T cells recognize foreign pathogens in the body when fragments of the pathogen, antigenic epitopes, are 'presented' to them by specific molecules, termed major histocompatibility complexes (MHC), on the surface of infected or malignant cells. This interaction activates the T cells, stimulating a multicellular cascade of actions that, ideally, both eliminates the foreign invaders and protects against future incursions. Hence, antigen presentation is an early and essential step in eliciting T cell-mediated immune responses.

Antigen Express technology focuses on modulating immune responses mediated by T helper (Th) cells, a class of lymphocytes that plays a multifaceted role in the immune system, both enhancing and suppressing immune responses. Th cells are essential both for obtaining a robust and long lasting response against infectious agents or cancer cells and for down regulating immune responses when the immune system becomes inappropriately stimulated, e.g. in autoimmune disease and allergy.

The heart of the Antigen Express technology platform is the Ii (invariant chain) protein, which regulates antigen presentation by MHC class II molecules and consequent T helper cell activation. We have established two technology platforms and advanced a number of product-focused projects toward the clinic based on the modulation of expression and use of the Ii protein. The first of these technologies involves suppression of expression of the Ii protein while the second involves the design of Ii 'hybrids', which contain both an MHC class II antigenic epitope and a portion of the Ii protein.


The normal function of the Ii protein is to ensure that only extracellular antigens (e.g., from virally infected or tumor cells) are presented by MHC class II molecules. It does so by blocking the antigenic peptide binding trough of MHC class II molecules at synthesis. The Ii protein is only removed in a coordinated process tightly linked to charging of class II molecules with peptides obtained from phagocytosed extracellular material (Figure 2a). When MHC class II molecules are synthesized in the absence of Ii, they are able to acquire and present antigens derived from intracellularly synthesized proteins, similar to the ‘survey’ function of MHC class I molecules that present antigens to cytotoxic T cells. In the case of tumor cells, it has been shown that they can effectively be forced to present tumor antigens when induced to express MHC class II molecules in the absence of Ii (Figure 2b). A number of studies have shown that this is sufficient to prevent tumor growth both in prevention and cure models (see references).

Another application of the Ii suppression technology is as an adjunct to DNA vaccines. In this case, the antigenic peptide encoded by the vaccine is synthesized intracellularly and will be available both for presentation by MHC class I and II molecules (i.e., when Ii expression is suppressed).


While suppression of Ii gene expression can force cells to process antigens for class II presentation, the use of Ii-Key hybrids entirely bypasses the need for antigen processing. Antigen Express scientists discovered that a portion of the Ii protein interacts with an allosteric site on MHC class II molecules. The interaction of this portion of the molecule, termed Ii-Key, with the allosteric site loosens the hold of the antigenic binding trough on any resident epitope. Antigen Express scientists have shown that hybrid peptides containing the Ii-Key ligand linked to an antigenic epitope also bind to MHC Class II molecules and discharge resident antigens from the antigen binding groove, as illustrated in Figure 2. When the Ii-Key end of the hybrid binds to the MHC Class II molecule, it constrains the antigenic end to a region close to the MHC Class II antigen binding groove. This anchoring compensates for the reduced binding affinity of the groove, so the hybrid antigen can occupy it and be presented to T helper cells. By these means, Ii-Key hybrids bypass all requirements for antigen processing and directly 'hijack' MHC class II molecules already on the surface of cells to present whatever epitope is present in the hybrid.

Ii-Key hybrid peptides are being used to selectively activate two different classes of T helper cell responses (Th1 responses, which increase the intensity and duration of the immune response, or Th2 responses, which induce immunotolerance) depending on how the peptides are administered. The use of Ii-Key hybrid peptides to induce primarily Th1 responses overcomes a critical limitation of peptide vaccines; i.e., their general lack of ability to elicit T helper cell responses that are required for a robust and long lived response. There are active programs at Antigen Express targeting both cancer and infectious diseases using hybrids to stimulate the Th1 response. Similarly, programs have been initiated to use Ii-Key hybrid peptides administered to selectively activate Th2 responses and thereby induce tolerance to antigens involved in harmful immune reactions, e.g. autoimmunity, allergy, and transplant rejection.