Trispecific Antibody Against Hiv-1 Demonstrate Anti-Viral Activity In Vivo And Have Potent Fc-Dependent Effector Functions

Abstract Broadly neutralizing antibodies (bNAbs) against HIV-1 have been suggested as a complementary immunotherapy to current combination small molecule anti-retroviral therapies (cART) for treatment of HIV-1 infection. Monoclonal bNAbs when used as a monotherapy demonstrate high susceptibility for escape in HIV-1 infected individuals, thus a trispecific bNAb targeting three independent HIV-1 envelope determinants was developed to achieve more robust suppression. Upon treatment of viremic simian-human immunodeficiency virus (SHIV)-infected macaques with the trispecific bNAb, plasma viral suppression of up to 1000-fold was observed. To elucidate a mechanism for the observed plasma viremia control, in vitro assays using the trispecific bNAb were conducted to determine Fc-mediated effector functions. First, we determined that the trispecific bNAb bound to HIV-1 infected cell lines with an equal or higher affinity than its parental bNAbs alone. We then conducted antibody-dependent cell cytotoxicity (ADCC) and antibody-dependent cell phagocytosis (ADCP) assays and found that the trispecific bNAb had comparable or better activity compared to its parental bNAbs alone. Similarly, when we measured direct virolysis of HIV-1 virus using an antibody-dependent complement-mediated virus lysis (ADCML) assay, the trispecific bNAb had comparable or better activity compared to its parental bNAbs alone. These studies demonstrate that the trispecific bNAb shows anti-viral activity in vivo and has potent Fc-dependent effector functions that target both free virus and virally infected cells compared to monoclonal bNAbs alone. Thus, the trispecific bNAb is a promising single immunotherapeutic protein for treatment of HIV-1 infection.