Antibody diversification by templated insertions: impact, mechanism and exploitation

Objectives

This project aims at investigating and exploiting a new mechanism of antibody diversification that we recently discovered (Tan et al., 2015). Briefly, we found that up to 10% of malaria-exposed individuals make antibodies in which the DNA encoding the extracellular domain of LAIR1 (a collagen-binding inhibitory receptor encoded on chromosome 19) is inserted in the immunoglobulin (Ig) genes, either between the V and DJ segments or in the switch region.

This objective will be achieved through:

• developing new sequencing strategies to identify templated insertions in Ig genes, to establish their frequency and origin
• understanding the mechanisms that cause templated insertions in Ig genes 
• producing a new format of bispecific antibodies by inserting antigen-binding domains, such as VHH, scFv or viral receptors, in the antibody VH-CH1 elbow, a format that we have recently identified in LAIR1-containing antibodies
• engineering primary B cells to make bispecific antibodies by inserting selected domains in the switch region leading to their expression in the VH-CH1 elbow