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).
