Gene edited B cells to co-express CNS-targeted antibodies

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ABSTRACT The CNS is a viral reservoir in HIV-infected individuals, 50% of whom will eventually develop HIV- associated neurodegeneration (HAND), despite antiretroviral drugs. Antibodies can also be powerful antivirals, promoting virus neutralization and the removal of HIV-infected cells through mechanisms such as ADCC and ADCP. Of special interest are broadly neutralizing antibodies (bnAbs), which can recognize the Env proteins from diverse viral strains and are therefore somewhat resistant to viral escape. As such, bnAbs are considered a promising approach for treating or preventing HIV infection, although the lack of induction of bnAbs by vaccination means that they are currently only used as injected proteins, or expressed from gene therapy vectors in non-immune tissues. An additional concern for CNS infections is that antibodies are present at lower rates in the CNS than the blood, although this can be enhanced by the addition of brain penetrating modules to the antibody. We have developed a gene editing strategy that allows us to reprogram human B cells to express specific antibodies. Our strategy takes advantage of the ability of B cells to respond to the presence of their cognate antigen, resulting in long-term secretion of the engineered antibody. We will now adapt this strategy to allow the co-expression of both bnAbs and modified brain-penetrating antibodies (BP-Ab) from the same edited cells. Using a range of assays, we will evaluate whether BP-Abs expressed from edited B cells retain full anti-HIV activities and show enhanced delivery to the CNS. In this way we will have developed the necessary proof of concept that a B cell therapy could be developed to provide long-term, HIV-responsive expression of brain- penetrating bnAbs.