科研之友
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摘要
Since the discovery of the "two-signal" model of T-cell activation in the 1980s, the field of T-cell co-stimulation has exploded and many biological drugs now in clinical development or on the market specifically target secondary co-stimulatory or checkpoint receptors. Co-stimulation of CD28 family molecules predominantly controls the priming of T lymphocytes and their differentiation into pathogenic effector cells. Blocking the CD28 pathway using CD80/86 antagonists (i.e., CTLA-4-Ig fusion proteins) has demonstrated clinical efficacy, as exemplified by abatacept (Orencia (R), Bristol-Myers Squibb) for autoimmune diseases and belatacept (Nulojix (R), Bristol-Myers Squibb) in transplantation. However, the co-stimulation field has evolved rapidly since these earlier agents, and negative checkpoint molecules of the CD28 family have been consistently shown to be critical for the establishment and maintenance of peripheral tolerance. Interaction of CD80/86 with cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) checkpoint molecules are well described as crucial mechanisms of immune tolerance, regulatory T-cell function and self-inhibition of autoreactive and memory T cells. Here, we summarize the fundamental differences and advantages in selectively targeting CD28 molecules instead of CD80/86, we explore the challenges of developing selective CD28 antagonists devoid of stimulatory activity, and we review preclinical proof of concept for selective CD28 antagonists in the prevention or treatment of autoimmunity.
- 出版日期2016-4
