Immune-mediated inflammatory disease therapeutics: past, present and future

Abstract

Immune-mediated inflammatory diseases are common and clinically diverse. Although they are currently incurable, the therapeutic armamentarium for immune-mediated inflammatory diseases has been transformed in the past two decades. We have moved from the wide application of broad-spectrum immune modulators to the routine use of agents with exquisite specificity, arising from monoclonal and molecular biotechnology and more recently from highly targeted medicinal chemistry. Here we describe key advances and lessons that drove this remarkable progress and thereafter reflect on the next steps in this ongoing journey.

Fig. 1. Timeline of therapeutic strategies for immune-mediated inflammatory diseases.

This timeline highlights the key lessons learnt over the past 40 years that led to the development of immune therapeutics, from broad spectrum to highly specific, for immune-mediated inflammatory diseases. JAK, Janus kinase; TNF, tumour necrosis factor.

Fig. 2. Key targets for the management of immune-mediated inflammatory diseases.

A selection of the key extracellular, membrane-bound and intracellular targets for biological and small-molecule therapies that have driven the transformation in management of immune-mediated inflammatory diseases is shown^,. BLyS, B lymphocyte stimulator; GM-CSF, granulocyte–macrophage colony-stimulating factor; IBD, inflammatory bowel disease; IFNγ, interferon-γ; IFNR, interferon receptor; JAK, Janus kinase; JIA, juvenile idiopathic arthritis; MS, multiple sclerosis; PDE4, phosphodiesterase 4; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SpA, spondyloarthritis; S1PR1, sphingosine 1-phosphate receptor 1; tmTNF, transmembrane tumour necrosis factor.

Fig. 3. Future approaches for immune-mediated inflammatory disease therapeutics.

We envisage future therapeutic design for immune-mediated inflammatory diseases to involve a combination of routes for candidate target discovery: kinome interrogation, novel cellular therapies, polyomic disease deconstruction and advances in regenerative medicine. In turn, this discovery programme will be enhanced by the application of artificial intelligence-based methods, in silico medicinal chemistry and in silico trialling, leading to immune homeostasis, immune tolerance and repair of organ damage.