Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody
Zachary A. Schiller, … , Mark S. Klempner, Yang Wang
Zachary A. Schiller, … , Mark S. Klempner, Yang Wang
Published April 29, 2021
Citation Information: J Clin Invest. 2021;131(11):e144843. https://doi.org/10.1172/JCI144843.
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Research Article Immunology Infectious disease

Blocking Borrelia burgdorferi transmission from infected ticks to nonhuman primates with a human monoclonal antibody

Abstract

Disrupting transmission of Borrelia burgdorferi sensu lato complex (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 mAb, 2217, prevents transmission of B. burgdorferi from infected ticks in animal models. Maintenance of a protective plasma concentration of a human mAb for tick season presents a significant challenge for a preexposure prophylaxis strategy. Here, we describe the optimization of mAb 2217 by amino acid substitutions (2217LS: M428L and N434S) in the Fc domain. The LS mutation led to a 2-fold 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 revealed that 2217 bound an epitope that was 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 preexposure 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.

Authors

Zachary A. Schiller, Michael J. Rudolph, Jacqueline R. Toomey, Monir Ejemel, Alan LaRochelle, Simon A. Davis, Havard S. Lambert, Aurélie Kern, Amanda C. Tardo, Colby A. Souders, Eric Peterson, Rebecca D. Cannon, Chandrashekar Ganesa, Frank Fazio, Nicholas J. Mantis, Lisa A. Cavacini, John Sullivan-Bolyai, Linden T. Hu, Monica E. Embers, Mark S. Klempner, Yang Wang

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Figure 2

LS mutation extends half-life of 2217 in FcRn mice and nonhuman primates.

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LS mutation extends half-life of 2217 in FcRn mice and nonhuman primates...
Observed 2217 (red circles) and 2217LS (blue squares) serum pharmacokinetic profile after a single dose of (A) 1 mg/kg in transgenic FcRn mice (n = 16 per group) and (B) 10 mg/kg in cynomolgus monkeys (n = 4 per group). The LS mutation reduced 2217 clearance in both species, leading to an observed 2-fold increase in half-life in both species (mouse P = 0.0105; nonhuman primate P = 0.006). Half-life comparisons were conducted using 2-sided Student’s t test. Symbols represent the means for each animal tested in n = 3 independent assays.