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Antibody-Mediated Therapy of HIV-1 Infection

Periodic Reporting for period 4 - HIV1ABTHERAPY (Antibody-Mediated Therapy of HIV-1 Infection)

Reporting period: 2020-07-01 to 2021-12-31

Antiretroviral therapy (ART) is effective for treating human immunodeficient virus (HIV-1) infection and in reducing the risk of infection when used as pre-exposure prophylaxis. Moreover, classical antiviral drugs are well-established and increasingly available in generic form. However, ART is a daily and life-long medication and side effects and development of resistance occur. Thus, novel treatment and prevention strategies are required. Novel broadly neutralizing antibodies (bNAbs) targeting HIV-1 hold promise for their use in the prevention and treatment of HIV-1 infection. Pre-clinical results have encouraged the evaluation of these antibodies in healthy and HIV-1-infected humans. In first clinical trials, highly potent bNAbs have demonstrated their safety and significant antiviral activity by reducing viremia and delaying the time to viral rebound in individuals interrupting antiretroviral therapy. While emerging antibody-resistant viral variants have indicated limitations of antibody monotherapy, strategies to enhance the efficacy of bNAbs in humans are under investigation. In this project, we aim to understand how we can exploit the unique potential of antibodies to effectively treat and prevent HIV-1 infection. To this end, we i.) developed strategies to isolate HIV-1 neutralizing antibodies with exceptional activity in vivo, ii.) investigated how these antibodies can be used to overcome HIV-1 escape, and iii.) explored how antiviral immune responses of the infected host can contribute to control HIV-1 replication. Identification of these key components will strongly increase the ability to use bNAbs to effectively prevent and treat HIV-1 infection. Finally, we have applied these strategies on the prevention and treatment of other viral infections, such as hepatitis C virus (HCV), Ebolavirus and severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2).
The following aspects are of particular importance to our working group from a scientific perspective and were addressed during the funding period:

We could demonstrate that bNAbs have the potential to play an important role in approaches for HIV-1 immunotherapy by evaluating the CD4bs bNAb 3BNC117 in a clinical trial. We demonstrated that passive bNAb administration can improve the autologous HIV-1 antibody response (Schoofs et al., 2016). Additionally, we have completed a clinical trial that investigated the safety, pharmacokinetics and anti-viral efficacy of a V3-stem targeting bNAb 10-1074. In this study, we demonstrated potent anti-viral activity of 10-1074 as well as deciphered the evolution of HIV-1 resistance (Caskey et al., 2017).
Since HIV-1 can rapidly escape from single drug regimens, we initiated a clinical trials combining two bNAbs (10-1074 and 3BNC117) in both HIV-1 viremic patients as well as patients that undergo an anti-viral treatment interruption. Indeed, the combination of two new generation highly potent bNAbs significantly reduced viremia and was able to limit HIV-1 escape (Bar-On et al., 2018; Mendoza et al. 2018)
Not only the combination of two bNAbs is one important mechanism to control infection for prolonged periods. Also, the identification and clinical development of new bNAbs targeting multiple HIV-1 envelope epitopes is of importance. SF12, a bNAb belonging to the group of antibodies that target a glycan-focused epitope on the silent face of gp120, was being identified (Schoofs et al. 2019). Also, 1-18, a new VH1-46-encoded CD4bs bNAb with outstanding breadth (97%) and potency (GeoMean IC50 = 0.048 μg/mL) was identified. The ability of 1-18 to effectively restrict HIV-1 escape pathways provides a new option to successfully prevent and treat HIV-1 infection (Schommers et al. 2020).

In summary, a detailed understanding of the antibody response against infectious pathogens is critical to inform on successful vaccination strategies and to investigate novel immune-mediated therapy approaches. Over the last years, our work has strongly impacted the development of new approaches for HIV-1 immunotherapy and vaccination. We have now intensified this research to generate comprehensive and high-throughput methods for the identification of new antibodies and have started to apply our knowledge and advanced techniques to other pathogens.
In the course of the ERC funding period, we were able to establish several methods, which are helpful tools in the development and testing of therapeutic antibodies targeting infectious pathogens:
The promising clinical results have led us to develop a particularly fast and efficient antibody isolation pipeline. In this regard, we have advanced existing concepts to develop a highly efficient high-throughput protocol with proven application for the isolation of potent antigen-specific antibodies against HIV-1. It is based on computationally optimized multiplex primer sets (openPrimeR), which guarantee high coverage of even highly mutated immunoglobulin gene segments as well as on optimized antibody cloning and production strategies (Gieselmann et al. 2021; Kreer et al. 2020).

In addition, we were able to expand our analytical and methodical spectrum to include other pathogens like Ebolavirus, SARS-CoV2 and HCV. Here, we are applying our knowledge and experience from HIV-1 antibody research to the discovery of neutralizing antibodies in order to develop successful treatment and prevention options for diseases caused by these pathogens.
For example, we were able to apply our developed B cell techniques during the SARS-CoV-2 pandemic (Kreer et al. 2020; Vanshylla et al. 2021). Using recently established highly effective experimental workflows, we identified and isolated neutralizing SARS-CoV-2 antibodies that could be used as an effective drug in a timely manner (Gieselmann et al. 2021). We finally selected 255 promising anti-SARS-CoV-2 antibody candidates for in vitro production and characterized their epitopes, binding affinities, and in vitro antiviral activity. In addition, we determined the pharmacokinetics of three potential antibody candidates. Through all these measures, we were able to identify and thoroughly characterize 10 highly potent neutralizing antibodies, one of which (DZIF-10c) was further developed and selected for a phase I/II clinical trial, which was being conducted in collaboration with Boehringer Ingelheim from 12/2020 until 08/2021.
Additionally, we examined the humoral immune response in a subset of human volunteers enrolled in a phase 1 rVSV-ZEBOV vaccination trial by performing comprehensive single B cell and electron microscopy structure analyses. Our findings will help to evaluate and direct current and future vaccination strategies and offer opportunities for novel EVD therapies (Ehrhardt et al. 2019).
Lastly, the high genetic diversity of HCV complicates effective vaccine development. We screened a cohort of 435 HCV-infected individuals and found that 2-5% demonstrated outstanding HCV-neutralizing activity. From four of these patients, we isolated 310 HCV antibodies, including neutralizing antibodies with exceptional breadth and potency. Our findings provide a deep understanding of the generation of broadly HCV-neutralizing antibodies that can guide the design of effective vaccine candidates (Weber et al. 2022).
Broadly neutralizing antibody 1-18, crystal structure (Schommers et al. 2020)