Broadly neutralizing anti-HIV-1 monoclonal antibodies in the clinic

Abstract

Combination anti-retroviral therapy (ART) has revolutionized the treatment and prevention of HIV-1 infection. Taken daily, ART prevents and suppresses the infection. However, ART interruption almost invariably leads to rebound viremia in infected individuals due to a long-lived latent reservoir of integrated proviruses. Therefore, ART must be administered on a life-long basis. Here we review recent preclinical and clinical studies suggesting that immunotherapy may be an alternative or an adjuvant to ART because, in addition to preventing new infections, anti-HIV-1 antibodies clear the virus, directly kill infected cells and produce immune complexes that can enhance host immunity to the virus.

Figure 1.. Approved monoclonal antibodies and bNAbs tested in clinical trials.

a.) Number of EMA (European Medicines Agency) and FDA (U.S. Food and Drug Administration) approved monoclonal antibodies up until the end of 2018. Red columns indicate the number of newly approved mAbs in a given year. Blue columns show the number of total mAbs approved. b.) Second generation bNAbs target various epitopes on the HIV-1 envelope trimer (grey). Antibodies against the CD4bs (orange; 3BNC117, VRC01, VRC07–523, N6), the V1/V2 loop (blue; PDGM1400), the V3-stem (green; 10–1074, PGT121), and the Membrane Proximal External Region (MPER; purple; 10E8V) are currently being investigated in clinical studies.

Figure 2.. bNAb characteristics and virus/host factors determine efficacy of passive immunotherapy for HIV-1 prevention and therapy.

Potency (bNAb concentration required to prevent infection), breadth (neutralization coverage of HIV-1 strains), and the ability to restrict HIV-1 escape pathways are mainly determined by the antigen binding site of the bNAb. In addition, antibody Fc domains interact with host immune cells to mediate antiviral effector functions and can also be modified to increase bNAb half-life. Finally, tolerability and safety are prerequisites for the clinical application of bNAbs. Besides these antibody-intrinsic properties, viral features and host characteristics are critical for efficient bNAb-mediated interventions. Detailed characterization information of the viral quasi-species within an infected individual to identify pre-existing bNAb resistance is relevant for therapy, while the overall prevalence of antibody-sensitivity across circulating viral strains at a population-level is crucial for prevention. The contribution of host immunity and the selection of well-designed strategies will further determine the efficacy of bNAb-mediated interventions.