In searching for urgently needed cures for COVID-19, a team of scientists at Jilin University, Beijing Institute of Microbiology and Epidemiology, and Inner Mongolia University for Nationalities, together with industry partners, has made a significant progress in developing antibody-based therapeutics. More specifically, the team explores an immunotherapeutic strategy by developing equine antisera as an option to fight against COVID-19. Comparably, human convalescent plasma has been approved in China, United States and some other countries as one of the experimental/investigational therapeutic options to treat severely sick COVID-19 patients. However, human convalescent plasma are typically not readily available in large quantities in outbreak situations such as the ongoing COVID-19 pandemic around the world. On the other hand, animals can quickly produce a large quantity of antisera (antibodies) by immunizing them with strategically designed antigens. Among animals, horses are the only species currently approved in many countries for producing therapeutic antibodies used in humans.
To develop effective antisera, the team immunized horses with an antigen containing a domain of the SARS-CoV-2 spike protein responsible for the viral binding to human cells. Therefore, the basic mechanism of action is to block the entry of SARS-CoV-2 viruses into human cells. Briefly, to prepare the antigen by a eukaryotic expression system, immunizing horses with the antigen, testing titers of the antisera samples, collecting antisera in a large amount, digesting antisera to prepare IgG F(ab′)2 that is the fragment of animal antibodies IgG for use in humans.
Based on the data provided by Dr. Mingyuan Liu who leads the research effort, after only three rounds of immunization, the equine antiserum has already reached a very satisfactory high titer, i.e., reached 10,240-fold dilution tested by an ELISA kit designed for evaluating the titers of human convalescent plasma. In fact, it is 128-fold higher than the eligible titer (1:160-fold dilution) of plasma collection from convalescent patients.
More importantly, the equine antiserum is highly potent in blocking the viral infection to human cells, the neutralization titer of it reached 5,120-fold dilution, which means it can protect 50% of the human cells from viral infection even after 5,120-fold dilution. Technically, a higher neutralization titer represents a more power in fighting the viral infection. In comparison to the viral neutralization titers of human convalescent plasma from COVID-19 patients in China, which ranged from 40 to 80-fold dilution based on an article published in Nature (https://www.nature.com/articles/s41586-020-2012-7), the equine antiserum is 128-fold more effective than human convalescent plasma.
Currently, the team has prepared the IgG F(ab′)2 from the equine antisera, ready for experimental or investigational treatment of COVID-19 patients. Based on the team’s data, 2.5 mL of the IgG F(ab′)2 solution is equivalent to 500 mL of human convalescent plasma, the maximal dose allowed in experimental therapy according to the “Guidance for Clinical Treatment of New Coronavirus Pneumonia Patients Using Human Convalescent Plasma” (Trial version 2) issued by the Chinese government (available in Chinese at http://www.gov.cn/zhengce/zhengceku/2020-03/05/content_5487145.htm). Currently, the horses are receiving additional rounds of immunization. Therefore, it is expected that the titer of equine antisera collected later will be higher and higher, and the using dosage for human will be less and less as well.
If experimental therapy using equine IgG F(ab′)2 is successful, doctors will have a powerful new option to fight against the ongoing COVID-19 pandemic.
Drafted by Guan Zhu, Texas A&M University, Texas, USA.
2020-03-29
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