By: Dr. Shelly Karuna, HVTN Core, Seattle, Washington, USA
Broadly neutralizing antibodies (bnAbs) have the potential to greatly contribute to global HIV prevention, treatment and cure efforts. These antibodies are naturally developed by the immune systems of some people living with HIV, though usually the virus evolves faster than the immune system’s antibody response. When HIV outpaces the development of these special antibodies, they may be unable to prevent, fully suppress, or eradicate the virus in the body of the person who made them. However, scientists can identify these bnAbs and make copies of them in a lab. Sometimes, scientists can also make small changes to these antibodies to improve their potential ability to prevent, treat, or cure HIV.
Antibodies are shaped a little like the letter Y, with two “arms” and a “foot.” Antibodies work to fight HIV in two primary ways. First is neutralization, in which the “fingertips” of the antibody bind to the HIV envelope protein (gp140, or Env) and prevent it from binding to and infecting target cells like healthy T-cells (see Figure 1). Second is through Fc-effector functions, in which the “foot” portion of an antibody recruits other healthy immune cells, like natural killer (NK) cells or macrophages, to help kill or remove HIV from the body (see Figure 2). BnAbs are special because they can do these functions for many of the different strains or types of HIV found around the world, whereas more common antibodies, those that are not broadly neutralizing, usually only recognize some viruses from one or a few strains of HIV. Different bnAbs can bind to several different parts (“epitopes”) of the HIV Env protein, including the CD4 binding site, the V2 loop, the V3 glycan region, the membrane-proximal external region (MPER), and others (see Figures 3-4). They can also work with other immune cells like NK cells or dendritic cells in different ways. This is comparable to how different antiretroviral drugs (ARVs) attack HIV at different places and in different ways.
Figure 1. Neutralization function of an antibody against HIV. Figure 4 in Karuna & Corey, Annu Rev Med, 2020.
Credit: Lisa Donohue
Figure 2. Fc-effector function of an antibody against HIV. Figure 5 in Karuna & Corey, Annu Rev Med, 2020.
Credit: Lisa Donohue
Since 2014, the HVTN has collaborated with many partners on the development and implementation of a portfolio of studies to evaluate the potential of several different bnAbs against HIV. These studies began with the HVTN 104 and HVTN 116 studies, which evaluated VRC01 and/or the longer-acting VRC01LS bnAbs, demonstrating their safety and providing more information about their pharmacokinetics in blood and in mucosal tissues. Pharmacokinetics (PK for short) describe how the antibodies travel in the body, and how much antibody is in the body over time.
In 2015, using information from the earlier trials, the HVTN, HPTN, Vaccine Research Center (VRC), and DAIDS began collaborating on the world’s first two bnAb HIV prevention efficacy trials—the Antibody Mediated Prevention (AMP) studies (HVTN 704/HPTN 085 and HVTN 703/HPTN 081). The AMP Study results are anticipated in late 2020, and the trials are designed to teach us whether the VRC01 bnAb can prevent HIV infection, and if so, what concentration of VRC01 in the blood is required for that protection.
Since AMP opened in early 2016 to evaluate VRC01, which attaches to the CD4 binding site, we have seen several other bnAbs enter clinical trials, including:
- additional VRC01-class antibodies with changes made to help them last longer in the body (e.g., VRC01LS, VRC07-523LS);
- several antibodies that bind to other HIV Env epitopes including the MPER (e.g., 10E8 and variants), V2 loop (e.g., PGDM1400), and V3 glycan region (e.g., PGT121 and 10-1074);
- and antibodies with multiple specificities, meaning that one antibody can attach to several places (e.g., trispecific bnAbs like SAR441236).
The HVTN and HPTN are collaborating with the National Institute of Allergy and Infectious Disease’s Vaccine Research Center (VRC), Sanofi, Rockefeller, CAPRISA, Beth Israel Deaconess Medical Center (BIDMC) and the International AIDS Vaccine Initiative (IAVI) to advance these bnAb products into DAIDS-sponsored clinical trials, and we have designed these trials to explore many research questions (e.g., dose, administration route, timing between infusions) to inform the next bnAb efficacy trial. We are now primarily looking at combinations of bnAbs to determine the safety of using them together. We think that using combinations of bnAbs that attach to different parts of HIV (see Figure 3-4) could lead to greater efficacy, both for prevention and for treatment, similar to how we need to use combinations of ARVs to effectively prevent and treat HIV infection. These phase 1 trials will also provide lessons crucial for the smooth implementation of the next efficacy trial, as HVTN 104 did for AMP. See Tables 1 & 2 for a summary of the current phase 1 bnAb portfolio.
Figure 3. Potential binding sites for bnAbs.
Credit: Lisa Donohue
Figure 4. Another view of potential binding sites for bnAbs.
Credit: Lisa Donohue
The first post-AMP phase 1 trial in the bnAb portfolio, HVTN127/HPTN 087, explores a range of doses and routes of administration, including the first evaluation of intramuscular (IM) bnAb administration in our field. It tests the potent CD4 binding site antibody, VRC07-523LS, which we think will be an anchor for a next-generation bnAb combination. This trial not only builds a robust safety database for VRC07-523LS, but it also allows us to compare bioavailability, neutralization, and PK profiles across IV, SC, and IM administration routes in preparation for future trials.
HVTN 128 supplements HVTN 127/HPTN 087 with data regarding mucosal concentrations of VRC07-523LS. This trial includes vaginal, rectal, and semen sample collections and builds upon the HVTN’s extensive bnAb/mucosal sampling experience in HVTN 104 and HVTN 116.
HVTN 129/HPTN 088 will truly be a vanguard trial, exploring the potential for a single bnAb that binds to three different HIV Env sites or epitopes. This manufactured “trispecific” bnAb from Sanofi includes elements from other bnAbs: binding to V2 from PGDM1400, binding to MPER from 10E8, and binding to the CD4 binding site from VRC01. We think this will provide greater breadth and potency than any single bnAb that has only one epitope specificity. It may also greatly simplify manufacturing, regulatory, operational, and other potential challenges of administration compared to using a combination of separate bnAbs. This trial, together with HVTN 130/HPTN 089, HVTN 136/HPTN 092, and others will explore the potential neutralization effects of bnAb combinations, including whether the combinations might result in the antibodies working against each other, helping each other, or building on each other. As HVTN 129/HPTN 088 builds the first-in-humans safety, PK, and neutralization profile of a multi-specific product for HIV prevention, it will also inform further bi- and trispecific bnAb development work being done by several groups in the HIV bnAb field.
HVTN 130/HPTN 089 and HVTN 136/HPTN 092 are, in many ways, partners to the trispecific trial, as they evaluate triple and dual combinations of bnAbs administered separately. All of the combinations are anchored by VRC07-523LS. The triple combination adds PGDM1400 and the V3-binding bnAb PGT121. One of the 2-bnAb combinations uses the V2-binding bnAb PGDM1400 with VRC07-523LS. The remaining 2-bnAb combinations use different V3 glycan binding bnAbs (10-1074 and PGT121 or its long-acting version, PGT121.414.LS) with VRC07-523LS. This will allow for a comparison of any differences in how the different V3 bnAbs contribute to neutralization when paired with VRC07-523LS. One of the key concepts these trials will explore is whether the site of action (where the bnAb attaches to HIV) influences the neutralization activity in the body, and whether this activity is similar when different combinations or binding sites are used.
HVTN 138/HPTN 098 also evaluates a dual combination of VRC07-523LS with a V2-binding bnAb, CAP256V2LS, that is particularly potent against Clade C HIV. The bnAb on which CAP256V2LS is based was identified from a participant in a trial at the Centre for the AIDS Programme of Research in South Africa (CAPRISA). The bnAb was then developed and manufactured by the VRC. Clade C is the major strain of HIV that causes infection in South Africa, and this study is planned for South Africa, as well as the US.
Table 1. Network bnAb trials fully enrolled.
Table 2. Network bnAb trials in development. Note that timelines are anticipated to shift due to the COVID-19 pandemic. (*AE in FIH means adverse event in first in human study)
The identification and optimization of bnAbs against HIV have helped scientists learn more about the structure of HIV and its vulnerabilities, which helps target and expedite efforts to develop an HIV vaccine. The efforts described here are advancing us toward a goal the HVTN has held for two decades—to expand the HIV prevention toolbox and, in particular, to achieve a safe and effective HIV vaccine as efficiently as possible, an effort the bnAb portfolio informs and thus advances.
Yet much work remains. Optimal bnAb combinations—and the effects of combining bnAbs in a multi-specific design or separately—must be further explored. Subcutaneous (SC) administration must be improved, such as making higher concentrations of the antibodies to allow a lower volume to be given, and testing different SC doses and routes, such as SC injection vs. infusion pump, or even wearable SC injectable devices. Changes to the Fc or “foot” portion of the bnAbs may help bnAbs last longer in the body (e.g., the LS modification) or may help bnAbs work better with immune cells to add to neutralization for improved HIV prevention, treatment and possibly cure. Additional mucosal studies may help us better understand how these antibodies get into different mucosal tissues and how they function. And perhaps most importantly, a marker such as antibody concentration in the blood could support more efficient advancement of bnAbs and HIV vaccines for future efficacy testing.
Many of these advances are possible starting with the suite of Network antibody trials described here, and moving forward with the next generations of bnAbs, to bring bnAbs for HIV prevention—and a preventive HIV vaccine—to communities throughout the world.
Dr. Shelly Karuna is the Director of Clinical Development at the HVTN.
Bioavailability - the proportion of a drug or other substance which enters the circulation when introduced into the body, and so is able to have an active effect.
Pharmacokinetics (PK) - how the antibody moves through the body and tissues, and how the body processes the antibody over time.
Editor’s Note: The research described in this article has been published: Karuna, S. T., & Corey, L. (2020). Broadly Neutralizing Antibodies for HIV Prevention. Annual Review of Medicine, 71, 329-346.