Overview of Research and Development for Anticancer Drugs

Anticancer drugs research and development have been the largest market area in the pharmaceutical industry in terms of the number of project, clinical trials and spending. In the last 10 - 30 years, targeting therapy for cancers has been developed and achieved enormous clinical effectiveness by transforming some previously deadly malignancies into chronically manageable conditions, but cure problem still remains. This mini review outlined the current status of anticancer drugs development and hinted the opinions of how to further increase the accuracy and efficacy of discovery for cancer treatment.

Universal chimeric Fcγreceptor T cells with appropriate affinity for IgG1 antibody exhibit optimal antitumor efficacy

Developing universal CARs with improved flexible targeting and controllable activities is urgently needed.While several studies have suggested the potential of CD16a in tandem with monoclonal antibodies to construct universal CAR-T cells,the weak affinity between them is one of the limiting factors for efficacy.Herein,we systematically investigated the impact of Fcγreceptor(FcγR)affinity on CAR-T cells properties by constructing universal CARs using Fcγreceptors with different affinities for IgG1 antibodies,namely CD16a,CD32a,and CD64.We demonstrated that the activities of these universal CAR-T cells on tumor cells could be redirected and regulated by IgG1 antibodies.In xenografted mice,64CAR chimeric Jurkat cells with the highest affinity showed significant antitumor effects in combination with herceptin in the HER2 low expression U251 MG model.However,in the CD20 high expression Raji model,64CAR caused excessive activation of CAR-T cells,which resulted in cytokine release syndrome(CRS)and the decline of antitumor activity,and 32CAR with a moderate affinity brought the best efficacy.Our work extended the knowledge about FcγR-based universal CAR-T cells and suggested that only the FcγRCAR with an appropriate affinity can offer the optimal antitumor advantages of CAR-T cells.

Neutralization of SARS-CoV-2 infection by antibodies targeting diverse epitopes

The CoVID-19 pandemic that started in late 2019 is sweeping through the world,posing historic challenges to global health,and disrupting social and economic lives.Previous and recent studies indicate that monoclonal antibodies can be efficacious in preventing and treating SARSCoV-1 and SARS-CoV-2 infections.Using a phage display platform,we have identified dozens of monoclonal antibodies that bind to diverse epitope groups on the SARS-CoV-2 spike protein.Many of them bound to the receptor binding domain(RBD)and inhibited ACE2-RBD interaction.

Mutational escape prevention by combination of four neutralizing antibodies that target RBD conserved regions and stem helix

New variants of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) appear rapidly every few months.They have showed powerful adaptive ability to circumvent the immune system. To further understand SARS-CoV-2’s adaptability so as to seek for strategies to mitigate the emergence of new variants, herein we investigated the viral adaptation in the presence of broadly neutralizing antibodies and their combinations. First, we selected four broadly neutralizing antibodies, including pan-sarbecovirus and pan-betacoronavirus neutralizing antibodies that recognize distinct conserved regions on receptor-binding domain(RBD) or conserved stem-helix region on S2 subunit.Through binding competition analysis, we demonstrated that they were capable of simultaneously binding.Thereafter, a replication-competent vesicular stomatitis virus pseudotyped with SARS-CoV-2 spike protein was employed to study the viral adaptation. Twenty consecutive passages of the virus under the selective pressure of individual antibodies or their combinations were performed. It was found that it was not hard for the virus to adapt to broadly neutralizing antibodies, even for pan-sarbecovirus and pan-betacoronavirus antibodies. The virus was more and more difficult to escape the combinations of two/three/four antibodies. In addition, mutations in the viral population revealed by high-throughput sequencing showed that under the selective pressure of three/four combinational antibodies, viral mutations were not prone to present in the highly conserved region across betacoronaviruses(stem-helix region), while this was not true under the selective pressure of single/two antibodies.Importantly, combining neutralizing antibodies targeting RBD conserved regions and stem helix synergistically prevented the emergence of escape mutations. These studies will guide future vaccine and therapeutic development efforts and provide a rationale for the design of RBD-stem helix tandem vaccine, which may help to impede the generation of novel variants.

Untargeted metabolomic analysis of pregnant women exposure to perfluorooctanoic acid at different degrees

Perfluorooctanoic acid(PFOA)is a novel type of persistent synthetic organic pollutant,and its exposure on pregnant women can cause some adverse effects,such as pregnancy-induced hypertension,gestational diabetes mellitus,and preeclampsia.Therefore,understanding the metabolic changes caused by PFOA exposure is of great significance to protect pregnant women from its adverse effects.In this study,the metabolomes from the urine samples of pregnant women exposure to PFOA at different degrees were analyzed by GC-MS and LC-MS.The samples in different groups were distinguished and the differential metabolites were screened based on the VIP value,FC,and P-value of each comparison group through multivariate statistical analysis.The pathways related to differential metabolites were searched to reveal the effects of PFOA exposure on metabolic changes in pregnant women at different degrees.Finally,the ROC of differential metabolites was performed,and the differential metabolites with large area under the curve(AUC)values were selected and compared to identify the mutually differential metabolites.Meanwhile,these metabolites were fitted with a multivariable to explore if they could be used to distinguish different groups.The quantitative comparison of mutually differential metabolites revealed that the levels of L-cysteine,glycine,and 5-aminovaleric acid were positively correlated with the degree of PFOA exposure,indicating that different degrees of PFOA exposure could affect the synthesis or degradation of GSH and change the metabolism of oral or intestinal microbiota.Additionally,they may cause oxidative stress and abnormal fat metabolism in pregnant women.

Freeze-Drying Formulations Increased the Adenovirus and Poxvirus Vaccine Storage Times and Antigen Stabilities

Successful vaccines induce specific immune responses and protect against various viral and bacterial infections. Noninactivated vaccines, especially viral vector vaccines such as adenovirus and poxvirus vaccines, dominate the vaccine market because their viral particles are able to replicate and proliferate in vivo and produce lasting immunity in a manner similar to natural infection. One challenge of human and livestock vaccination is vaccine stability related to the antigenicity and infectivity. Freeze-drying is the typical method to maintain virus vaccine stability, while cold chain transportation is required for temperatures about 2 °C–8 °C. The financial and technological resource requirements hinder vaccine distribution in underdeveloped areas. In this study, we developed a freeze-drying formula consisting of bovine serum albumin(BSA), L-glutamic acid(L-Glu), polyethylene glycol(PEG), and dextran(DEX) to improve the thermal stability and activity of viral vaccines, including vaccinia recombinant vaccine(rTTV-OVA) and adenovirus vaccine(Ad5-ENV). We compared a panel of five different formulations(PEG: DEX: BSA: L-GLU = 50:9:0:0(#1), 50:5:4:0(#2), 50:10:9:0(#3),50:0:0:9(#4), and 50:1:0:8(#5), respectively) and optimized the freeze-drying formula for rTTV-OVA and Ad5-ENV. We found that the freeze-drying formulations #2 and #3 could maintain rTTV-OVA infectivity at temperatures of 4 °C and25 °C and that r TTV-OVA immunogenicity was retained during lyophilization. However, formulations #4 and #5 maintained Ad5-ENV infectivity under the same conditions, and Ad5-ENV immunogenicity had maximum retention with freeze-drying formulation #4. In summary, we developed new freeze-drying formulations that increased virus vaccine storage times and retained immunogenicity at an ambient temperature.