A novel mechanism of antibody synergy mediated through lateral interactions

The CyRPA protein of Plasmodium falciparum is essential for the parasite to get inside human red blood cells. If we can stop erythrocyte invasion, then we can prevent malaria. To guide us in our goal of generating CyRPA-based vaccines, we therefore wanted to understand how CyRPA-targeting antibodies can prevent erythrocyte invasion.

cyrpamabs

A small panel of monoclonal antibodies targeting CyRPA was collected and Rob Ragotte assessed the ability of each to block erythrocyte invasion. These antibodies were divided into those with growth inhibitory activity and those without. However, most interesting was the ability of different growth inhibitory antibodies to synergise with each other. Three antibodies were more growth inhibitory when combined together in pairs than would be expected from adding together their individual potencies. How do they do this?

To answer this question, Rob joined us to use structural biology tools to assess how these synergistic antibodies function. He was able to map the binding of the key antibodies to CyRPA, finding their epitopes. He also determined a structure of CyRPA bound simultaneously to all three synergistic growth-inhibitory antibodies. This structure showed that these antibodies do not just bind to CyRPA. They also bind to each other, through lateral antibody-antibody interactions. Binding studies also showed that these lateral interactions increase the stability of the antibody-CyRPA complexes.

These CyRPA antibodies show us for the first time that antibodies can make lateral ‘heterotypic’ interactions with other antibodies, stabilising their binding to an important antigen and increasing their potency. This discovery has consequences for vaccine design as vaccine immunogens which generate such synergistic antibody mixtures are likely to give a robust immune response.

Ragotte, R.J., Pulido, D., Lias, A.M., Quinkert, D., Alanine, D.G.W., Jamwal, A., Davies, H., Nacer, A., Lowe, E.D., Grime, G.W., Illingworth, J.J., Donat, R.F, Garman, E.F., Bowyer, P.W., Higgins, M.K.*, Draper, S.J.* (2022) Heterotypic interactions drive antibody synergy against a malaria vaccine candidate. Nature Communications 13 933 (* joint corresponding)