Removing the Achilles heel of therapeutic antibodies for multiple sclerosis


An international team of researchers coordinated by the Institute of Research in Biomedicine (IRB, affiliated with the University of Italian Switzerland) has discovered why a monoclonal antibody drug prescribed for the treatment of multiple sclerosis are not effective in some patients. The scientists at IRB and Sanofi used this information to design a new version of the antibody that avoids this problem. X-ray crystallography carried out on the ESRF’s MASSIF-1 (ID30A-1) beamline was critical to enable successful structure based de-immunization. 

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Monoclonal antibodies are a new class of powerful drugs used to treat autoimmune diseases and various cancers, but their effectiveness can be compromised by the immune system's ability to develop antibodies against the drugs themselves. Natalizumab is a monoclonal antibody which is very effective drug in the treatment of patients with relapsing-remitting multiple sclerosis. The drug is able to block the migration of leukocytes into the central nervous system and therefore reduces inflammation. Unfortunately, about 6% of patients cannot benefit from this treatment because they produce anti-drug antibodies that neutralize the activity of natalizumab. Understanding the biological basis of this unwanted immune response is essential for the development of  more effective versions of natalizumab and of therapeutic antibodies in general.

The team of researchers isolated a class of monoclonal antibodies from patients with multiple sclerosis who had experienced an allergic reaction after receiving natalizumab. They discovered that some of these antibodies interacted so strongly with the drug that it neutralized its activity. Furthermore, the researchers found that this antibody response is triggered by a few T cells that can recognize a small portion of the drug. Using this information, they were able to engineer a ‘de-immunized’ version of the drug that is not recognized by such T cells.

The scientists carried out X-ray crystallography experiments on the ESRF’s MASSIF-1 (ID30A-1) beamline to elucidate the inter-molecular interactions of various neutralizing antibodies with natalizumab. According to Luca Piccoli, coordinator and co-author of the study, "By integrating the most advanced technologies, such as the ESRF, we have successfully identified the Achilles heel of an antibody effective in treating multiple sclerosis. This is a very powerful approach to guide the de-immunization strategies of new-generation antibodies". Vincent Mikol from Sanofi, supervisor of the structural study and in charge of the deimmunization design adds ““The high quality beamline at the ESRF combined with its high throughput, fully automated data collection system has enabled us to readily collect data and solve in a timely fashion the crystal structure of these antibody complexes providing a structural template for successful deimmunization of natalizumab”.

The results obtained here may be important for the development of other monoclonal antibody drugs treating diseases such as cancer, for example. Antonio Lanzavecchia, director of the IRB and co-author of the study, states: "The deimmunization strategy that we’ve used for natalizumab can be used for the improvement of other therapeutic antibodies currently in use, including ‘immune checkpoint inhibitors’ used for cancer therapy and which in some patients also cause an undesirable immune response".

The study, published in the renowned scientific journal Nature Medicine, was produced in collaboration with researchers from Sanofi (France), the University of Innsbruck (Austria) and the Mondino Foundation of Pavia (Italy). This work was supported by the Swiss National Science Foundation (grant no. 176165 to A.L.) and by the Innovative Medicines Initiative Joint Undertaking ABIRISK (Anti-Biopharmaceutical Immunization: Prediction and analysis of clinical relevance to minimize the risk) project under grant agreement no. 115303, resources of which are composed of financial contribution from the European Union’s Seventh Framework Program (FP7/2007-2013) and EFPIA Companies.

Cassota, A., et al, Nature Medicine,
 volume 25, pages1402–1407 (2019).

Top image: Structure of a neutralizing antibody (blue) binding to natalizumab (grey) (courtesy of Luca Piccoli; structure provided by Vincent Mikol and collaborators).