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Structural, genetic and functional analyses of broadly neutralizing antibodies against human pathogens

Periodic Reporting for period 3 - BROADimmune (Structural, genetic and functional analyses of broadly neutralizing antibodies against human pathogens)

Reporting period: 2018-10-01 to 2020-03-31

We are interested to understand the basis of antibody-mediated protection from infectious agents, in particular influenza virus and P. falciparum. In particular, we address the problem of immunodominance, the role of antigen-specific T cells in shaping the antibody response and the role of somatic mutations in antibody diversification. The most significant and unexpected result was the discovery of a new mechanism of antibody diversification through templated DNA insertion into antibody genes. Collectively our results identify potent and broadly neutralizing antibodies that represent candidates for prophylaxis and therapy of infectious diseases as well as essential cues for the development of better vaccines. Our main objective is to advance these approaches to the clinical phase to bring our research to fruition for the society.
We made progress on the characterization of broadly neutralizing antibodies against the HA stem. We isolated a human monoclonal antibody with unprecedented breadth and potency. We also isolated and mapped a large panel of anti HA head antibodies and developed a quantitative and site-specific serological assay to measure serum antibody levels against distinct HA sites. We developed a peptidomics platform for the identification of naturally processed peptides and determined the molecular basis for immunodominance by comparing the naïve and memory repertoires. We also discovered public antibodies that potently block sporozoite infection of hepatocytes and therefore have the potential to provide sterilizing immunity. Finally, we discovered a new type of receptor-based antibodies generated by templated DNA insertion into antibody genes.
The most significant discovery, and definitely beyond the state of the art, is the finding of a new type of receptor-based antibodies generated by templated insertions into an antibody gene of DNA encoding a pathogen receptor. In 10% of malaria-exposed individuals a single B cell clone with a LAIR1 insert generates a dominant antibody response (left panel). Furthermore, templated inserts are frequently found in antibody genes of European blood donors (right panel). In conclusion, we learned from nature how to engineer antibodies by insertion of an antigen-binding domain in the VH-CH1 elbow. Before the end of the project we expect to find other examples of receptor-based antibodies and to fully exploit the new antibody format for the production of bispecific antibodies and for B cell engineering.
Scheme showing the LAIR1 insert