Periodic Reporting for period 3 - ATAC (Antibody therapy against coronavirus (COVID-19))
Période du rapport: 2022-08-01 au 2023-07-31
The emergence and spread of the novel human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has led to a pandemic with significant impacts on global health and the world economy. Passive immunization using plasma, either through polyclonal or monoclonal antibodies from convalescent blood of COVID-19-infected donors, holds strong potential for reducing the mortality rate among infected individuals.
The ATAC (Antibody Therapy Against Coronavirus) project was a 40-month initiative falling under the topic "SC1-PHE-CORONAVIRUS-2020: Advancing knowledge for the clinical and public health response to the COVID-19 epidemic" within the Horizon 2020 Health work program. The project was coordinated by the Karolinska Institutet in Stockholm, Sweden. The consortium also included the Institute for Research in Biomedicine in Bellinzona, Switzerland; the Joint Research Centre of the European Commission in Brussels, Belgium; Technische Universitaet Braunschweig in Braunschweig, Germany; and Fondazione IRCCS Policlinico San Matteo in Pavia, Italy.
The project aimed to develop a human antibody therapy against COVID-19 based on antibodies from convalescent patients using three independent strategies: hyperimmune plasma, monoclonal antibodies from B cells, and phage libraries.
The specific objectives and achievement of ATAC included:
• Rapid development of antibody therapy based on human plasma containing high titers neutralizing antibodies derived from COVID-19 convalescent donors
• Discovery, characterization, pre-clinical and 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
The ATAC (Antibody Therapy Against Coronavirus) project was a 40-month initiative falling under the topic "SC1-PHE-CORONAVIRUS-2020: Advancing knowledge for the clinical and public health response to the COVID-19 epidemic" within the Horizon 2020 Health work program. The project was coordinated by the Karolinska Institutet in Stockholm, Sweden. The consortium also included the Institute for Research in Biomedicine in Bellinzona, Switzerland; the Joint Research Centre of the European Commission in Brussels, Belgium; Technische Universitaet Braunschweig in Braunschweig, Germany; and Fondazione IRCCS Policlinico San Matteo in Pavia, Italy.
The project aimed to develop a human antibody therapy against COVID-19 based on antibodies from convalescent patients using three independent strategies: hyperimmune plasma, monoclonal antibodies from B cells, and phage libraries.
The specific objectives and achievement of ATAC included:
• Rapid development of antibody therapy based on human plasma containing high titers neutralizing antibodies derived from COVID-19 convalescent donors
• Discovery, characterization, pre-clinical and 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
Plasma therapy for treatment of COVID-19 patients:
We have identified several factors, including the time elapsed after infection, age, severity of COVID-19, and vaccination, that are positively associated with higher neutralizing antibody titers at the time of donation (Percivalle et al. Euro Surveill 2020; Sherina et al Med 2021). The hyperimmune plasma was also tested against emerging SARS-CoV-2 variants (Zuo et al. Lancet Reg Health West Pac 2023; Zuo et al. Nat Commun 2022). These findings will aid in optimizing the selection of hyperimmune convalescent plasma donors for plasma therapy. Furthermore, we conducted an assessment of the early utilization of hyperimmune plasma for treating COVID-19 patients requiring either non-invasive or invasive mechanical ventilation. Our observations revealed a reduction in hospital mortality among patients treated with hyperimmune plasma.
Isolation of monoclonal antibodies to SARS-CoV-2 using purification of B cells and phage display:
The consortium has identified the first lead monoclonal antibody candidates with exceptional neutralizing activity in less than 6 months. One of these antibodies, STE73-2E9, which was discovered from a naïve library, demonstrated the ability to neutralize SARS-CoV-2 with high efficiency in a plaque assay (Bertoglio et al., Nat Commun 2021). In addition, neutralizing human monoclonal antibodies C121, C144, and C135, which bind to distinct epitopes on the SARS-CoV-2 spike receptor binding domain (RBD), were obtained from convalescent patients (Robbiani et al., Nature 2020). More recently, antibodies targeting the conserved spike region were found and shown to be broadly neutralizing (Bianchini et al., Sci Immunol 2023).
Characterization and engineering of therapeutic antibodies:
The binding properties of monoclonal antibodies to SARS-CoV-2 were comprehensively characterized, encompassing aspects such as binding affinity, epitope mapping, and neutralization. Building upon the promising antibody candidates C121 and C135 (Robbiani et al., Nature 2020), a bispecific antibody known as CoV-X2 was engineered (De Gasparo et al., Nature 2021). This unique antibody simultaneously engages with two distinct sites on the RBD and effectively neutralizes the G614 virus variant in both cell culture assays and animal models.
In more recent developments, a different bispecific antibody named CoV-X4042, which combines sd1.040 and rbd.042 antibodies targeting the conserved spike region, has demonstrated the ability to neutralize all variants of concern, from the original virus to the currently circulating Omicron variants. Furthermore, this antibody has exhibited protective properties in animal models. Importantly, CoV-X4042 was manufactured in accordance with GMP standards, and toxicology tests were conducted (Bianchini et al., Sci Immunol 2023). In addition, we observed that dimeric and secretory IgA recombinant antibodies are more potent than the parental IgG for binding and neutralizing SARS-CoV-2 including Omicron variants. In hACE2 transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron.
Dissemination and exploitation of results:
ATAC rapidly disseminated results to help respond to the current COVID-19 epidemic. More than 56 papers were published, including publications with a high impact factor project, thereby reaching a wide scientific and medical audience. 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/) and the LinkedIn profile (https://www.linkedin.com/in/atac-project-0aa1951aa/).
We have identified several factors, including the time elapsed after infection, age, severity of COVID-19, and vaccination, that are positively associated with higher neutralizing antibody titers at the time of donation (Percivalle et al. Euro Surveill 2020; Sherina et al Med 2021). The hyperimmune plasma was also tested against emerging SARS-CoV-2 variants (Zuo et al. Lancet Reg Health West Pac 2023; Zuo et al. Nat Commun 2022). These findings will aid in optimizing the selection of hyperimmune convalescent plasma donors for plasma therapy. Furthermore, we conducted an assessment of the early utilization of hyperimmune plasma for treating COVID-19 patients requiring either non-invasive or invasive mechanical ventilation. Our observations revealed a reduction in hospital mortality among patients treated with hyperimmune plasma.
Isolation of monoclonal antibodies to SARS-CoV-2 using purification of B cells and phage display:
The consortium has identified the first lead monoclonal antibody candidates with exceptional neutralizing activity in less than 6 months. One of these antibodies, STE73-2E9, which was discovered from a naïve library, demonstrated the ability to neutralize SARS-CoV-2 with high efficiency in a plaque assay (Bertoglio et al., Nat Commun 2021). In addition, neutralizing human monoclonal antibodies C121, C144, and C135, which bind to distinct epitopes on the SARS-CoV-2 spike receptor binding domain (RBD), were obtained from convalescent patients (Robbiani et al., Nature 2020). More recently, antibodies targeting the conserved spike region were found and shown to be broadly neutralizing (Bianchini et al., Sci Immunol 2023).
Characterization and engineering of therapeutic antibodies:
The binding properties of monoclonal antibodies to SARS-CoV-2 were comprehensively characterized, encompassing aspects such as binding affinity, epitope mapping, and neutralization. Building upon the promising antibody candidates C121 and C135 (Robbiani et al., Nature 2020), a bispecific antibody known as CoV-X2 was engineered (De Gasparo et al., Nature 2021). This unique antibody simultaneously engages with two distinct sites on the RBD and effectively neutralizes the G614 virus variant in both cell culture assays and animal models.
In more recent developments, a different bispecific antibody named CoV-X4042, which combines sd1.040 and rbd.042 antibodies targeting the conserved spike region, has demonstrated the ability to neutralize all variants of concern, from the original virus to the currently circulating Omicron variants. Furthermore, this antibody has exhibited protective properties in animal models. Importantly, CoV-X4042 was manufactured in accordance with GMP standards, and toxicology tests were conducted (Bianchini et al., Sci Immunol 2023). In addition, we observed that dimeric and secretory IgA recombinant antibodies are more potent than the parental IgG for binding and neutralizing SARS-CoV-2 including Omicron variants. In hACE2 transgenic mice, a single intranasal dose of the dimeric IgA DXP-604 conferred prophylactic and therapeutic protection against Omicron.
Dissemination and exploitation of results:
ATAC rapidly disseminated results to help respond to the current COVID-19 epidemic. More than 56 papers were published, including publications with a high impact factor project, thereby reaching a wide scientific and medical audience. 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/) and the LinkedIn profile (https://www.linkedin.com/in/atac-project-0aa1951aa/).
Our results have contributed to establishing the foundation for selecting the optimal timing and patient characteristics for collecting plasma from hyperimmune convalescent patients, intended for plasma therapy. Furthermore, we have demonstrated that plasma therapy shows promise as an approach to treating COVID-19 patients, especially when administered during the early stages of the disease.
Efforts were undertaken to identify antibodies that not only exhibit robust virus-neutralizing capabilities but also possess the ability to neutralize multiple variants of the virus. The engineered bispecific antibody, CoV-X4042, demonstrated efficacy in preclinical studies, including against the Omicron variant (Bianchini et al. Sci. Immunol 2023). This antibody was produced on a larger scale under GMP conditions and will be tested in a Phase I clinical trial in the future.
Nasal administration of IgA antibodies to prevent virus transmission or impede the virus from accessing the lungs will undergo further investigation. This is based on our studies, which indicated their increased efficacy against SARS-CoV-2 compared to IgG, as well as on our findings showing that high levels of mucosal IgA against SARS-CoV-2 are associated with reduced breakthrough infections in humans (Zuo et al. N Engl J Med 2022).
The antibodies developed during the project could be used individually or as a cocktail of multiple antibodies for passive protection in either prophylaxis for at-risk populations (such as patients under immunosuppressive therapy or immunocompromised individual) or for treatment against current or future outbreaks of COVID-19 or related coronaviruses.
Efforts were undertaken to identify antibodies that not only exhibit robust virus-neutralizing capabilities but also possess the ability to neutralize multiple variants of the virus. The engineered bispecific antibody, CoV-X4042, demonstrated efficacy in preclinical studies, including against the Omicron variant (Bianchini et al. Sci. Immunol 2023). This antibody was produced on a larger scale under GMP conditions and will be tested in a Phase I clinical trial in the future.
Nasal administration of IgA antibodies to prevent virus transmission or impede the virus from accessing the lungs will undergo further investigation. This is based on our studies, which indicated their increased efficacy against SARS-CoV-2 compared to IgG, as well as on our findings showing that high levels of mucosal IgA against SARS-CoV-2 are associated with reduced breakthrough infections in humans (Zuo et al. N Engl J Med 2022).
The antibodies developed during the project could be used individually or as a cocktail of multiple antibodies for passive protection in either prophylaxis for at-risk populations (such as patients under immunosuppressive therapy or immunocompromised individual) or for treatment against current or future outbreaks of COVID-19 or related coronaviruses.