A new molecular mechanism that generates different types of antibodies by insertion of extra fragments. Antibody engineering by nature

BELLINZONA (Switzerland) – August 23, 2017 – 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/en/feeds/4411), 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.

Comments from the researchers

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”.

Kathrin Pieper, a first co-author of the paper, says: "It is interesting that the novel mechanism of DNA insertion in antibody genes can be frequently found not only in the context of malaria, but also in the general population. Building upon these findings we can now develop new approaches to engineer B cells."

Joshua Tan, another first co-author of the paper, says: “It is interesting that such an unusual mechanism can be used by a relatively large number of people from malaria-endemic countries to generate anti-parasite antibodies.”

Luca Piccoli, another first co-author of the paper, says: “It’s surprising to find that our immune system can naturally produce bispecific antibodies through this new molecular mechanism. This discovery has potential for the engineering of new therapeutic antibodies”.

Claudia Daubenberger, Head of the Clinical Immunology Unit of the Swiss Tropical and Public Health Institute in Basel says: “P. falciparum malaria, one of the strongest evolutionary forces on the human genome, shaped occurrence of red blood cell disorders and genetics of the human immune system. Studying the functional interactions between humoral immunity and malaria at the single cell level adds another dimension to our appreciation of the impact of malaria on human physiology”.

Peter Crompton, group leader at the Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, in Rockville, Maryland says: “This is an exciting example of how studying natural infections in humans can yield new insights into the extraordinary capacity of the immune system to diversify its response to pathogens.”

About the Institute for Research in Biomedicine (IRB)

The Institute for Research in Biomedicine (IRB) was founded in 2000 in Bellinzona and was affiliated to the Università della Svizzera Italiana (USI) in 2010. Financed by private and public institutions, and by competitive grants, the IRB currently hosts 12 research groups and 115 researchers that investigate the mechanisms of host defence against infectious agents, cancer and degenerative diseases. With more than 530 publications in leading scientific journals, the IRB has gained an international reputation as a centre of excellence in human immunology. www.irb.usi.ch

Article reference

Public antibodies to malaria antigens generated by two LAIR1 insertion modalities. Kathrin Pieper, Joshua Tan, Luca Piccoli, Mathilde Foglierini, Sonia Barbieri, Yiwei Chen, Chiara Silacci-Fregni, Tobias Wolf, David Jarrossay, Marica Anderle, Abdirahman Abdi, Francis M. Ndungu, Ogobara K. Doumbo, Boubacar Traore, Tuan M. Tran, Said Jongo, Isabelle Zenklusen, Peter D. Crompton, Claudia Daubenberger, Peter Bull, Federica Sallusto & Antonio Lanzavecchia. DOI: 10.1038/nature23670. Advance Online Publication (AOP) on www.nature.com

Image captions

Fig.1: The scheme shows conventional antibodies with the antigen-recognizing variable region (in blue) and the new antibodies with the extra fragment LAIR1 (in red) generated through two different molecular mechanisms (courtesy of Luca Piccoli).

Fig. 2: The figure shows the different chromosomal origin of the inserts found in the antibody switch region in chromosome 14 of European donors (courtesy of Mathilde Foglierini).

Fig. 3: The image shows fluorescence staining of Plasmodiumfalciparum-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)

Further information are available from:

Antonio Lanzavecchia: [email protected] tel: +41765781508