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In vivo engineered B cells retain memory and secrete high titers of anti-HIV antibodies in mice

By Alessio D Nahmad, Cicera R. Lazzarotto, Natalie Zelikson, Talia Kustin, Mary Tenuta, Deli Huang, Inbal Reuveni, Miriam Horovitz-Fried, Iris Dotan, Rina Rosin-Arbesfeld, David Nemazee, James E. Voss, Adi Stern, Shengdar Q. Tsai, Adi Barzel

Posted 09 Apr 2021
bioRxiv DOI: 10.1101/2021.04.08.438900

As a potential single-shot HIV therapy, transplanted engineered B cells allow robust secretion of broadly neutralizing antibodies (bNAbs). However, ex vivo engineering of autologous B cells is expensive and requires specialized facilities, while allogeneic B cell therapy necessitates MHC compatibility. Here, we develop in vivo B cell engineering, by injecting two adeno associated viral vectors, one coding for saCas9 and another coding for a bNAb. Following immunizations, we demonstrate memory retention and bNAb secretion at neutralizing titers. We observed minimal CRISPR/Cas9 off-target cleavage, using unbiased CHANGE-Seq analysis, while on-target cleavage at undesired tissues is reduced by expressing saCas9 from a B cell specific promoter. In vivo B cell engineering is thus a safe, potent and scalable method for expressing desired antibodies against HIV and beyond.

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