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

Abstract

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.

Anchor Side Chains of Short Peptide Fragments Trigger Ligand-Exchange of Class II MHC Molecules

“…Compared to Ac-FR-NH 2 , the dipeptides with aliphatic MLE side chains exhibited only between 12% (L) and 4% (V) of the activity. Similar catalytic activity was also detected for some unmodified tripeptides as well as for two peptides derived from invariant chain (LRMK, LRMKLPK) [16]. As ‘Ii-key’ they had been described to facilitate MHC-loading by targeting an allosteric invariant chain binding site located outside the P1 pocket.…”

“…*‘Minimal peptide-MLE’ and ‘catalytic tripeptides’ are introduced in this study, catalytic activity for ‘invariant chain derived peptides’ has been reported for LRMK and LRMKLPK [16] and for LRKPPKPV [17].**The ‘Catalytic Rate Enhancement’ coefficient ( k ) represents the relative increase of the spontaneous loading rate (r spont ) in the presence of the catalytic peptide (P cat ). The total rate (r tot ) can be calculated by (r tot  = r spont + k [P cat ] r spont ).…”

“…*‘Minimal peptide-MLE’ and ‘catalytic tripeptides’ are introduced in this study, catalytic activity for ‘invariant chain derived peptides’ has been reported for LRMK and LRMKLPK [16] and for LRKPPKPV [17].…”

Boosting immune response with the invariant chain segments via association with non-peptide binding region of major histocompatibility complex class II molecules

“…Animal models illustrate the efficiency of Ii hybrid methodology in using melanoma peptides [21,26], subvirion influenza A (H5N1) HA [22], human papilloma virus 16 E7(8–22) [23], Listeria Th [24] and hepatitis C virus [25] epitopes. The mechanistic hypothesis states that the Ii -key binds initially to an allosteric site just outside the MHC class II binding groove at the cell surface [26,27]. This induces a conformational change in the trough, facilitating antigenic epitope charging [22,28], and a concomitant increase in the potency of antigen presentation compared with the unmodified class II epitope [29,30].…”

Breast cancer vaccines: ongoing National Cancer Institute-registered clinical trials

“…Covalent linkage of the Ii-Key segment to class II peptides facilitates direct antigenic epitope charging of MHC class II molecules [41,42], resulting in increased antigen presentation that can increase potency to ≥250 times that of the unmodified class II epitope in vitro [43,44]. Because it is a class II peptide, AE37 stimulates Th cells.…”