3-month period for the measurements of metabolic and hormonal parameters. Peripheral blood mononuclear cells (PBMCs) were isolated for the determination of the expression of RAGE and SR-A. The high-AGE diet-fed rats exhibited increased glucose, insulin and testosterone levels as well as decreased oestradiol and progesterone levels compared with the low-AGE diet-fed ones, thus indicating a metabolic and hormonal dysregulation attributed to high-AGE dietary exposure. The expression of RAGE was significantly down-regulated in the PBMCs of the high-AGE diet-fed rats (PZ0.041), and it was correlated negatively with insulin and testosterone levels and positively with progesterone levels. The expression of SR-A was also decreased in the high-AGE diet-fed rats to marginal significance. Decreased monocytic expression of scavenger receptors such as RAGE and SR-A may result in a higher deposition of AGEs in peripheral endocrine tissues, thus promoting endocrine-related abnormalities and diseases.

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“…Furthermore, although evidence suggests that hyperglycaemia affects negatively the development of albuminuria and progression of diabetic nephropathy [3] and also the results of De Muro et al support the existence of a strong influence of hyperglycaemia on GAGs metabolism [17,18], we (as Poplawska-Kita et al and Hansen et al) didn't find any correlation between GAGs levels and markers of glycaemic or metabolic control. On the other hand, we found significant correlations between urine GAGs and markers of inflammation such as CD40, a significant regulator of the low-grade inflammation in type 1 diabetes [19,20] and also MCP-1. These correlations indicate once again that low grade chronic inflammation is a factor of great importance for the initiation and progression of diabetic complications [21,22].…”

Section: Discussionmentioning

confidence: 73%

Investigation of Mechanisms That Are Involved in The Pathogenesis of Diabetic Angiopathy and Nephropathy and Development of Indicators of Scouting Diagnosis of The Above Complications in Diabetes Mellitus Type1

Ellina¹

2019

J Med - Clin Res & Rev

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Background:The aim of the present study was to evaluate the role of extracellular matrix-associated glycosaminoglycans (GAGs), connective tissue growth factor (CTGF), angiogenic vascular endothelial growth factor (VEGF) and inflammatory factors CD40, in the development of diabetic nephropathy in type 1 diabetes (T1DM).Methods: Plasma and urine samples from 30 T1DM patients and 20 healthy controls were used to measure the levels of CTGF, VEGF, MCP-1, CD40 and IFN-γ by ELISA. Plasma and urine GAGs were measured using a spectrophotometric method.Results: Plasma levels of GAGs, CD40 and MCP-1 and urine levels of GAGs and CTGF were significantly elevated in normoalbuminuric T1DM patients. A tendency to higher plasma VEGF levels was found in patients compared to controls. The urine/plasma GAGs ratio of T1DM patients was almost similar to that of healthy subjects (HS), whereas the urine/plasma CTGF ratio was about three times greater in diabetic patients compared to HS. Conclusion:Conclusively, increased GAGs and CTGF excretion are evident in T1DM normoalbuminuric juveniles, possibly reflecting early renal injury signs, before the initiation of albuminuria.

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CD40 Expression and its Association with Low-grade Inflammation in a Greek Population of Type 1 Diabetic Juveniles: Evidence for Differences in CD40 mRNA Isoforms Expressed by Peripheral Blood Mononuclear Cells

Abstract: Homeostatic dysregulation of CD40 and its association with inflammatory markers in T1DM patients, especially in those with poor glycaemic control, implies a pathophysiological role of CD40 in the low-grade inflammatory process in T1DM.

Cited by 22 publications

References 27 publications

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

First-in-human clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody

Dietary glycotoxins affect scavenger receptor expression and the hormonal profile of female rats

Investigation of Mechanisms That Are Involved in The Pathogenesis of Diabetic Angiopathy and Nephropathy and Development of Indicators of Scouting Diagnosis of The Above Complications in Diabetes Mellitus Type1

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