Next-generation bNAbs Antibody engineering strategies for HIV-1 cure

Despite ART effectively suppressing HIV-1 replication, viral reservoirs persist and prevent a cure. Broadly neutralizing antibodies (bNAbs) can neutralize virions and mediate clearance of infected cells, but their efficacy is limited by low Env density, high viral diversity, immune cell exhaustion, and short antibody half-life. To address these challenges, this thesis focused on antibody engineering strategies to enhance bNAb potency, effector function, and capacity to eliminate HIV-1–infected cells. Engineering approaches included developing multivalent constructs to increase Env binding, glycoengineering to boost FcγRIIIa affinity and NK cell activation, and Fc modifications to enhance complement-dependent cytotoxicity. Subclass switching, hinge elongation, and introduction of activating mutations further optimized antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP). In addition, bispecific antibodies were designed to simultaneously target HIV-1 Env and NK cell receptors, achieving improved immune cell recruitment and killing of infected cells. Overall, this thesis demonstrates that antibody engineering can overcome key limitations of current bNAb therapies. By improving effector function, immune engagement, and mechanisms of infected cell clearance, engineered antibodies show strong potential to reduce the viral reservoir. These findings support the advancement of next-generation antibody therapies as a promising step toward durable ART-free control or a functional cure for HIV-1.