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Anti-coronavirus bispecific neutralizing antibody and application

A bispecific antibody and coronavirus technology, applied in antiviral agents, antiviral immunoglobulins, applications, etc., can solve problems such as immune escape, error, drug failure or reduced neutralization ability

Active Publication Date: 2022-03-08
ACADEMY OF MILITARY MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, because SARS-CoV-2 is an RNA virus, it is easy to make mistakes during the replication process. A large number of replications can cause multiple mutations, and the mutation speed is extremely fast. Therefore, immune escape often occurs due to mutations, resulting in a decline in the protection of the vaccine. , Some monoclonal antibody drugs developed in the early stage failed or their neutralization ability was greatly reduced

Method used

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  • Anti-coronavirus bispecific neutralizing antibody and application
  • Anti-coronavirus bispecific neutralizing antibody and application
  • Anti-coronavirus bispecific neutralizing antibody and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0111] Example 1. Exploring the binding sites of parental antibodies SFC3 and HSA-1F to wild-type SARS-CoV-2 RBD

[0112] By analyzing the anti-COVID-19 virus monoclonal antibodies obtained in the previous work, the present inventor unexpectedly found that: the two murine monoclonal antibodies targeting the RBD region of the SARS-CoV-2 S protein obtained in the previous work can be Lower concentrations completely blocked the virus from infecting host cells, and showed a certain synergistic effect. In addition, the binding epitopes of the two monoclonal antibodies were identified by ForteBio based on BLI technology, and the epitopes of the two monoclonal antibodies binding to RBD were found. bits are different. On this basis, two humanized monoclonal antibodies, namely SFC3 and HSA-1F, were used to construct bispecific antibodies, and an IgG-like bispecific antibody BI31 was constructed. The bispecific antibody BI31 is obtained by modifying the parental antibodies SFC3 and HSA...

Embodiment 2

[0116] Example 2, Preparation of anti-new coronavirus bispecific antibody

[0117] 1. The structure of the bispecific antibody BI31

[0118] The IgG-like bispecific neutralizing antibody was prepared by using the humanized monoclonal antibody SFC3 and HSA-1F, named BI31 (the constant region of the heavy chain is IgG1, and the light chain is Kappa). The bispecific antibody BI31 is a scFv fused with SFC3 at the N-terminus of the humanized antibody HSA-1F (ie, the N-terminus of the heavy chain variable region of HSA-1F) (ie, the single-chain antibody SFC3 scFv). The single-chain antibody SFC3 scFv uses an oligonucleotide linker to connect the heavy chain variable region (VH) and light chain variable region (VL) of the humanized antibody SFC3 to form a single polypeptide chain . The constructed bispecific antibody BI31 contains the single-chain antibody SFC3scFv and the complete humanized antibody HSA-1F structure, which has a highly stable symmetrical structure (the structure o...

Embodiment 3、BI31

[0170] Example 3, Detection of specific binding ability of BI31 antibody and parental antibody

[0171] 1. Elisa detection antibody affinity to SARS-CoV-2 RBD protein

[0172] 1. Dilute SARS-CoV-2 RBD recombinant protein (Shenzhou, 40592-V08H5) with carbonate coating buffer (pH 9.6) to 2ng / ul, and add it to the microtiter plate (Corning, 9018), each experimental well was set up with 3 replicate wells, and coated overnight at 4°C.

[0173] 2. On the next day, wash the overnight coated ELISA plate with PBST 6 times, add PBS blocking solution containing 2% (mass percentage) skimmed milk powder, and incubate at 37°C for 2h.

[0174] 3. After blocking, discard the blocking solution, add 100 μL of 2-fold diluted BI31 antibody solution (initial concentration: 50 nM) to each well, set up a total of 11 gradients, incubate at 37°C for 90 minutes, and then wash the plate 6 times with PBST.

[0175] 4. After completing the above steps, take the ELISA plate, add 100 μL of 1:4000 dilution...

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Abstract

The invention discloses an anti-coronavirus bispecific neutralizing antibody and application thereof. Specifically, the invention discloses a bispecific antibody specifically combined with different epitopes of a novel coronavirus S protein receptor binding domain and application thereof. The bispecific antibody comprises a single-chain antibody SFC3scFv and a complete humanized antibody HSA-1F structure, has a highly stable symmetric structure, shows better neutralizing activity compared with a parent antibody and when the bispecific antibody is combined with the parent antibody, and also shows better neutralizing activity on an SARS-CoV-2 variant strain, an SARS-CoV virus and an MERS-CoV virus. According to the bispecific antibody, the neutralizing effect of the novel coronavirus is remarkably improved, the probability of generation of virus escape mutation is reduced, the treatment and prevention means of COVID-19 are enriched, and the bispecific antibody has a huge prospect of becoming a broad-spectrum antibody drug aiming at the coronavirus and has important significance on prevention and treatment of coronavirus infection.

Description

technical field [0001] The invention belongs to the field of biomedicine, and specifically relates to anti-coronavirus bispecific neutralizing antibodies and their applications, in particular to anti-COVID-19 virus neutralizing antibodies and their applications. Background technique [0002] In terms of systematic classification, coronaviruses belong to the order Nidovirales, the family Coronaviridae, and the genus Coronavirus. Viruses of the genus Coronavirus are RNA viruses with an envelope and a linear single-stranded positive strand genome. The shape of coronavirus particles is round or oval, and the shape of virus particles under the electron microscope presents a crown, which is widely present in the biological world. Coronaviruses are divided into four species, namely α, β, γ, and δ. SARS-CoV-2 and SARS-CoV viruses and MERS-CoV viruses all belong to the β subgenus of coronaviruses. [0003] The new coronavirus (SARS-CoV-2) is a single-stranded positive-strand RNA vi...

Claims

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Application Information

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IPC IPC(8): C07K16/46C07K16/10C12N15/13C12N15/85A61K39/42A61P31/14G01N33/569
CPCC07K16/468C07K16/10C12N15/85A61P31/14G01N33/56983C07K2317/56C07K2317/565C07K2317/76C07K2317/622C07K2317/31C07K2317/92G01N2333/165G01N2469/10A61K2039/505Y02A50/30
Inventor 杨志新王荣郭家正陆健昇杜鹏余云舟陈蕾
Owner ACADEMY OF MILITARY MEDICAL SCI
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