Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand

Kawai, Tatsuo; Andrews, David; Rb, Colvin; Sachs, Daniela; Ab, Cosimi

doi:10.1038/72162

Cited by 606 publications

(414 citation statements)

References 8 publications

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“…Because inhibition of CD40L by antibodies results in thromboembolic complications, which precludes its clinical use (14), targeting of CD40, the receptor for CD40L, or the CD40-associated signaling intermediates, specifically, the TNF receptorassociated factors (TRAFs), has become an interesting opportunity in inflammatory diseases.…”

Section: Significancementioning

confidence: 99%

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Chatzigeorgiou

Seijkens

Zarzycka

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

131

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Significance Inflammation is a critical contributor to the pathogenesis of metabolic disorders associated with obesity. A group of molecules crucial in regulating the immune system are costimulatory molecules, including CD40. Our current study shows that CD40 acts as a double-edged sword in the metabolic syndrome through the initiation of differential signaling cascades. The CD40-TNF receptor-associated factor (TRAF) 2/3/5 signaling pathway protects against metabolic dysfunction and inflammation associated with obesity; conversely, the CD40-TRAF6 pathway contributes to the detrimental consequences of obesity. In the present study, we therefore designed, validated, and used a small-molecule inhibitor that blocks CD40-TRAF6 interactions. The improvement of insulin resistance by this specific CD40-TRAF6 inhibitor could represent a therapeutic breakthrough in the field of immunometabolism.

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Section: Significancementioning

confidence: 99%

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Chatzigeorgiou

Seijkens

Zarzycka

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

112

131

View full text Add to dashboard Cite

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“…However, clinical trials that evaluated the efficacy of anti-CD40L antibodies were stopped because of the occurrence of thromboembolic events resulting from disrupted CD40L-aIIbb3 interactions in arterial thrombi (72). An alternative approach, blockage of CD40, was well tolerated and able to slightly improve disease severity in Crohn's disease (73).…”

Section: The Therapeutic Potential Of Costimulatory Dyads In Obesitymentioning

confidence: 99%

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

et al. 2014

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In the past two decades, numerous experimental and clinical studies have established the importance of inflammation and immunity in the development of obesity and its metabolic complications, including insulin resistance and type 2 diabetes mellitus. In this context, T cells orchestrate inflammatory processes in metabolic organs, such as the adipose tissue (AT) and liver, thereby mediating obesity-related metabolic deterioration. Costimulatory molecules, which are present on antigen-presenting cells and naïve T cells in the AT, are known to mediate the crosstalk between the adaptive and innate immune system and to direct T-cell responses in inflammation. In this Perspectives in Diabetes article, we highlight the newest insights in immune cell interactions in obesity and discuss the role of costimulatory dyads in its pathogenesis. Moreover, the potential of therapeutic strategies that target costimulatory molecules in the metabolic syndrome is explored.

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“…This approach showed great promise in preclinical mouse models of arthritis (6) and allograft transplant (7). However, the first human clinical trial using anti-CD154-blocking mAb was halted as the result of several fatal thromboembolic events (8), which may have been due to the effect of immune complexes upon activated platelets expressing CD154. Although a variety of approaches to blocking CD40-CD154 interactions have since been explored and may prove successful (5), an attractive alternative is direct inhibition of the CD40-mediated activation pathway.…”

mentioning

confidence: 99%

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

Bankert

Oxley

Smith

et al. 2015

The Journal of Immunology

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Blocking the interaction of CD40 with its ligand CD154 is a desirable goal of therapies for preventing and/or ameliorating autoimmune diseases and transplant rejection. CD154-blocking mAbs used in human clinical trials resulted in unanticipated vascular complications, leading to heightened interest in the therapeutic potential of antagonist mAbs specific for human CD40. Abs that do not require physical competition with CD154 to inhibit CD40 signaling have particular therapeutic promise. In this study, we demonstrate that the antagonist anti-human CD40 mAb PG102 fails to trigger CD40-mediated activation, as well as impairs CD154-mediated CD40 activation, via a distinct nonstimulatory CD40 signaling mechanism. PG102 did not induce early CD40-induced signaling events, and it inhibited early kinase and transcription factor activation by CD154 or agonist anti-CD40 mAbs. However, PG102 stimulated normal CD40-mediated TNFR-associated factor (TRAF)2 and TRAF3 degradation. PG102 induced the formation of a CD40 signaling complex that contained decreased amounts of both TRAF2 and TRAF3 and TRAF2-associated signaling proteins. Additionally, PG102-induced CD40 signaling complexes failed to recruit TRAF6 to detergent-insoluble membrane fractions. Fab fragments of PG102, while retaining CD40 binding, did not induce TRAF degradation, nor could they inhibit CD154-stimulated B cell signaling, indicating that CD40 aggregation is required for the signaling inhibition induced by PG102. The antagonistic impact of PG102 on CD40 signaling reveals that the manner of CD40 ligation can determine sharply different outcomes for CD40 signaling and suggests that such information can be used to therapeutically manipulate these outcomes.

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Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand

Cited by 606 publications

References 8 publications

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance

Immune Cell Crosstalk in Obesity: A Key Role for Costimulation?

Induction of an Altered CD40 Signaling Complex by an Antagonistic Human Monoclonal Antibody to CD40

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