Antibody engineering by nature

A publication in the renowned scientific journal Nature describes two new types of non-conventional antibodies that are frequently produced by malaria-exposed individuals and that contain an extra fragment targeting malaria parasites. The study was conducted at the Institute for Research in Biomedicine (IRB), which is affiliated to the Università della Svizzera Italiana (USI), in collaboration with the KEMRI-Wellcome Trust Research Programme in Kenya, the Malaria Research and Training Centre in Mali, the Ifakara Health Institute in Tanzania, the Swiss Tropical and Public Health Institute in Basel and the University of Oxford. The study was supported by the Swiss Vaccine Research Institute, the Fondazione Aldo e Cele Daccò and the European Research Council (ERC).

Background

The Plasmodium falciparum parasite causes the most severe and deadly form of malaria. Nevertheless, individuals living in malaria-endemic regions can become protected by producing antibodies that recognize different malaria parasites.

Two years ago (www.usi.ch/it/comunicati-stampa/2045), the IRB team and their collaborators discovered a new class of antibodies that showed broad reactivity to malaria parasites thanks to the presence of a large extra fragment in the antibody structure. This fragment, called LAIR1, originated from a DNA piece on chromosome 19 that was inserted into the antibody gene on chromosome 14 to generate non-conventional antibodies that bind to specific parasite proteins named RIFINs. These results showed, in the relevant context of malaria infection, a novel mechanism of antibody diversification, but at this point the frequency of these particular antibodies and the underlying mechanism were not known.

The discovery

The IRB team and their collaborators discovered that LAIR1-containing antibodies are present in up to 10% of malaria-exposed individuals from Kenya, Mali and Tanzania, which suggests that this new type of antibody is a common way to fight the infection. Many of these antibodies are similar to the ones previously described, but others showed a novel structure in which LAIR1 is inserted in the so-called “elbow” of the antibody. This insertion mechanism differs from the one described in the first study as it is capable of generating an antibody with two different specificities (called a bispecific antibody). Importantly, by studying European donors not exposed to malaria, the researchers found that DNA sequences derived from all chromosomes can be inserted into antibody genes and, in some cases, may generate new bispecific antibodies. These results suggest that the new insertion modality represents an additional mechanism of antibody diversification that can be selected in the immune response against pathogens and exploited for B cell engineering to develop new therapeutic approaches.

Accroding to Antonio Lanzavecchia, director of the IRB, and senior author of the study, says:  “It is amazing that today we still discover new types of antibodies generated through a new molecular mechanism. This shows how the study of the human immune response, which we have working on for a long time at IRB, can lead not only to fundamental discoveries, but also to new therapeutic applications. For many years, scientists have searched for new ways to engineer antibodies. Now we know that nature has already exploited this mechanism”.

The image shows fluorescence staining of Plasmodium falciparum-infected red blood cells. The LAIR1-containing antibody binds to a parasite protein on the membrane of the red bloods cell (in red). The parasite nuclei are stained in green (courtesy of Joshua Tan)