on September 11, 2019
An international research team led by the Institute for Research in Biomedicine, affiliated to the Università della Svizzera italiana, has discovered why some patients with multiple sclerosis make an immune reaction that curtails the effectiveness of natalizumab, a therapeutic antibody used for the treatment of the disease and used this information to engineer a new version of the antibody that avoids this problem.
This work, published in the renowned scientific journal Nature Medicine, was carried out in collaboration with researchers from Sanofi R&D (France), from the Innsbruck Medical University (Austria) and from the Mondino Foundation in Pavia (Italy). The study was partially funded by the Swiss National Science Foundation (SNSF) and by the Innovative Medicines Initiative Joint Undertaking ABIRISK.
Background
Monoclonal antibodies, such as natalizumab, are a novel class of drugs that can be used to effectively treat autoimmune diseases and cancer, but their efficacy is undermined by the capacity of the immune system to mount an antibody response against the drug itself. In particular, natalizumab is a very effective drug in the treatment of patients with relapsing-remitting multiple sclerosis by blocking the migration of inflammatory leukocytes into the central nervous system thus reducing inflammation. Unfortunately, about 6% of the patients cannot benefit of this treatment because they produce anti-drug antibodies that block natalizumab activity. Understanding the biological basis of this unwanted immune response is crucial to develop a more effective version of natalizumab as well as of other therapeutic antibodies.
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| Structure of a neutralizing antibody (blue) binding to natalizumab (grey) (courtesy of Luca Piccoli; structure provided by Vincent Mikol and collaborators). |
The discovery
The Swiss team isolated a panel of monoclonal antibodies from multiple sclerosis patients who had an allergic reaction to natalizumab infusion and discovered that some antibodies acquired neutralizing activity by making a strong interaction with the drug. Interestingly, they also found that this anti-drug antibody response was driven by just a few specific T cells that recognized a small portion of the drug. Using this information, they were able to engineer a “deimmunized” version of the drug that is not recognized by specific T cells.
In summary, this study has demonstrated a general approach to remove the Achilles’ heel of therapeutic antibodies with the potential to increase their efficacy.
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| Identification of the Achilles’ heel (blue) of natalizumab (grey) responsible for its immunogenicity. Deimmunization of this portion does not affect binding to NZM target (orange) that occurs through other sites of the antibody (green) (courtesy of Luca Piccoli) |
Comments from the researchers
Luca Piccoli, coordinator and senior author of the study, says: “The successful integration of the most advanced technologies allowed us to identify the Achilles’ heel of an effective antibody used to treat multiple sclerosis. This is a very powerful approach to guide the deimmunization strategies of next-generation antibodies”.
Antonino Cassotta, a co-author of the paper says: “It’s amazing to find how such a small region in the natalizumab molecule can trigger a broad and potent neutralizing antibody response in different patients and it’s even more exciting to be able to reduce the immunogenicity of a drug”.
Antonio Lanzavecchia, director of IRB and co-author of the paper says: “The successful deimmunization strategy applied for natalizumab is encouraging for the improvement of other therapeutic antibodies that are currently in use, including checkpoint inhibitors for cancer therapy that cause an unwanted immune response in some patients. Reciprocally, this approach could also be used to improve the immunogenicity of vaccines”.
Federica Sallusto, coauthor of the study says: “The detailed analysis shows how interconnected are the different players of the immune response against biological drugs. More patients will benefit from rational engineering that generates deimmunized versions of these biomolecules”.
Article
A single T cell epitope drives the neutralizing anti-drug antibody response to natalizumab in multiple sclerosis patients. Antonino Cassotta, Vincent Mikol, Thomas Bertrand, Stéphanie Pouzieux, Josiane Le-Parc, Paul Ferrari, Jacques Dumas, Michael Auer, Florian Deisenhammer, Matteo Gastaldi, Diego Franciotta, Chiara Silacci-Fregni, Blanca Fernandez Rodriguez, Isabella Giacchetto-Sasselli, Mathilde Foglierini, David Jarrossay, Roger Geiger, Federica Sallusto, Antonio Lanzavecchia, Luca Piccoli. DOI: 10.1038/s41591-019-0568-2. Nature Medicine, volume 25, pages1402–1407 (2019)
