Fc-Disabled Anti-Mouse CD40L Antibodies Retain Efficacy in Promoting Transplantation Tolerance

Daley, Stephen R.; Cobbold, Stephen; Waldmann, Herman

doi:10.1111/j.1600-6143.2008.02382.x

Cited by 24 publications

(26 citation statements)

References 56 publications

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“…We cannot exclude that MR1, in addition, directly removes host-reactive CD4 + T cells, which express CD40L via F c -mediated depletion. However, most previous studies found no proof for Ab-mediated depletion of host-reactive T cells by MR1 (19,28,29). Recently, a small population of CD8 + T cells, which display a helper cell function and express CD40L, has been identified (30,31).…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cell–Dependent and –Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade

Vogel

Verbinnen

Gool

et al. 2016

The Journal of Immunology

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Blocking of costimulatory CD28/B7 and CD40/CD40L interactions is an experimental approach to immune suppression and tolerance induction. We previously reported that administration of a combination of CTLA-4Ig and MR1 (anti-CD40L mAb) for blockade of these interactions induces tolerance in a fully mismatched allogeneic splenocyte transfer model in mice. We now used this model to study whether regulatory T cells (Tregs) contribute to immune suppression and why both pathways have to be blocked simultaneously. Mice were injected with allogeneic splenocytes, CD4+ T cells, or CD8+ T cells and treated with MR1 mAb and different doses of CTLA-4Ig. The graft-versus-host reaction of CD4+ T cells, but not of CD8+ T cells, was inhibited by MR1. CTLA-4Ig was needed to cover CD8+ T cells but had only a weak effect on CD4+ T cells. Consequently, only the combination provided full protection when splenocytes were transferred. Importantly, MR1 and low-dose CTLA-4Ig treatment resulted in a relative increase in Tregs, and immune suppressive efficacy was abolished in the absence of Tregs. High-dose CTLA-4Ig treatment, in contrast, prevented Treg expansion and activity, and in combination with MR1 completely inhibited CD4+ and CD8+ T cell activation in a Treg-independent manner. In conclusion, MR1 and CTLA-4Ig act synergistically as they target different T cell populations. The contribution of Tregs to immune suppression by costimulation blockade depends on the concentration of CTLA-4Ig and thus on the degree of available CD28 costimulation.

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Section: Discussionmentioning

confidence: 99%

Regulatory T Cell–Dependent and –Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade

Vogel

Verbinnen

Gool

et al. 2016

The Journal of Immunology

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“…In contrast, the need for Fc-mediated effector function for therapeutic benefit, notably T cell depletion via Ab-dependent cell-mediated cytotoxicity, remains unresolved. The report by Ferrant et al (19) concluded that Fc effector function was a necessary component for therapeutic benefit, whereas a detailed study by Waldmann's group (20) suggested that an aglycosylated anti-CD40L IgG1 mAb (lacking Fc effector function) was equipotent to the wild-type IgG1 molecule in models of autoimmune diseases and transplantation.…”

mentioning

confidence: 99%

Engineering of a Novel Anti-CD40L Domain Antibody for Treatment of Autoimmune Diseases

Xie

Yamniuk

Borowski

et al. 2014

The Journal of Immunology

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CD40–CD40L interactions play a critical role in regulating immune responses. Blockade of CD40L by Abs, such as the anti-CD40L Ab 5c8, demonstrated positive clinical effects in patients with autoimmune diseases; however, incidents of thromboembolism (TE) precluded further development of these molecules. In this study, we examined the role of the Fc domain interaction with FcγRs in modulating platelet activation and potential for TE. Our results show that the interaction of the 5c8 wild-type IgG1 Fc domain with FcγRs is responsible for platelet activation, as measured by induction of PAC-1 and CD62P. A version of 5c8 with a mutated IgG1 tail was identified that showed minimal FcγR binding and platelet activation while maintaining full binding to CD40L. To address whether Fc effector function is required for immunosuppression, a potent Ab fragment, termed a “domain Ab” (dAb), against murine CD40L was identified and fused to a murine IgG1 Fc domain containing a D265A mutation that lacks Fc effector function. In vitro, this dAb–Fc demonstrated comparable potency to the benchmark mAb MR-1 in inhibiting B cell and dendritic cell activation. Furthermore, the anti-CD40L dAb–Fc exhibited a notable efficacy comparable to MR-1 in various preclinical models, such as keyhole limpet hemocyanin–induced Ab responses, alloantigen-induced T cell proliferation, “heart-to-ear” transplantation, and NZB × NZW F1 spontaneous lupus. Thus, our data show that immunosuppression and TE can be uncoupled and that a CD40L dAb with an inert Fc tail is expected to be efficacious for treating autoimmune diseases, with reduced risk for TE.

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“…However, generation of these reagents required a complicated “sewing PCR” technique, and large scale production of these reagents for clinical use may prove challenging. (5). …”

Section: Discussionmentioning

confidence: 99%

“…A previous report suggested that the tolerogenic effects of anti-CD154 antibodies were Fc- and complement-dependent (4). However, Daley and colleagues demonstrated that an aglycosylated form of anti-CD154, which exhibits reduced ability to bind Fc receptors and activate complement, was able to prolong graft survival as effectively as the glycosylated form (5). In addition, antibodies that target the CD40 molecule have also been shown to be efficacious in preventing alloreactivity in both mouse and non-human primates (6, 7).…”

Section: Introductionmentioning

confidence: 99%

An Anti-CD154 Domain Antibody Prolongs Graft Survival and Induces Foxp3+ iTreg in the Absence and Presence of CTLA-4 Ig

Pinelli

Wagener

Liu

et al. 2013

American Journal of Transplantation

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The use of monoclonal antibodies targeting the CD154 molecule remains one of the most effective means of promoting graft tolerance in animal models, but thromboembolic complications during early clinical trials have precluded their use in humans. Furthermore, the role of Fc-mediated deletion of CD154-expressing cells in the observed efficacy of these reagents remains controversial. Therefore, determining the requirements for anti-CD154-induced tolerance will instruct the development of safer but equally efficacious treatments. To investigate the mechanisms of action of anti-CD154 therapy, two alternative means of targeting the CD40–CD154 pathway were used: a non-agonistic anti-CD40 antibody, and an Fc-silent anti-CD154 domain antibody. We compared these therapies to an Fc-intact anti-CD154 antibody in both a fully allogeneic model and a surrogate minor antigen model in which the fate of alloreactive cells could be tracked. Results indicated that anti-CD40 mAbs as well as Fc-silent anti-CD154 domain antibodies were equivalent to Fc-intact anti-CD154 mAbs in their ability to inhibit alloreactive T cell expansion, attenuate cytokine production of antigen-specific T cells, and promote the conversion of Foxp3+ iTreg. Importantly, iTreg conversion observed with Fc-silent anti-CD154 domain antibodies was preserved in the presence of CTLA4-Ig, suggesting this therapy is a promising candidate for translation to clinical use.

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Fc-Disabled Anti-Mouse CD40L Antibodies Retain Efficacy in Promoting Transplantation Tolerance

Cited by 24 publications

References 56 publications

Regulatory T Cell–Dependent and –Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade

Regulatory T Cell–Dependent and –Independent Mechanisms of Immune Suppression by CD28/B7 and CD40/CD40L Costimulation Blockade

Engineering of a Novel Anti-CD40L Domain Antibody for Treatment of Autoimmune Diseases

An Anti-CD154 Domain Antibody Prolongs Graft Survival and Induces Foxp3+ iTreg in the Absence and Presence of CTLA-4 Ig

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