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We’re so happy to see that the FDA included some of our favorite topics: Tregitope (as modulator of regulatory T cells), HLA (correlation with …) and analysis of HLA class II binding epitopes (presumably with silico tools, like our ISPRI toolkit) in their new Immunogenicity Guidelines. For a copy, click here.


The guidelines suggest that “more advanced analyses of [therapeutic protein or monclonal antibody] primary sequence are also likely to detect HLA class II binding epitopes in nonpolymorphic human proteins. Such epitopes may elicit and activate regulatory T cells which enforce self tolerance, or opposingly, could activate T helper (Th) cells when immune tolerance to the endogenous protein is not robust.”

Gotta love it! And it just so happens that we’re the only group out there that can perform an “advanced analysis” of protein therapeutics that includes proprietary knowledge of T cell epitopes that activate regulatory T cells (a.k.a. Tregitopes)! If you are interested in having us do that for you, please contact us here.


If you want to go to our original publications cited in this section of the FDA draft guidelines, here they are:  Weber et al.; T cell epitope: friend or foe?, Immunogenicity of biologics in context. Adv Drug Deliv Rev. 2009; and the Tregitope paper, De Groot et al. 2008. While we’re at it, there are three (!!) new Tregitope publications available on line, all published in 2013 – with more to come! See all of our Tregitope Publications here.

And How:

tregitope diagram
How does Tregitope suppress immune response to biologics? Here’s what we think is going on…(see picture). Tregitopes present in IgG antibodies such as monoclonals (some have them, some don’t) are processed and presented to Tregitope-specific regulatory T cells. These cells actively suppress (via cytokines, and by directly influencing the APC phenotype) the immune response of nearby T-effectors that are responding to the protein therapeutic (monoclonal antibody, or as shown, another protein drug). We (and others) have shown that the effector T cell may be altered following this interaction, becoming an “induced” or “adaptive” Treg that is specific to the protein that is administered with Tregitope. The effect is localized (not systemic) and antigen-specific. Clearly, Tregitopes are relevant for a wide range of applications in biologic therapeutics, and now the FDA thinks so too!

As can be seen here, not only is this relevant to monoclonal antibodies, but it’s relevant to biologics too (think enzyme-replacement therapy, blood factors such as FVIII, and so on). And, in an exciting new publication, Federico Mingozzi demonstrates that Tregitopes can suppress immune response to antigen-specific CD8+ T cells, a finding that has enormous relevance to the gene therapy field. For more information about the fabulous Tregitopes, send us a request for a presentation, collection of papers, or in-person meeting here.

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