Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody
| Autor: | Chandrashekar Ganesa, Colby A. Souders, John Sullivan-Bolyai, Frank Fazio, Nicholas J. Mantis, Eric Peterson, Monica E. Embers, Zachary A. Schiller, Havard S. Lambert, Alan LaRochelle, Rebecca D. Cannon, Yang Wang, Michael J. Rudolph, Aurelie Kern, Lisa A. Cavacini, Mark S. Klempner, Monir Ejemel, Jacqueline R. Toomey, Linden T. Hu, Amanda C. Tardo, Simon A. Davis |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Male medicine.drug_class Lipoproteins Mutation Missense Mice Transgenic Biology Tick Monoclonal antibody Epitope 03 medical and health sciences Mice 0302 clinical medicine Lyme disease Ticks parasitic diseases medicine Animals Humans Borrelia burgdorferi Lyme Disease Transmission (medicine) Antibodies Monoclonal General Medicine biology.organism_classification medicine.disease bacterial infections and mycoses Virology Antibodies Bacterial Macaca mulatta Bacterial vaccine Rhesus macaque Disease Models Animal Macaca fascicularis 030104 developmental biology Amino Acid Substitution 030220 oncology & carcinogenesis Antigens Surface Bacterial Vaccines Research Article Bacterial Outer Membrane Proteins |
| Zdroj: | J Clin Invest |
| Popis: | Disrupting transmission of Borrelia burgdorferi (B. burgdorferi ) from infected ticks to humans is one strategy to prevent the significant morbidity from Lyme disease. We have previously shown that an anti-OspA human monoclonal antibody, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Maintenance of a protective plasma concentration of a human monoclonal antibody for tick season presents a significant challenge for a pre-exposure prophylaxis strategy. Here, we describe the optimization of 2217 by amino acid substitutions (LS, M428L and N434S) into the Fc domain. The LS mutation led to a twofold-increase in half-life in cynomolgus monkeys. In a rhesus macaque model, 2217LS protected animals from tick transmission of spirochetes at a dose of 3 mg/kg. Crystallographic analysis of Fab in complex with OspA reveals that 2217 binds a novel epitope that is highly conserved among the B. burgdorferi, B. garinii, and B. afzelii species. Unlike most vaccines that may require boosters to achieve protection, our work supports the development of 2217LS as an effective pre-exposure prophylaxis in Lyme-endemic regions with a single dose at the beginning of tick season offering immediate protection that remains for the duration of exposure risk. . |
| Databáze: | OpenAIRE |
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