Therapeutic anti-glycan antibodies against antibiotic resistant Staphylococcus aureus

Abstract

Antibiotic resistance threatens clinical control of bacterial infections while the genetic adaptability of microbes continues to outpace small-molecule development. The combinatorial diversity of antibodies offers a solution to this problem. However, under normal circumstances the polymeric glycans of bacterial surfaces avoid adaptive recognition by not binding to MHC molecules. Thus, they are T cell independent antigens and targeted only by low affinity IgM responses. Glycoconjugate vaccines have been developed to provide bystander T cell help to overcome this limitation but have failed to elicit protective responses against antibiotic resistant Staphylococcus aureus in clinical trials. To address limitations in current conjugate vaccine approaches, we optimized anti-glycan B cell help through three convergent prongs: exploiting cognate T cell help, using a B cell-centric adjuvant, and using synthetic minimal glycans. This prototype next generation conjugate vaccine was used to produce nanomolar affinity anti-glycan responses in proof-of-concept studies. Focusing on antibiotic resistant Staphylococcus aureus three glycan targets of the cell wall and bacterial capsule have been selected and used to produce monoclonal antibodies. These antibodies were characterized structurally, biophysically, and by B cell sequencing to confirm high affinity, maturation, and specificity towards the intended targets. The potential therapeutic benefits are currently being tested in three preclinical mouse models: skin, lung, and systemic infection, using passive and active immunization. Preliminary studies have shown therapeutic efficacy in both a preventative and interventional model for some of these antibodies. Kenna Nagy supported by: NIH TL1TR002551 For this project P.I. Luc Teyton supported by: NIH U01 AI160338, NIH R01 AI139748