Genetically engineered red cells expressing single domain camelid antibodies confer long-term protection against botulinum neurotoxin

Nai-Jia Huang, Novalia Pishesha, Jean Mukherjee, Sicai Zhang, Rhogerry Deshycka, Valentino Sudaryo, Min Dong, Charles B. Shoemaker () and Harvey F. Lodish ()
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Nai-Jia Huang: Whitehead Institute for Biomedical Research
Novalia Pishesha: Whitehead Institute for Biomedical Research
Jean Mukherjee: Tufts Cummings School of Veterinary Medicine
Sicai Zhang: Harvard Medical School
Rhogerry Deshycka: Whitehead Institute for Biomedical Research
Valentino Sudaryo: Whitehead Institute for Biomedical Research
Min Dong: Harvard Medical School
Charles B. Shoemaker: Tufts Cummings School of Veterinary Medicine
Harvey F. Lodish: Whitehead Institute for Biomedical Research

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract A short half-life in the circulation limits the application of therapeutics such as single-domain antibodies (VHHs). We utilize red blood cells to prolong the circulatory half-life of VHHs. Here we present VHHs against botulinum neurotoxin A (BoNT/A) on the surface of red blood cells by expressing chimeric proteins of VHHs with Glycophorin A or Kell. Mice whose red blood cells carry the chimeric proteins exhibit resistance to 10,000 times the lethal dose (LD50) of BoNT/A, and transfusion of these red blood cells into naive mice affords protection for up to 28 days. We further utilize an improved CD34+ culture system to engineer human red blood cells that express these chimeric proteins. Mice transfused with these red blood cells are resistant to highly lethal doses of BoNT/A. We demonstrate that engineered red blood cells expressing VHHs can provide prolonged prophylactic protection against bacterial toxins without inducing inhibitory immune responses and illustrates the potentially broad translatability of our strategy for therapeutic applications.

Date: 2017
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DOI: 10.1038/s41467-017-00448-0

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