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ABSTRACTThe amino-acid composition of the immunoglobulin variable region has been observed to impact antibody pharmacokinetics (PK). Here, we sought to improve the PK of the broad HIV−1-neutralizing VRC01-class antibodies, VRC07-523LS and N6LS, by reducing the net positive charge in their variable domains. We used a structure-guided approach to generate a panel of antibody variants incorporating select Arg or Lys substituted to Asp, Gln, Glu, or Ser. The engineered variants exhibited reduced affinity to heparin, reduced polyreactivity, and improved PK in human FcRn-transgenic mice. One variant, VRC07-523LS.v34, with three charge substitutions, had an observed in vivo half-life and an estimated human half-life of 10.8 and 60 days, respectively (versus 5.4 and 38 days for VRC07-523LS) and retained functionality, neutralizing 92% of a 208-strain panel at a geometric mean IC80

In addition to advancing important options for treatment and prevention of HIV infection, bNAbs also serve as a window into the levels of activity a future HIV vaccine will need to be able to trigger [11]. Antibody-mediated prevention, HIV vaccine efficacy, broad neutralizing antibodies, HIV treatment and prevention, long-acting, pre-exposure prophylaxis Keywords: antibody-mediated prevention; broad neutralizing antibodies; HIV treatment and prevention; HIV vaccine efficacy; long-acting; pre-exposure prophylaxis EN antibody-mediated prevention broad neutralizing antibodies HIV treatment and prevention HIV vaccine efficacy long-acting pre-exposure prophylaxis 1 2 2 11/24/21 20211102 NES 211102 The development of highly effective treatment and prevention strategies for HIV has been a significant scientific achievement over the past 25 years. [Extracted from the article]