Multidimensional development of high-affinity anti-glycan antibodies to fight deadly bacterial infections

Abstract The development of immunotherapies focused on the surface glycans of bacteria is hypothesized to be a potential paradigm shift in the fight against life-threatening and antibiotic-resistant bacteria, an emerging and increasing health concern for which therapeutic options are limited. Our PO1 team will use chemistry to deconstruct and display bacterial glycan structures on an artificial platform to make them immunogenic and recognized by the immune system. Immune responses will be analyzed and dissected by bacteriologists, cellular and structural immunologists to determine the characteristics of what makes a vaccine or an antibody against glycans effective as an antibiotic and deployable in pre-clinical studies. This program that assembles some of the world experts in their respective fields is ambitious and intends to pioneer the effort of placing immunotherapy next to chemotherapy for the treatment of bacterial infections. Our unique combination of chemistry-immunology- bacteriology-structural biology will provide the necessary mechanistic understanding of what qualifies a vaccine or an antibody to be effective in immunotherapy. The team is already productive and has published the proofs of principle of the approach on which the science of this application is based: very high affinity antibodies can be produced against bacterial glycans exposed at the surface of antibiotic resistant bacteria and are effective at combating infectious challenges. We will expand our strategy to the surface glycans of three bacterial pathogens listed by WHO as "critical" or "high" priority: Staphylococcus aureus, Klebsiella pneumoniae, and Neisseria gonorrhea. The fundamental knowledge that we will gain from our studies should establish a very detailed blueprint of the immune recognition of glycans and glycopeptides by the immune system. The integration of the chemistry, immunology, and structural biology facets of the project directly into the bacteriology and in vivo models, will identify glycans targets and strategies to initiate pre-clinical studies.