Superagonistic anti-CD28 antibodies: potent activators of regulatory T cells for the therapy of autoimmune diseases

Abstract

This paper reviews the existing evidence regarding the use of superagonistic anti-CD28 antibodies (CD28 superagonists) for therapeutic manipulation of regulatory T cells (T(reg) cells). The molecular properties of superagonistic anti-CD28 antibodies allow the generation of a strong activating signal in mature T cells, including T(reg) cells, without additional stimulation of the T cell receptor complex. CD28 superagonist administration in vivo leads to the preferential expansion and strong activation of naturally occurring CD4+CD25+CTLA-4+FoxP3+ T(reg) cells over conventional T cells. In animal models, both prophylactic and therapeutic administration of a CD28 superagonist prevented or at least greatly mitigated clinical symptoms and induced remission. Adoptive transfer experiments have further shown that CD28 superagonists mediate protection by expansion and activation of CD4+CD25+ T(reg) cells. Therefore, superagonistic anti-CD28 antibodies offer a promising novel treatment option for human autoimmune diseases and the first clinical trials are eagerly awaited.

Figure 1

Two classes of CD28 specific monoclonal antibodies (mAbs): "conventional" and "superagonistic". Conventional anti-CD28 mAbs are, only in the context of costimulation, capable of driving interleukin (IL)-2 production and T cell proliferation. In contrast, superagonistic anti-CD28 antibodies do not depend on exogenous T cell receptor (TCR) triggering for full T cell activation.

Figure 2

Bivalent linear complex formation could be the molecular clue to superagonistic CD28 stimulation. Only CD28 superagonists (red), but not conventional anti-CD28 antibodies (yellow) or B7 molecules (green), bind to a lateral motif of the CD28 molecule (A).⁴ Therefore, only CD28 superagonists are capable of forming linear complexes with CD28 molecules (B, C). In these complexes activating signalling components, presumably, get aggregated, which is sufficient to surpass the threshold for T cell activation.

Figure 3

A numerical and/or functional imbalance between autoreactive effector T cells and regulatory T cells (T_reg cells) contributes to the induction and maintenance of autoimmunity. CD28 superagonists are capable of re-establishing peripheral tolerance via the activation and expansion of regulatory T cells.