Periodic Reporting for period 1 - ATAC (Antibody therapy against coronavirus (COVID-19))
Reporting period: 2020-04-01 to 2021-03-31
The ATAC (Antibody Therapy Against Coronavirus) project is a two year project that falls into the topic “SC1-PHE-CORONAVIRUS-2020: Advancing knowledge for the clinical and public health response to the COVID-19 epidemic” of the Horizon 2020 Health work program. The project is coordinated by Karolinska Institutet (Stockholm, Sweden), and includes the Institute for Research in Biomedicine (Bellinzona, Switzerland), the Joint Research Centre of the European Commission (Brussels, Belgium), Technische Universitaet Braunschweig (Braunschweig, Germany) and Fondazione IRCCS Policlinico San Matteo (Pavia, Italy).
The project aims at developing a human antibody therapy against COVID-19. The specific objectives and achievement of ATAC includes:
• Rapid development of antibody therapy (passive immunization) based on hyperimmune plasma derived from COVID-19 convalescent donors
• Discovery, characterization and pre-clinical development of human monoclonal antibodies against COVID-19
• Rapid dissemination of the results to help respond to the emergency
• Acquire an understanding of the neutralization of COVID-19 by human monoclonal and serum antibodies to counteract future epidemics
More specifically, the work of the ATAC consortium includes: obtain blood samples from coronavirus convalescent human donors in Italy, and other sources; isolate human antibodies with three independent strategies (hyperimmune plasma, monoclonal antibodies from B cells and phage library); select, characterize and optimize lead candidate monoclonal antibodies for preclinical development through a combination of high-throughput screening, rapid experimental work and computational analysis; and consult with EMA to ensure that regulatory aspects are embedded right from the start.
We have assessed the SARS-CoV-2-specific immune responses in convalescent patients who experienced severity of the disease ranging from mild to critical from Italian and Swedish cohorts (Sherina et al. 2021, Med). Our data suggest that anti-SARS-CoV-2 IgG antibodies and neutralization activities remain relatively stable for 6 months and that T and B cell responses are maintained in majority of patients for a period of at least six-eight months following infection. We also identified factors (severity, age, time of blood collection) associated with high neutralizations titers which can be used to select the more suitable donor for plasma therapy. Subsequently, hyperimmune plasma therapy was shown to reduce the mortality rate from an average of 15 to 6% in patients experiencing a moderate to severe case (Perotti et al. 2020, Haematologica).
Isolation of monoclonal antibodies to SARS-CoV-2 using purification of B cells and phage display:
The consortium has identified the first lead candidate monoclonal antibodies with exceptional neutralizing activity within less than 6 months. Two reports on the analysis of plasmas, and on the discovery and characterization of human monoclonal antibodies were published (Robbiani et al. 2020, Nature 2020; Gaebler et al. 2021, Nature). Three antibodies (C121, C144 and C135) binding to three distinct epitopes on the SARS-CoV-2 spike receptor binding domain (RBD) and neutralizing the virus with half-maximal inhibitory concentrations (IC50 values) as low as 2 ng ml−1 were isolated from convalescent patients (Robbiani et al. 2020, Nature). In addition, the antibody STE73-2E9 isolated from a naive library was neutralizing and showed an IC50 of 0,41nM in a plaque-reduction neutralization assay (Bertoglio et al. 2021, Nature Communication).
Characterization and engineering of therapeutic antibodies:
Using recombinant protein antigens from SARS-CoV-2, the binding properties of monoclonal antibodies were extensively characterized including binding affinity, epitope mapping, and neutralization. Based on the lead antibody candidates C121 and C135 (Robbiani et al. 2020, Nature), a bispecific antibody, named CoV-X2, that simultaneously binds two independent sites on the RBD was engineered (DeGasparo et al. 2021, Nature). Unlike its parental antibodies, the antibody completely prevents spike binding to the ACE2 receptor and neutralizes the G614 virus variant in cell culture assays and in animal models without detection of escape mutants. The bispecific antibody also neutralizes the UK (IC50 0.2nM) South African (IC50=12nM) and Brazilian (IC50=2.1nM) variants.
Dissemination and exploitation of results:
Besides providing lead human antibody candidates for therapy, ATAC rapidly disseminated results to help respond to the current COVID-19 epidemic. More than 15 papers were published during the first 12 months of the project, including publications with a high impact factor. The project and results received important coverage on tv, radio, press, social media and were amply discussed by the general public in online blogs. The publications and related news were posted on the ATAC public-access website (https://covidantibodytherapy.info/) Twitter account (@atac76312929) and the LinkedIn profile (https://www.linkedin.com/in/atac-project-0aa1951aa/). Furthermore, a patent on the bispecific antibody was filed (PCT/EP2020/085342).
The most potent antibodies discovered to date may lead to virus escape and work is ongoing to identify antibodies that in addition to being potent virus neutralizers are also capable to neutralize multiple variants of the virus, which are of great concern because of enhanced transmissibility. The engineered bispecific antibody, CoV-X2, shown to be efficient in preclinical studies including against variant of concerns, is planned to be scaled-up under GMP conditions to obtain clinical-grade material. Once the toxicology studies confirm suitability, we will perform a phase I clinical trial. Such antibodies could be used individually or as a cocktail of multiple antibodies for passive protection in either prophylaxis for at-risk populations (patients under immunosuppressive therapy or immunocompromised) or for treatment against current or future outbreaks of COVID-19 or related coronavirus.