Lonaprevive and sotrobimab – From SARs-CoV-2 specific neutralizing antibody to broad neutralizing antibody – from Dr. Joe Chiba

Lonaprieve, which was granted special approval in July 2021, was initially limited to inpatients, but since August, the Ministry of Health, Labour and Welfare (MHLW) has issued an administrative communication entitled “Distribution of the neutralizing antibody drugs casiribimab and imdevimab in new-type coronavirus infection to medical institutions” (hereinafter “Administrative Communication In 2021, the “Administrative Instructions (Revision and Addition of Questions and Answers) (partially revised on August 25, 2021)” was partially revised several times, allowing outpatient administration without the intervention of health centers, as long as the division of roles and responsibilities are clarified in advance. In reality, however, various uses seem to coexist, as some cases in Tokyo and Osaka Prefecture described in the recently reported “Administrative Communication (Partial Revision of September 10, 2021)” involve the intervention of public health centers. According to the September 17, 2021 Office Announcement (https://www.mhlw.go.jp/content/000834046.pdf), it is now possible to administer the drug on a “house call” basis if the medical system is well established. In September, Chugai Pharmaceutical issued “To doctors who administer Lonapreve in outpatient clinics” (https://chugai-pharm.jp/content/dam/chugai/product/ron/div/doc/ron_gairaitouyo.pdf) in September.

According to an actual case report from Tokyo, Japan, as described in the September 17, 2012, if Lonaprieve is administered intravenously within 3-4 days after the onset of symptoms, the onset of symptoms will not be delayed until the next day. 41.5% of the patients were reported to be mildly relieved by 2 days. Of the 230 subjects, 215 (93.5%) were mildly relieved, 15 (6.5%) were non-improved, and 0 (0%) died. Although the data were obtained from 420 cases out of 1,048 reported cases, and from which non-vaccinated subjects were selected, they are important data showing that high therapeutic efficacy can be expected even for delta strains (most of which are presumed to be delta strains based on the timing of administration) if administered appropriately.

As mentioned above, medical facilities and administration methods for Lonaprieve administration are being prepared and its administration is becoming more active. On September 4, an application for special exception approval of sotrovimab (development number: S309/Vir7831/Vir7832) developed by GlaxoSmithKline (GSK) of the UK and Ville Biotechnology, a US biotechnology venture, was submitted and approved on September 27 as “Zebudi intravenous solution” (sotrovimab).

Sotrovimab was produced from antibody genes taken from B cells of patients who recovered from infection with SARS-CoV-1, the virus responsible for the SARS epidemic that began in 2002. According to the U.S. NIH guidelines, the target patients and usage are the same as for Lonaprev, but it should be noted that the mechanism of action is different from that of Lonaprev.

Lonaprev is specific for SARS-CoV-2 and is a cocktail of neutralizing antibodies that bind to the receptor binding domain (RBD) of the spike protein, whereas sotrovimab is specific for the corona-associated virus sarbecovirus clade 1 (SARS-CoV-2 associated) The RBD is a single broadly neutralizing antibody that binds to a common structure containing a glycan structure in the RBD of the spike protein of the SARS-CoV-1 virus (SARS-CoV-1 virus + SARS-CoV-1 related virus). Although sotrovimab’s in vitro neutralizing activity is not high, it has been shown to have the ability to activate NK cells and other cells via the Fc receptor in vitro and to kill SARS-CoV-2 infected cells. Furthermore, it has been shown to maintain activity against mutant strains of concern/notable mutants, including delta and lambda strains, and has also shown efficacy in neutralization studies using hamsters (Andrea L Cathcart et.al.,bioRxiv 2021.03.09.434607), leading to overseas The drug has advanced to clinical trials and has been approved for emergency use by the U.S. FDA (GSK September 6 press release).

Sotrovimab, the first broadly neutralizing antibody product developed along these lines to receive emergency use approval in the United States, raises the following concerns.

1. It has been evaluated in only 1,057 foreign clinical trials, and its subsequent real-world clinical evaluation against Delta strains is unknown (the September revision of the FDA’s Sotrovimab Fact Sheet indicates that it retains in vitro activity against Delta strains, albeit at a reduced level).
2. There are no reports that the U.S. government has purchased the product, and its evaluation and distribution record in the U.S. is unknown.
3. If neutralizing activity is low (Rappazzo CG, et al., Science. 2021 Feb 19;371(6531):823-829.) and Fc receptor-mediated activation of NK cells occurs, the balance between killing infected cells and activating the immune system may be problematic, but the No evaluation has been made.
4. Ville Biotechnology, the U.S. biotech company that developed sotrovimab, has since developed S2X259, an antibody that more broadly neutralizes corona-associated viruses (Tortorici MA, et al. 2021. PMID: 34280951).

This one could be the main goal.

Currently, following sotrovimab, a broadly neutralizing antibody, ADG-2, a highly neutralizing antibody from Adagio therapeutics of the U.S., is in global phase 2/3 clinical trials. S2X259, mentioned above, does not appear to have entered clinical trials. In the midst of this fierce competition, NT-193, a seed antibody with high potential to become a domestically produced broad neutralizing antibody, was developed and published in Immunity (10.1016/j.immuni.2021.08.025). It is highly praiseworthy that the seed of an antibody drug has been experimentally proven to have the potential to neutralize even mutant strains that may emerge in the future. We hope that this world-class, domestically produced neutralizing antibody will be developed as an antibody drug, and that a system for the stable supply of neutralizing antibodies in Japan will be established as soon as possible.

Reference article: Nikkei Biotech article, “New corona, domestically produced neutralizing antibody seeds to suppress a wide range of mutant strains,” https://bio.nikkeibp.co.jp/atcl/news/p1/21/09/07/08597/