An antibody cocktail with broadened mutational resistance and effective protection against SARS-CoV-2

Neutralizing antibodies have been proven to be highly effective in treating mild and moderate COVID-19 patients,but continuous emergence of SARS-CoV-2 variants poses significant challenges.Antibody cocktail treatments reduce the risk of escape mutants and resistance.In this study,a new cocktail composed of two highly potent neutralizing antibodies(HB27 and H89Y)was developed,whose binding epitope is different from those cocktails that received emergency use authorization.This cocktail showed more potent and balanced neutralizing activities(IC_(50)0.9–11.3 ng mL^(-1))against a broad spectrum of SARS-CoV-2 variants over individual HB27 or H89Y antibodies.Furthermore,the cocktail conferred more effective protection against the SARS-CoV-2 Beta variant in an aged murine model than monotherapy.It was shown to prevent SARS-CoV-2 mutational escape in vitro and effectively neutralize 61 types of pseudoviruses harbouring single amino acid mutation originated from variants and escape strains of Bamlanivimab,Casirivimab and Imdevimab with IC_(50)of 0.6–65 ng mL^(-1).Despite its breadth of variant neutralization,the HB27+H89Y combo and EUA cocktails lost their potencies against Omicron variant.Our results provide important insights that new antibody cocktails covering different epitopes are valuable tools to counter virus mutation and escape,highlighting the need to search for more conserved epitopes to combat Omicron.

Antibody Cocktail Exhibits Broad Neutralization Activity Against SARS-CoV-2 and SARS-CoV-2 Variants

Severe acute respiratory syndrome coronavirus 2(SARS-Co V-2)has precipitated multiple variants resistant to therapeutic antibodies.In this study,12 high-affinity antibodies were generated from convalescent donors in early outbreaks using immune antibody phage display libraries.Of them,two RBD-binding antibodies(F61 and H121)showed high-affinity neutralization against SARS-Co V-2,whereas three S2-target antibodies failed to neutralize SARS-Co V-2.Following structure analysis,F61 identified a linear epitope located in residues G446–S494,which overlapped with angiotensinconverting enzyme 2(ACE2)binding sites,while H121 recognized a conformational epitope located on the side face of RBD,outside from ACE2 binding domain.Hence the cocktail of the two antibodies achieved better performance of neutralization to SARS-Co V-2.Importantly,these two antibodies also showed efficient neutralizing activities to the variants including B.1.1.7 and B.1.351,and reacted with mutations of N501 Y,E484 K,and L452 R,indicated that it may also neutralize the recent India endemic strain B.1.617.The unchanged binding activity of F61 and H121 to RBD with multiple mutations revealed a broad neutralizing activity against variants,which mitigated the risk of viral escape.Our findings revealed the therapeutic basis of cocktail antibodies against constantly emerging SARS-Co V-2 variants and provided promising candidate antibodies to clinical treatment of COVID-19 patients infected with broad SARS-Co V-2 variants.

Neutralizing monoclonal antibodies present new prospects to treat SARS-CoV-2 infections

The coronavirus disease 2019(COVID-19)has caused global public health and economic crises.Thus,new therapeutic strategies and effective vaccines are urgently needed to cope with this severe pandemic.The development of a broadly neutralizing antibody against severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)is one of the attractive treatment strategies for COVID-19.Currently,the receptor-binding domain(RBD)of the spike(S)protein is the main target of neutralizing antibodies when SARS-CoV-2 enters human cells through an interaction between the S protein and the angiotensin-converting enzyme 2 expressed on various human cells.A single monoclonal antibody(mAb)treatment is prone to selective pressure due to increased possibility of targeted epitope mutation,leading to viral escape.In addition,the antibody-dependent enhancement effect is a potential risk of enhancing the viral infection.These risks can be reduced using multiple mAbs that target nonoverlapping epitopes.Thus,a cocktail therapy combining two or more antibodies that recognize different regions of the viral surface may be the most effective therapeutic strategy.