Human antibodies: from natural and artificial engineering to the analysis of repertoires

• Applicant: Professorin Dr. Kathrin de la Rosa
• Subject Area: Immunology
• Term: from 2018 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 394523286

A vast repertoire of antibody specificities is created by the somatic recombination and imprecise joining of a limited number of variable (V), diversity (D) and joining (J) segments, followed by somatic mutations. Recently, we discovered a new mechanism of antibody diversification whereby non-VDJ-sequences are inserted into antibody genes to provide the crucial antigen-binding element. Specifically, more than 5% of malaria exposed individuals produce antibodies that contain an extra domain encoded by the LAIR1 gene that creates a hybrid-antibody that broadly binds to Plasmodium falciparum infected erythrocytes. Importantly, there is preliminary evidence that other non-VDJ DNA sequences are integrated into antibody-genes, a finding that hints at a general relevance of templated insertions in the generation of antibody diversity. The proposed research project aims to develop an in vitro system to investigate the origin of the inserts and the molecular mechanisms that lead to templated DNA insertion into the antibody genes. Besides its fundamental interest, deciphering this mechanism bears the potential to exploit it for the engineering of primary B cells. Therefore, another objective of this project is to develop an in vitro method by which antibodies specific for challenging pathogens are generated by the insertion of pathogen-receptor domains. Finally, the research proposal aims to study human antibody repertoires and to characterize other DNA-sequences that contribute to functional antibodies by donating pathogen binding elements. As these novel antibodies are expected to be rare, high throughput repertoire sequencing will be combined with functional antibody screenings to address other relevant immunological questions by dissecting the B cell repertoire with regard to its specificity.The proposed program addresses basic immunological research and develops a novel approach for the engineering of primary B cells which has translational potential.

• DFG Programme: Independent Junior Research Groups