The immediate efforts of CARE were focused on identifying existing drugs to provide fast therapeutic options to patients suffering from COVID-19 (drug repositioning). Multiple drugs were identified, although previously identified by others. Other drugs were identified as active in cell culture, but none was found suitable for clinical deployment. In parallel, large screening campaigns in novel phenotypic (infected-cell) assays and target-based (on several essential enzymes) assays were conducted, totalling >1.5 millions compounds screened. During the screening process, profiling assays in translation models were set up a. A great deal of enzyme, assays, structures, and mode of action have been determined and published, to feed drug discovery. CARE has also produced a collection of clones, reagents, and protocols available to the scientific community.
The small molecule drug discovery efforts have led to the identification of several antiviral compound series with innovative mechanism of action which can form the basis of preventive or therapeutic interventions against coronaviruses. A selection of compound series is being developed towards candidate drugs and proof-of-concept in an infectious animal model has been obtained for three of the programs. CARE has indeed validated several animals models, including mouse, syrian hamster and non-human primate models.
CARE has delivered three well-characterized potent monoclonal antibodies, CH-P5C3, CH-P2G3 and CH-P4-J15, isolated from human donor B cells, with different epitopes. The three antibodies showed complete prophylactic protection in hamsters or non-human primates challenged with SARS-CoV-2 virus. CARE transitioned from identifiying emergency track neutralizing antibodies with potency against SARS-CoV-2 to developing preparedness track neutralizing antibodies with broader activity against Sarbecoviruses and/or betacoronaviruses, with a dual strategy, i.e. to 1) screen for broadly active anti-coronavirus monospecific antibodies and 2) evaluate bispecific antibodies that would synergize in neutralizing potency and breadth by binding two conserved epitopes on the Spike protein. CARE successfully identified broadly active neutralizing antibodies against different coronavirus subfamilies, and characterization is underway. Although there has been no significant breakthrough to date with the bispecific antibodies, efforts continue with our extensive toolbox and antibodies clones reported in the literature.
OMICS experiments are ongoing to evaluate the physiopathology of SARS-CoV-2 infection and CARE is now validating hits identified by pharmacological or genetic approaches. This will complement the analyses of the samples from French and Swiss COVID-19 cohorts which highlighted neutrophil activation as a hallmark of severe disease, and characterized a “core signature” of gene expression in convalescent severe COVID-19 patients and a gene expression profile associated with thrombosis in these subjects.
CARE has establish a complete Clinical Trial Platform infrastructure for the design and conduct of clinical trials targeting COVID-19. The platform covers different aspects to speed up the setup and conduct of a clinical trial. The clinical trial platform also offers services that may be of interest to outside stakeholders looking for a clinical trial network with a specific expertise in COVID-19.
