Could vaccine adjuvants lead to new Lupus therapies?

Therapeutic vaccines are hot right now thanks to Dendreon’s recent approval for Provenge and the H1N1 scare of 2009 that resulted in the government pumping hundreds of millions of dollars into venture backed vaccine companies.  Many of the therapeutic vaccines now in development are subunit vaccines that require co-administration with an adjuvant to pump up the seroconversion.  As a result, Toll-like receptors (TLRs) have become one of the hottest areas of adjuvant development for venture and strategic investors alike. 

While I have seen a number of interesting TLR stimulant opportunities over the last year, I have only seen one TLR antagonist idea – and it happened to be a pretty darn cool one.

Lupus is a disease that occurs when a person’s immune system turns on its owner, resulting in significant inflammation and subsequent tissue damage to healthy cells.  One of the key mediators of Lupus-associated inflammation is interferon-alpha (INF-α), a cell signaling molecule that recruits immune cells to destroy pathogens, or in the case of Lupus, the person’s healthy cells.  The binding of pathogens to TLR, specifically TLR-7 and TLR-9, has been shown to increase the expression of INF-α, making researchers wonder if by antagonizing TLR activation could they decreased INF-α expression and subsequent destructive inflammation?

Dynavax Technologies Corp. and the Baylor Institute for Immunology Research published a study in Nature where they administered a TLR-7 / TLR-9 antagonist in two separate lupus prone mouse strains and then monitored INF-α expression levels.  What the researchers found was fairly astonishing, namely that by antagonizing TLR-7/9 they were able to decrease INF-α expression.  As the INF-α levels dropped, the mice became more sensitive to glucocorticoid therapy, the standard steroid therapy used to treat inflammation. 

This is positive news for Lupus patients because over time most stop responding to low dose steroid therapies, which in turn forces doctors to increase dose strength.  While increasing the steroid dose decreases inflammation, it is also associated with a litany of dangerous side effects.  By antagonizing TLR-7/9, there is a glucocorticoid dose sparing effect that could protect Lupus patients from many of the unwanted side effects associated with prolonged exposure to high dose steroids.

Toll-like receptors are ideal adjuvant targets because they promote the activation of cell-specific immunostimulation, but it would now seem the same principle holds true in reverse.  TLRs might also be a new class of drug targets for a number of inflammatory disorders including rheumatoid arthritis, Lupus, and Crohn’s disease, that could benefit from selective inhibition of molecules that mediate inflammation.  

University of Michigan > A New Tysabri

iBridge is a great resource for entrepreneurs who are looking for technologies to license.  Many premiere universities including Michigan, Columbia, MIT, Penn, and Harvard, participate in the iBridge program.  Launched by the Kauffman Foundation, iBridge “provides a public, centralized source for unbiased information about early stage technologies and inventions”.

Recently, an iBridge post by the Michigan tech transfer office caught my eye.

Inflammation is a fundamental response to tissue injury and invasion of pathogens, but it is detrimental in clinically important inflammatory disorders such as multiple sclerosis and inflammatory bowel disease. Leukocytes are key players in the inflammatory response cascade because of their antimicrobial, secretory, and phagocytic activities. They are recruited to the inflamed tissue by sequential adhesive interactions between leukocytes and the endothelium that are mediated by cell-adhesion molecules (CAMs) on the surface of the interacting cells.

Interactions of cell adhesion molecules (CAM) play central roles in mediating immune and inflammatory responses and understanding the mechanism CAM binding to their ligands is integral to developing therapeutic agents to treat diseases such as multiple sclerosis and inflammatory bowel disease.  MADCAM-1 and VCAM-1 are two CAMs that are tightly regulated by a4b7 integrin, which plays a crucial role in the physiological homing of T cells and monocytes on the intestinal microvasculature.

A team at the University of Michigan have designed a humanized antibody that blocks a4b7 integrin binding to MADCAM-1, which could provide a new therapeutic modality for inflammatory diseases. 

The a4b integrin family might be familiar to some people as this class includes the a4b1 integrin natralizumab, better known as Tysabri.  Natralizumab has wonderful efficacy but also the unintended side effect of making the brain vulnerable to the activation of the JC virus, which can lead to progressive multifocal leukoencephalopathy (PML). 

The Michigan team developed a more specific treatment of inflammatory and autoimmune diseases by targeting an interaction between adhesion molecules preferentially expressed on pathogenic T cells and in chronically infected gut and liver. The inventors used the animal model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), to show previously undocumented expression of the α4-β7 integrin complex and MADCAM-1. This targeted approach to CAM inhibition has great potential to induce  strong efficacy with relatively less side effects when translated to the clinic.