Targeting co-stimulatory molecules in autoimmune disease

Abstract

Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, and efforts have focused in particular on the CD28 family members CTLA-4 and PD-1. In autoimmunity, these same pathways can be targeted to opposite effect, to curb the overexuberant immune response. The CTLA-4 checkpoint serves as an exemplar, whereby CTLA-4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA-4 in autoimmunity. Here we review the targeting of costimulatory molecules in autoimmune disease, focusing in particular on the CD28 family and TNFR family members. We present the state-of-the-art in costimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.

Sintilimab: A Promising Anti-Tumor PD-1 Antibody

“…Immune checkpoints (ICs) are important immune regulators in maintaining immune homeostasis and preventing autoimmune diseases. There are co-stimulatory ICs, like CD28 and TNFRSF9, and inhibitory ICs, like CTLA-4 (1). Under normal conditions, ICs allow the immune system to respond to infections, malignancies and protect tissues.…”

Ectopic Lymphoid Follicles in Multiple Sclerosis: Centers for Disease Control?

“…While ACCLAIM, a phase 2 clinical trial studying the efficacy of abatacept in patients with RRMS, showed no clinical benefit, a subsequent study of samples obtained from patients participating in that trial showed that T FH cells and T reg cells were selectively decreased, the latter of which may be a significant disadvantage of this treatment (142,170). Abatacept was followed by the development of belatacept, which has a higher affinity for both CD80 and CD86, and MEDI5256, which binds CD80 with greater affinity than CD86, although these have not been studied in the context of MS (171,172). Interestingly, in a nonhuman primate model of transplantation, crosstalk between T FH cells and B cells was more potently affected by treatment with a CD28 antagonist, FR104, compared to belatacept, suggesting that targeting CD28 directly might be more beneficial (162,163,(172)(173)(174)(175).…”

“…Abatacept was followed by the development of belatacept, which has a higher affinity for both CD80 and CD86, and MEDI5256, which binds CD80 with greater affinity than CD86, although these have not been studied in the context of MS (171,172). Interestingly, in a nonhuman primate model of transplantation, crosstalk between T FH cells and B cells was more potently affected by treatment with a CD28 antagonist, FR104, compared to belatacept, suggesting that targeting CD28 directly might be more beneficial (162,163,(172)(173)(174)(175).…”

“…ICOS is a critical signal for T FH cell development, functions such as IL-21 secretion, and is highly expressed on T FH cells as well as on T H 17 cells, albeit to a lesser extent ( 180 , 181 ). Importantly, and in contrast to CD28 and CTLA4, ICOS expression is thought to be restricted to T FH cells and antigen-experienced CD4 + memory T cells and is upregulated during reactivation ( 172 , 182 ). In MS, the increase in IL-21- and ICOS-expressing CD4 + T cells would suggest a potential benefit in targeting ICOS-ICOSL interactions.…”

The non-coding RNA miR-17~92 is a central mediator of T cell activation

“…Due to its centrality for T cell and immune responses more generally, CD28 is an important target in therapeutic immunology 2,5,6 . CD28 blockade by CTLA4-Ig is clinically used to prevent renal allograft rejection and to treat rheumatic disease 2 .…”