ABSTRACT
With the burgeoning development of glycobiology, a growing body of research shows a significant relationship between the development of various diseases and polysaccharides. Glycocalyx, an important component of the vascular endothelium, has a villi-like structure and plays a highly crucial role in maintaining vascular homeostasis. In-depth multidisciplinary studies have further revealed that the biological functions of glycocalyx are not only limited to vascular homeostasis, but are also closely related to various diseases in vivo. Foundations of glycocalyx composition and biological function, this paper reviews the latest research of glycocalyx biodegradation mechanism from the perspective of biological relevance of glycocalyx main components [heparan sulfate (HS), chondroitin sulfate (CS), hyaluronic acid (HA) and core protein] to cancer, corona virus disease 2019 (COVID-19), trauma surgery and other diseases by visualization and molecular biology experimental methods, and intends to provide new thoughts for clinical development of novel diagnostic methods and therapeutic targets.
ABSTRACT
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs), especially the latest Omicron, have exhibited severe antibody evasion. Broadly neutralizing antibodies with high potency against Omicron are urgently needed for understanding the working mechanisms and developing therapeutic agents. In this study, we characterized the previously reported F61, which was isolated from convalescent patients infected with prototype SARS-CoV-2, as a broadly neutralizing antibody against all VOCs including Omicron BA.1, BA.1.1, BA.2, BA.3 and BA.4 sublineages by utilizing antigen binding and cell infection assays. We also identified and characterized another broadly neutralizing antibody D2 with epitope distinct from that of F61. More importantly, we showed that a combination of F61 with D2 exhibited synergy in neutralization and protecting mice from SARS-CoV-2 Delta and Omicron BA.1 variants. Cryo-Electron Microscopy (Cryo-EM) structures of the spike-F61 and spike-D2 binary complexes revealed the distinct epitopes of F61 and D2 at atomic level and the structural basis for neutralization. Cryo-EM structure of the Omicron-spike-F61-D2 ternary complex provides further structural insights into the synergy between F61 and D2. These results collectively indicated F61 and F61-D2 cocktail as promising therapeutic antibodies for combating SARS-CoV-2 variants including diverse Omicron sublineages.
ABSTRACT
Objective To observe the toxic reaction of recombinant fully human monoclonal antibody against novel coronavirus (2B11) injection to rhesus monkeys after repeated administration for 2 weeks, and to determine the non-toxic reaction The relationship between the safe dose and administration dose, administration time and toxicity can provide reference for clinical medication. Methods Thirty healthy rhesus monkeys were randomly divided into 3 groups, 10 in each group, half male and half male. The vehicle control group was given 0.9% sodium chloride injection, and the experimental group was given 2B11 100 and 400 mg·kg, respectively. -1 . Administer once every 6 d iv, 3 times in 2 weeks, and recover for 9 weeks after drug withdrawal. During the experiment, general symptom observation, body weight, food intake, body temperature, ophthalmological examination, blood pressure, electrocardiogram, blood routine, hemostasis, blood biochemistry and electrolytes, urine, system anatomy, organ coefficient, histopathology and immunology were tested. At the same time, anti-drug antibody (ADA) and blood drug concentrations were detected, and toxicokinetic parameters were analyzed. Results The general symptoms, body weight, food intake, body temperature, ophthalmological examination, blood pressure, electrocardiogram, blood routine, hemostasis, blood biochemistry and electrolytes, urine, organ coefficient, histopathology and No obvious changes related to the test substance were found in the indicators such as immunological detection. 2B11 No ADA was detected in the two dose groups. The changes of plasma drug concentrations were basically the same and proportional to the administered dose. The ratio of peak concentration and exposure was also proportional to the administered dose. Linear dynamic characteristics. Conclusion Under the conditions of this experiment, it is safe for rhesus monkeys to be given 2B11 3 times by iv for 2 weeks, and no clinical adverse reactions were observed at 400 mg·kg -1.
ABSTRACT
As the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to threaten public health worldwide, the development of effective interventions is urgently needed. Neutralizing antibodies (nAbs) have great potential for the prevention and treatment of SARS-CoV-2 infection. In this study, ten nAbs were isolated from two phage-display immune libraries constructed from the pooled PBMCs of eight COVID-19 convalescent patients. Eight of them, consisting of heavy chains encoded by the immunoglobulin heavy-chain gene-variable region (IGHV)3-66 or IGHV3-53 genes, recognized the same epitope on the receptor-binding domain (RBD), while the remaining two bound to different epitopes. Among the ten antibodies, 2B11 exhibited the highest affinity and neutralization potency against the original wild-type (WT) SARS-CoV-2 virus (KD = 4.76 nM for the S1 protein, IC50 = 6 ng/mL for pseudoviruses, and IC50 = 1 ng/mL for authentic viruses), and potent neutralizing ability against B.1.1.7 pseudoviruses. Furthermore, 1E10, targeting a distinct epitope on RBD, exhibited different neutralization efficiency against WT SARS-CoV-2 and its variants B.1.1.7, B.1.351, and P.1. The crystal structure of the 2B11-RBD complexes revealed that the epitope of 2B11 highly overlaps with the ACE2-binding site. The in vivo experiment of 2B11 using AdV5-hACE2-transduced mice showed encouraging therapeutic and prophylactic efficacy against SARS-CoV-2. Taken together, our results suggest that the highly potent SARS-CoV-2-neutralizing antibody, 2B11, could be used against the WT SARS-CoV-2 and B.1.1.7 variant, or in combination with a different epitope-targeted neutralizing antibody, such as 1E10, against SARS-CoV-2 variants.