The Emerging Jamboree of Transformative Therapies for Autoimmune Diseases

Abstract

Standard treatments for autoimmune and autoinflammatory disorders rely mainly on immunosuppression. These are predominantly symptomatic remedies that do not affect the root cause of the disease and are associated with multiple side effects. Immunotherapies are being developed during the last decades as more specific and safer alternatives to small molecules with broad immunosuppressive activity, but they still do not distinguish between disease-causing and protective cell targets and thus, they still have considerable risks of increasing susceptibility to infections and/or malignancy. Antigen-specific approaches inducing immune tolerance represent an emerging trend carrying the potential to be curative without inducing broad immunosuppression. These therapies are based on antigenic epitopes derived from the same proteins that are targeted by the autoreactive T and B cells, and which are administered to patients together with precise instructions to induce regulatory responses capable to restore homeostasis. They are not personalized medicines, and they do not need to be. They are precision therapies exquisitely targeting the disease-causing cells that drive pathology in defined patient populations. Immune tolerance approaches are truly transformative options for people suffering from autoimmune diseases.

Keywords: autoimmunity; biologics; immune checkpoints; immune tolerance; immunotherapy; nanomedicine; precision medicine; safety.

Figure 1

Major integrins and tissue receptors involved in leukocyte homing during IBD. VLA-4 is expressed by most leukocytes, LPAM is specifically found on lymphocytes isolated from the gastrointestinal tract and αEβ7 is displayed by intraepithelial T cells. VCAM-1 is broadly expressed by inflamed endothelium; MAdCAM-1 is selectively expressed by high endothelial venules of Peyer's patches and gut lymphoid tissues and E-cadherin is found on epithelial cells. Due to their specific target and epitope binding (see text), the indicated antibodies will be more or less selective for the gastrointestinal tissue and hence for IBD. Colored arrows indicate the spectrum of specificity for the different mAbs.

Figure 2

Major immune checkpoints considered as targets for immunotherapy to ameliorate AID. Solid lines represent intended targeted intervention (e.g., only targeting T cell function -unidirectional arrow to T cell side-, or also blocking helper/effector T cell function -bidirectional arrow- as in CD40/CD40L therapies that aim for the inhibition of T cell activation as well as the prevention of germinal center formation). The best known immunotherapeutics, registered or under development (see text), are included in the scheme indicating (with dotted lines) their receptor specificity and whether they are antagonist (red) or agonistic (green). GSK2831781 is displayed as a “functional” antagonist since the main function of the mAb is to eliminate LAG3 expressing cells, rather than agonizing this coinhibitory pathway, as it is the case for IMP761. NN means compound code not named (not known in public domain).

Figure 3

Graphical representation of the major approaches being followed by pharma and biotech companies to induce immune tolerance. Antigen (Ag) could be one or more whole proteins or derived peptides involved in the autoimmune response. Further explanation on the different MoA is presented in the text.