The more I read about the science behind cancer vaccines the more I realize the Reiner Laus and his fellow Dendreon scientists were way, way ahead of the game when it came to the design of the antigen delivery cassette. One of the keys in that design is something that the company seems to mention only in passing when discussing the cassette technology…
Antigen Engineering… We engineer antigens to develop proprietary active immunotherapies. Our antigen engineering is designed to trigger and maximize cell-mediated immunity by augmenting the uptake and processing of the target antigen by antigen-processing cells. We can affect the quality and quantity of the immune response that is generated by adding, deleting or modifying selected sequences of the antigen gene, together with inserting the modified antigen into our proprietary Antigen Delivery Cassette.
Why is this such a big deal? A study that is described here shows why a well designed engineered antigen is one of the most important aspects or the most important aspect of a vaccine. Research done by Andrea Sant, Ph.D., professor within the David H. Smith Center for Vaccine Biology and Immunology at the University of Rochester Medical Center, claims to be new and groundbreaking but Laus, et al. incorporated all these aspects into the Antigen Delivery Cassette years ago. The points made in this article also help to explain why the GVAX concept was a dud…
Current strategies for designing vaccines against HIV and cancers, for instance, may enable some components in multi-component vaccines to cancel the effect of others on the immune system, eliminating their ability to provide protection, according to an article to be published shortly in the Proceedings of the National Academy of Sciences (PNAS).
What these folks found was that the avidity with which an antigen binds to the presenting mechanism of a dendritic cell, the MHC molecule, determines whether or not that antigen is going to produce a potent immune response and these peptides or antigen pieces were called “immunodominant.” Immunodominant peptides hold on to the MHC presenting molecule of a dendritic cell ten to a thousand times longer than nondominant peptides. By changing one amino acid of an antigen or the side chain of an amino acid so that it bound more tightly to the “anchor residues” of the MHC presenting “cleft” the antigen could induce a much stronger immune response. They called this “kinetic stability” of an antigen and identify it as perhaps the most important trait of an effective vaccine.
Sant and members of her laboratory including Francisco Chaves, Christopher Lazarski and Weaver have already shown that by switching out single amino acid building blocks, the team was able to drastically increase the potency of the T cell response to target peptides, including those that would otherwise fail to achieve a T cell response in the presence of other immunodominant peptides. Sant's team increased the ability of a cryptic peptide to hold onto MHC class II proteins by making changes to one or more of their four "anchor residues" responsible for binding into the pocket on the MHC Class II proteins, changes that sustained T cell responses.
Laus and his buddies incorporated this very trait into the Antigen Cassette years ago which may be one of the keys that account for the success of Provenge and the flexibility it gives Dendreon to make improvements in future Cassette designs of antigens that may be found to induce an even better immune response.
