MHC Class II Allosteric Site Drugs: New Immunotherapeutics for Malignant, Infectious and Autoimmune Diseases

The discovery of the interactions of the ‘Ii‐Key’ segment of the Ii protein with the major histocmpatibility complex (MHC) Class II allosteric site, which is adjacent to the antigenic peptide‐binding site, creates therapeutic opportunities by regulating the antigenic peptide binding to MHC class II molecules. The binding of Ii‐Key to the MHC class II allosteric site loosens the hold of the MHC Class II ‘clamshell’ on antigenic peptides and leads to highly efficient antigenic peptide charging to or releasing from the MHC class II antigenic peptide‐binding groove. Ii‐Key peptide‐induced spilling of bound antigenic peptide, or replacement with inert blockers, leads to ‘inert immunosuppression’. Highly efficient replacement of ambient with vaccine peptides by Ii‐Key permits ‘active immunosuppression’ for antigen‐specific control of autoimmune diseases in the absence of cytokines or adjuvants. On the other hand, active immunization against cancer or infectious disease can result from epitope replacement mediated by Ii‐Key and accompanied by cytokines or other adjuvants. Finally, linking the Ii‐Key peptide through a simple polymethylene bridge to an antigenic sequence vastly increases the potency of MHC Class II peptide vaccines. In summary, the discovery of the MHC class II allosteric site allows one to increase the efficiency of MHC class II‐related, antigenic epitope‐specific therapy for malignant, infectious, and autoimmune diseases. The focus of this review is on the mechanism and potential clinical use of such novel allosteric site‐directed, Ii‐key drugs.