ABSTRACT
The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants poses challenges to the effectiveness of neutralizing antibodies. Rational design of antibody cocktails is a realizable approach addressing viral immune evasion. However, evaluating the breadth of antibody cocktails is essential for understanding the development potential. Here, based on a replication competent vesicular stomatitis virus model that incorporates the spike of SARS-CoV-2 (VSV-SARS-CoV-2), we evaluated the breadth of a number of antibody cocktails consisting of monoclonal antibodies and bispecific antibodies by long-term passaging the virus in the presence of the cocktails. Results from over two-month passaging of the virus showed that 9E12+10D4+2G1 and 7B9-9D11+2G1 from these cocktails were highly resistant to random mutation, and there was no breakthrough after 30 rounds of passaging. As a control, antibody REGN10933 was broken through in the third passage. Next generation sequencing was performed and several critical mutations related to viral evasion were identified. These mutations caused a decrease in neutralization efficiency, but the reduced replication rate and ACE2 susceptibility of the mutant virus suggested that they might not have the potential to become epidemic strains. The 9E12+10D4+2G1 and 7B9-9D11+2G1 cocktails that picked from the VSV-SARS-CoV-2 system efficiently neutralized all current variants of concern and variants of interest including the most recent variants Delta and Omicron, as well as SARS-CoV-1. Our results highlight the feasibility of using the VSV-SARS-CoV-2 system to develop SARS-CoV-2 antibody cocktails and provide a reference for the clinical selection of therapeutic strategies to address the mutational escape of SARS-CoV-2.
ABSTRACT
Numerous mutations in the spike protein of SARS-CoV-2 B.1.1.529 Omicron variant pose a crisis for antibody-based immunotherapies. The efficacy of emergency use authorized (EUA) antibodies that developed in early SARS-CoV-2 pandemic seems to be in flounder. We tested the Omicron neutralization efficacy of an early B cell antibody repertoire as well as several EUA antibodies in pseudovirus and authentic virus systems. More than half of the antibodies in the repertoire that showed good activity against WA1/2020 previously had completely lost neutralizing activity against Omicron, while antibody 8G3 displayed non-regressive activity. EUA antibodies Etesevimab, Casirivimab, Imdevimab and Bamlanivimab were entirely desensitized by Omicron. Only Sotrovimab targeting the non-ACE2 overlap epitope showed a dramatic decrease activity. Antibody 8G3 efficiently neutralized Omicron in pseudovirus and authentic virus systems. The in vivo results showed that Omicron virus was less virulent than the WA1/2020 strain, but still caused deterioration of health and even death in mice. Treatment with 8G3 quickly cleared virus load of mice. Antibody 8G3 also showed excellent activity against other variants of concern (VOCs), especially more efficient against authentic Delta plus virus. Collectively, our results suggest that neutralizing antibodies with breadth remains broad neutralizing activity in tackling SARS-CoV-2 infection despite the universal evasion from EUA antibodies by Omicron variant.
ABSTRACT
Emerging SARS-CoV-2 variants are threatening the efficacy of antibody therapies. Combination treatments including ACE2-Fc have been developed to overcome the evasion of neutralizing antibodies (NAbs) in individual cases. Here we conducted a comprehensive evaluation of this strategy by combining ACE2-Fc with NAbs of diverse epitopes on the RBD. NAb+ACE2-Fc combinations efficiently neutralized HIV-based pseudovirus carrying the spike protein of the Delta or Omicron variants, achieving a balance between efficacy and breadth. In an antibody escape assay using replication-competent VSV-SARS-CoV-2-S, all the combinations had no escape after fifteen passages. By comparison, all the NAbs without combo with ACE2-Fc had escaped within six passages. Further, the VSV-S variants escaped from NAbs were neutralized by ACE2-Fc, revealing the mechanism of NAb+ACE2-Fc combinations survived after fifteen passages. We finally examined ACE2-Fc neutralization against pseudovirus variants that were resistant to the therapeutic antibodies currently in clinic. Our results suggest ACE2-Fc is a universal combination partner to combat SARS-CoV-2 variants including Delta and Omicron.
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with ACE2 interface, which gives 2G1 ability to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar IC50 in vitro. In SARS-CoV-2 and Beta- and Delta-variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 could be potentially capable of dealing with emerging SARS-CoV-2 variants in future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.
ABSTRACT
@#Tumor immunotherapy is currently the new direction for the treatment of cancer. Bispecific antibody can bind two different antigens, so the development prospect in the field of tumor treatment is very attractive. The most compelling trifunctional antibody and bispecific T-cell engager in bispecific antibodies have been marketed separately, with representative drugs as catumaxomab and blinatumomab, respectively. So far, nearly 100 antitumor bispecific antibody drugs are undergoing clinical trials and in-depth understanding of their mechanisms of action will provide more powerful solutions for cancer treatment. This review summarizes the progress of catumaxomab, blinatumomab and current highly promising bispecific antibody drugs, for the further development and application of tumor therapy.
ABSTRACT
Objective To analyze the efficacy and safety of CyberKnife combined with temozolomide (TMZ) in treatment of brain metastasis of non-small cell lung cancer (NSCLC). Methods From March 2013 to March 2016, 62 NSCLC patients with brain metastases in department of oncology of the 187th Hospital of PLA were divided into two groups according to the random number table method, the CyberKnife combined with TMZ group (CyberKnife + TMZ group, 31 cases) and simple CyberKnife group (CyberKnife group, 31 cases). Hypofractionated radiation of CyberKnife was given 18-36 Gy in 1-5 fractions of 5-25 Gy. CyberKnife+ TMZ group was given temozolomide 150 mg·m-2·d-1 for 5 days in first cycle, then every 28 days they received temozolomide therapy from the second to the sixth cycles: 200 mg·m-2·d-1 for 5 days. The clinical symptom remission rate after the treatment of CyberKnife in one week, the effective rate after CyberKnife in 3 months, the median intracranial progression-free survival time, overall survival, and the incidences of adverse reaction were comparatively analyzed. Results The clinical symptom remission rates of CyberKnife+TMZ group and CyberKnife group after the treatment of CyberKnife in one week were 93.6 ％ (29/31) and 96.8 ％ (30/31). There was no significant difference in the clinical symptom remission rates (χ2= 1.207, P=0.547). The effective rates of the two groups after CyberKnife in 3 months were 93.6 ％ (29/31) and 90.3 ％(28/31). There was no significant difference in the effective rates (χ2 = 0.695, P= 0.706). The median intracranial progression-free survival time in CyberKnife + TMZ group (14.0 months) was significantly higher than that in the CyberKnife group (9 months) (χ2=8.977, P=0.003), and the median overall survival time in CyberKnife + TMZ group (15.0 months) was also significantly higher than that in the CyberKnife group (12.0 months) (χ2 = 5.190, P= 0.023). There was no significant difference in the adverse reaction of the central nervous system between the two groups (χ2=0.746, P=0.689), but the adverse reactions of the digestive system (χ2 = 6.062, P= 0.014) and the hematologic system (χ2 = 6.613, P= 0.010) in CyberKnife + TMZ group were significantly higher than those in the CyberKnife group. Systemic adverse reactions of the two groups were tolerated by most patients. Conclusions CyberKnife combined with TMZ is a feasible therapeutic option for NSCLC patients with brain metastases. This therapy can improve the median survival time to cerebral progression of the disease and the median overall survival time.
