Chapter 129
Controlling Our Immune System — 6
Nanoparticles top my list. More than two decades ago, Pere Santamaria at the University of Calgary, who suffers from the autoimmune condition of myasthenia gravis, made a groundbreaking discovery with iron oxide nanoparticles loaded with “bait” antigens (fig. 9.3). The bait antigens (from the major histocompatibility complex or MHC) attract T cells, which in turn multiply and develop into Tregs. The process simulates the antigen-presenting cells—dendritic, immature macrophages, and B cells—that have MHC class II molecules to present to T cells. The massive number of Tregs generated in this way can bind and deactivate cells that carry a multitude of antigens. The University of Calgary spun out Pere Santamaria’s company, Parvus Therapeutics, which has signed licensing and collaboration agreements with Genentech and others worth more than $1 billion, and started its first clinical trial with what are now called “navacims” in 2024 for autoimmune hepatitis.
Figure 9.3. “Bait” antigens: nanoparticles carry an antigen from the major histocompatibility complex to attract T cells, which in turn can generate a massive number of Tregs. Adapted from Cassandra Willyard, “Can autoimmune diseases be cured? Scientists see hope at last,” Nature 625, no. 7996 (January 2024): 646–48, https://doi.org/10.1038/d41586-024-00169-7.
Speaking of hepatitis, a disease-causing liver inflammation, most people would not have thought a basis for curing autoimmune disease might operate through that organ. But more than a decade ago, a paper was published that portrayed the liver as “a type of ‘school’ where liver antigen-presenting cells function as ‘teachers’ and circulating immune cells function as ‘students.’ ” By attaching sugar molecules (glycosylated) to antigens, Jeffrey Hubbell and colleagues at the University of Chicago were able to get the liver antigen-presenting cells to delete autoreactive CD4+ and CD8+ cells and expand Tregs, preventing type 1 diabetes in the experimental mouse model. Subsequently, the same team used this approach with glycosylated myelin proteins in a mouse model of multiple sclerosis, which stopped neural damage and reversed symptoms, and a nonhuman primate model. Their company, Anokion, has completed phase 1 trials in multiple sclerosis and celiac disease and is moving onto phase 2 for these conditions.
In mouse models, there’s been success with tolerogenic vaccines for autoimmune encephalomyelitis, the animal model that resembles multiple sclerosis, and in the preclinical model for rheumatoid arthritis. The former was achieved by an mRNA-based nanoparticle approach by BioNTech, a company behind the COVID mRNA vaccine, using a myelin oligodendrocyte peptide as the antigen. A vaccine comprised of a glycosylated collagen antigen that binds to a T cell receptor was effective in the rheumatoid arthritis model with a potent effect of stimulating Tregs and protecting against arthritis. These are examples of single autoantigen vaccines, but there are many others, such as the use of a cocktail of autoantigens, and ongoing clinical trials for a variety of autoimmune disorders. The term inverse vaccines—deactivating the immune response—has gained usage because, historically, vaccines were intended to strengthen our immune system, whereas these and related approaches have the opposite goal.