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

Información del proyecto

BROADimmune

Identificador del acuerdo de subvención: 670955

DOI

10.3030/670955

Proyecto cerrado

Fecha de la firma de la CE 30 Septiembre 2015

Fecha de inicio 1 Octubre 2015

Fecha de finalización 30 Septiembre 2020

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 867 500,00

Aportación de la UE

€ 1 867 500,00

Coordinado por

FONDAZIONE PER L'ISTITUTO DI RICERCA IN BIOMEDICINA
Switzerland

Periodic Reporting for period 4 - BROADimmune (Structural, genetic and functional analyses of broadly neutralizing antibodies against human pathogens)

Período documentado: 2020-04-01 hasta 2020-09-30

Resumen del contexto y de los objetivos generales del proyecto

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.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

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 peptidomic 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, and most importantly, we discovered a new type of receptor-based antibodies generated by templated DNA insertion into antibody genes.

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

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 or LILRB1 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.

Scheme showing the LAIR1 insert