Therapeutic targeting of immune checkpoints has garnered significant attention in the area of cancer immunotherapy, in which efforts have focused in particular on cytotoxic T lymphocyte antigen 4 (CTLA4) and PD1, both of which are members of the CD28 family. In autoimmunity, these same pathways can be targeted to opposite effect: to curb the over-exuberant immune response. The CTLA4 checkpoint serves as an exemplar, whereby CTLA4 activity is blocked by antibodies in cancer immunotherapy and augmented by the provision of soluble CTLA4 in autoimmunity. Here, we review the targeting of co-stimulatory molecules in autoimmune diseases, focusing in particular on agents directed at members of the CD28 or tumour necrosis factor receptor families. We present the state of the art in co-stimulatory blockade approaches, including rational combinations of immune inhibitory agents, and discuss the future opportunities and challenges in this field.
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The authors thank A. Pesenacker for helpful comments on the manuscript.
G.C. is a full-time employee and shareholder of AstraZeneca. J.S.R. is an employee and shareholder of Novartis Pharmaceuticals. L.S.K.W. declares research collaborations and consultancy with AstraZeneca and Immunocore. N.M.E. declares no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Phase IIa results for AMG 557: https://acrabstracts.org/abstract/a-phase-2a-study-of-medi5872-amg557-a-fully-human-anti-icos-ligand-monoclonal-antibody-in-patients-with-primary-sjogrens-syndrome/
Phase II interim results for belimumab plus rituximab in lupus nephritis: https://acrabstracts.org/abstract/phase-2-trial-of-induction-therapy-with-anti-cd20-rituximab-followed-by-maintenance-therapy-with-anti-baff-belimumab-in-patients-with-active-lupus-nephritis/
The state of unresponsiveness of the immune system to antigens that have the potential to induce an immune response. Self-tolerance to an individual’s own antigens is achieved through both central tolerance and peripheral tolerance mechanisms.
- Pattern recognition receptors
Cell-surface receptors expressed by cells in the body in order to sense molecules that are associated with infection or tissue damage. They play a crucial role in the initiation of innate immune responses.
A peripheral mechanism for tolerizing T cells. Anergic T cells are functionally unresponsive and unable to proliferate due to a block at the G1 phase of the cell cycle.
- Experimental autoimmune encephalomyelitis
An animal model of the human autoimmune disease multiple sclerosis. Experimental autoimmune encephalomyelitis is induced in experimental animals by immunization with myelin or peptides derived from myelin. The animals develop a paralytic disease with inflammation and demyelination in the brain and spinal cord.
- Keyhole limpet haemocyanin (KLH) immunization
KLH is a xenogeneic, T cell-dependent antigen that is frequently used as a carrier protein for vaccines. KLH immunization is also used to assess the efficacy of immunotherapies targeting primary antibody responses.
An agonist that is able to induce a response far greater than an endogenous ligand for its target receptor. CD28 superagonists are capable of activating T cells by binding to CD28 alone without concurrent T cell receptor engagement.
- Antibody-dependent cellular cytotoxicity
(ADCC). The process in which targeted cells become coated with antibody, and are then lysed by effector cells that have cytolytic activity and specific immunoglobulin crystallizable fragment (Fc) receptors. Lysis requires direct cell-to-cell contact and does not involve complement.
A peptide fused to the Fc region of an antibody allowing for increased half-life compared with unmodified therapeutic peptides.
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Edner, N.M., Carlesso, G., Rush, J.S. et al. Targeting co-stimulatory molecules in autoimmune disease. Nat Rev Drug Discov 19, 860–883 (2020). https://doi.org/10.1038/s41573-020-0081-9
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