This work describes targeted mutations applied to several HIV-1 neutralizing antibodies that have been isolated from HIV+ donors. The mutations are designed to increase breadth, potency and half-life to improve potential efficacy for therapeutic application and to decrease immunogenicity to allow for more effective and longer lasting in vivo function. There are also structure-based mutations designed to improve affinity and neutralization potency, which are based on the crystal structures. These modifications are tested against a panel of HIV-1 viruses to determine the breadth and strength of their ability to neutralize. The most potent of these candidates are then selected for testing in in vivo models with the long term goal of testing in humans. In this regard, we are developing improved variants of 10E8 HIV neutralizing antibody that retain broad neutralizing activity against HIV-1 and test the best candidate in NHP models for pharmacokinetic parameters and protection from mucosal SHIV challenges. In addition, we have started collaborative work with Sanofi to develop trispecific anti-HIV-1 antibodies that combine 3 different anti-HIV-1 specificities in one IgG like molecule for both HIV-1 prevention and therapy. In another collaborative effort with GSK, we are developing improved N6-like antibodies for use in HIV-1 therapy. The treatment of AIDS with combination antiretroviral therapy (cART) remains lifelong largely because the virus persists in latent reservoirs. Elimination of latently infected cells could therefore reduce treatment duration and facilitate immune reconstitution. We have developed immunomodulatory proteins that combines the specificity of a HIV-1 broadly neutralizing antibody with that of an antibody to the CD3 component of the T-cell receptor. These immunomodulatory proteins could potentially help to eliminate latently infected cells and deplete the viral reservoir in HIV-1-infected individuals. In addition, we have started collaborative work with Sanofi to develop multifunctional immunomodulatory proteins that activate T cells to lyse HIV-1 infected cells.
