Advancing HIV Broadly Neutralizing Antibodies: From Discovery to the Clinic

Abstract

Despite substantial progress in confronting the global HIV-1 epidemic since its inception in the 1980s, better approaches for both treatment and prevention will be necessary to end the epidemic and remain a top public health priority. Antiretroviral therapy (ART) has been effective in extending lives, but at a cost of lifelong adherence to treatment. Broadly neutralizing antibodies (bNAbs) are directed to conserved regions of the HIV-1 envelope glycoprotein trimer (Env) and can block infection if present at the time of viral exposure. The therapeutic application of bNAbs holds great promise, and progress is being made toward their development for widespread clinical use. Compared to the current standard of care of small molecule-based ART, bNAbs offer: (1) reduced toxicity; (2) the advantages of extended half-lives that would bypass daily dosing requirements; and (3) the potential to incorporate a wider immune response through Fc signaling. Recent advances in discovery technology can enable system-wide mining of the immunoglobulin repertoire and will continue to accelerate isolation of next generation potent bNAbs. Passive transfer studies in pre-clinical models and clinical trials have demonstrated the utility of bNAbs in blocking or limiting transmission and achieving viral suppression. These studies have helped to define the window of opportunity for optimal intervention to achieve viral clearance, either using bNAbs alone or in combination with ART. None of these advances with bNAbs would be possible without technological advancements and expanding the cohorts of donor participation. Together these elements fueled the remarkable growth in bNAb development. Here, we review the development of bNAbs as therapies for HIV-1, exploring advances in discovery, insights from animal models and early clinical trials, and innovations to optimize their clinical potential through efforts to extend half-life, maximize the contribution of Fc effector functions, preclude escape through multiepitope targeting, and the potential for sustained delivery.

Keywords: HIV; antibody; immunotherapy; neutralization; non-human primate.

Figure 1

Cultivation of bNAbs for treatment and prevention of HIV. The progression of bNAb development is visualized as organic growth seeded from observations in the 1980s−1990s that passive transfer of virus-neutralizing polyclonal IgG from subjects living with HIV countered new infection. The subsequent yield of 1st generation bNAbs in the 1990s demonstrated protection from SHIV in NHP models, and B cell technology advancement in the 2000s enabled the isolation of the 2nd generation bNAbs that are highly broad and potent and protected humanized mice and NHP models at low doses. The cache of 2nd generation bNAbs quickly expanded in the 2010s as cohorts of large and diverse study subjects also multiplied. The swift advancement of these bNAbs to the clinic in the same decade was nurtured by technological advancements in molecular and cellular biology and systems immunology, and their applications in the clinic continue to increase. The 2020s has begun with the recent completion of the first large-scale human efficacy trial with one of the early 2nd generation bNAbs. Advanced immune repertoire mining technology is becoming a new standard for discovery, and studies are underway with new modification ideas. Expectations for future clinical applications include novel concepts for delivery methods and utilizing engineered bNAb cocktails. The figure legend illustrates and describes each element fostering a continuum in growth of bNAb utility over time. Elements are presented in the decade of first use, although concepts, processes, and materials may continue over multiple decades.

Figure 2

Epitope regions on the HIV-1 Envelope targeted by bNAbs. The HIV-1 envelope glycoprotein (Env) is the sole target for bNAbs and is displayed on the surface of virions as a trimer of gp120 and gp41 heterodimers. Each of the three gp120 protomers are shown in white above the viral membrane with the three gp41 regions shown embedded within the viral membrane. For simplicity, glycans and variable regions on HIV Env are not depicted in this figure. The image is an artistic rendering to illustrate the five primary conserved epitope regions on the HIV Env surface proteins targeted by bNAbs. The epitope regions shown are labeled as follows: (1) V2 apex–yellow; (2) CD4 binding site–green; (3) gp120/gp41 interface–purple; (4) gp41 membrane proximal region (MPER)–red; and (5) V3 glycan supersite–blue. Several representative human monoclonal antibodies known to target each of these regions are listed.