Academician Xiaoliang Xie’s Team Has Discovered a Combination of Highly Potent and Fully Human Antibodies with Broad-spectrum Neutralizing Efficacy Against Concerning SARS-CoV-2 Variants

 

“Focusing on the highly unmet clinical needs of treating infectious diseases and cancers, developing effective and affordable medicine for the people of China”

 

 
 

On August 25 2021, the research group of Dr. Xiaoliang Xie, the  co-founder of Singlomics and professor of Beijing Advanced Innovation Center for Genomics (ICG), Peking University-Tsinghua University Joint Center for Life Sciences (CLS) and School of Life Sciences, Peking University, and the research group of Dr. Junyu Xiao, jointly published a research paper, "Structures of SARS-CoV-2 B.1.351 neutralizing antibodies provide insights into cocktail design against concerning variants" in Cell Research.

In a previous study, via analyzing the immune response toward the B.1.351 variant in long-term convalescents and those vaccinated against COVID-19, Dr. Xiaoliang Xie’s team identified a panel of monoclonal antibodies that could effectively neutralize this particular variant (Cao et al., Cell Research 31: 732-741, 2021). In the newly published work, the molecular mechanisms and pairing of these neutralizing antibodies were further explored. 

First, two antibodies, BD-812 and BD-836, were found to have very high activity in experiments to measure their ability in neutralizing B.1.351 pseudoviruses, exhibiting half maximal inhibitory concentration (IC50) close to pM level (Figure 1, a). A high-resolution single-particle cryo-electron microscopy study demonstrated that BD-812 and BD-836 bound to the left and right shoulders, respectively, of the receptor binding domain (RBD) on the spike protein of B.1.351 variant (Figure 1, b, c). Their binding epitopes are completely non-interfering, and both could directly block the binding of RBD to host cell ACE2 receptor. More importantly, the binding of BD-812 or BD-836 to RBD was not affected by the two mutation sites, L452R and T478K, in the Delta variant. The analysis on pseudovirus further showed that both antibodies could effectively neutralize the Delta variant.

 

 

Figure 1 Molecular Mechanism of Neutralizing Antibodies Targeting SARS-CoV-2 Variant B.1.351

 
Dr. Xie’s team also analyzed the mechanism by which other antibodies target the B.1.351 spike protein. The combination of BD-821 and BD-771 closely resembles the binding pattern of BD-812/BD-836 described above, with both being potent at neutralizing the Delta variant. However, BD-821 covers a smaller interface on RBD compared to BD-812, accounting for its weaker neutralizing ability relative to the latter. BD-813 binds to the backside of RBD, directly blocking the binding of RBD to host ACE2, and also maintaining activity against the Delta variant. Additionally, BD-744, BD-667, and BD-804 bind to the "chest" portion of RBD and their epitopes do not overlap with the binding site of the spike protein to host ACE2. The epitopes of all these three antibodies encompass residue Leu452, and the Delta variant can escape from these antibodies. In essence, the L452R mutation present in the Delta variant will invalidate many otherwise neutralizing antibodies whose binding sites encompass L452.


In conclusion, this study systematically analyzed a series of fully human neutralizing antibodies targeting the B.1.351 spike protein, explored their actions in combinations based on structural information, and most importantly, measured their efficacy on the Delta variant. In particular, the BD-812/BD-836 antibody combination, taken from long-term convalescents, was prominent, exhibiting   pM-level neutralizing activity against variants such as Alpha, Beta, Kappa, and Delta, etc. This combination is expected to be a promising drug candidate for combating concerning Covid variants.

Paper link:

https://www.nature.com/articles/s41422-021-00555-0

 

 

About Singlomics

 

 

Singlomics Biopharmaceuticals Co., Ltd., registered in June 2020, is a biotechnology company led by Dr. Xiaoliang Xie, an internationally renowned biophysical chemist and member of four National Academies in both China and US. Singlomics is committed to using single-cell sequencing technology platforms to research and develop antibody drugs, and to promoting the discovery of innovative medicine for the treatment of infectious and autoimmune diseases. The members of the core scientific team all graduated from Harvard University, Peking University and other prestigious universities, and have substantial experience in single-cell genomics, transcriptomics, methylomics, immunology, etc.

 

Singlomics has completed the first round of financing from China's medical and health investors, and is preparing to build an antibody drug production base in the Changping District of Beijing with a focus on expanding the company’s product portfolio and enhancing manufacturing capability. DXP593 and DXP604, two current products of the company, are monoclonal antibodies with potent neutralizing ability against concerning Covid variants. They were screened from convalescent COVID-19 patients by using the company’s state-of-the-art single-cell sequencing technology platform. Both are currently under clinical development for the treatment and prevention of COVID-19.

 

Singlomics Contact：

Ms. Zeng

Email：contact@singlomics.com

Tel: +86-10-80765087