ArchivePersonalized peptide therapeutic tumor vaccine is a kind of precision medical product prepared according to the tumor heterogeneity and human leukocyte antigen heterogeneity in patients. It has strong anti-tumor specificity, low toxic and side effects, definite antigen sequence, and is easy to be prepared and controlled. Additionally, the economic cost is relatively low. This kind of vaccine has become a hot spot in tumor vaccine development. This paper analyzes and summarizes the Ⅰ~Ⅲ phase clinical pharmacodynamics researches of personalized tumor-associated antigen peptide therapeutic tumor vaccines and personalized tumor neoantigen peptide therapeutic tumor vaccines in the recent 2 decades, in order to provide a reference for the development and evaluation of such vaccines. At present, the specific humoral and cellular immune response rates of patients vaccinated with personalized tumor-associated peptide therapeutic tumor vaccines are about 70% and 60%, respectively. The specific cellular immune response can be induced in patients by about 60% of the neoantigens in personalized tumor neoantigen peptide therapeutic tumor vaccines. The most common adverse reaction of the two types of vaccines was skin reaction at the injection site, both of which generally had good immunogenicity and tolerability.
To develop quality control methods for recombinant anti-interleukin-23 monoclonal antibodies (anti-IL23 mAb).
Peptide map analysis by RP-HPLC was used for identification of an anti-IL-23 mAb. The purity was measured by reduced/non-reduced capillary electrophoresis-sodium dodecyl sulfonate (CE-SDS) and size exclusion-high performance liquid chromatography (SEC-HPLC). Charge heterogeneity was measured by imaging capillary isoelectric focusing electrophoresis (icIEF). LC isoAsp95 was measured by RP-HPLC. The biological activity was determined on U2OS IL23R/IL12RB1 dimerization cell. Other quality control items complied with corresponding requirements of “Chinese Pharmacopeia” 2015 edition and related guidelines.
Peptide mapping showed the specific spectrum of the anti-IL23 mAb, which could be adopted for the identification test. The area percentage of heavy chain, NGHC and light chain was (97.84±0.12)% as detected by reduced CE-SDS; the area percentage of main peak detected by non-reduced CE-SDS was (97.23±0.11)%. The area percentage of monomer peak and total aggregate peak detected by SEC-HPLC were (99.26±0.005)% and (0.71±0.005)%, respectively. The area percentage of main peak, acid peak and alkaline peak detected by icIEF were (73.83±0.29)%, (24.03±0.34)% and (2.10±0.09)%, respectively. The percentage of LC isoAsp95 was (3.37±0.52)%. The relative biological activity was (102.25±8.47)%.
A series of quality control methods for anti-IL23 mAbs has been established, which can be adaptable in ensuring the safety, effectiveness and quality controllability for similar biologics. The study is of great significance as a representative quality control reference for anti-IL23 mAbs.
Since the administration of “Measures for the Administration of Stem Cell Clinical Research (for Trial Implementation)” in 2015, Cell Collection and Research Center of Institutes for Biological Products Control, National Institutes for Food and Drug Control has undertaken the task of reviewing the quality of stem cell preparations used in clinical research. During the technical communication with stem cell preparation developers and data reviewprocess, some problems were found in cell preparation technique and quality standards of formulation. It was also found that there were a number of non-compliance with the safety and effectiveness test of stem cells. This paper briefly summarizes and analyzes the problems found in the stem cell quality review in our center, so as to provide valuable insights into the research, manufacture, quality control and clinical use of stem cell products.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has widely spread around the world, exerting great impacts on economic growth and human life. It is the highest priority to develop safe and effective drugs. Neutralizing antibodies have achieved good results in previous clinical applications of some viral infectious diseases. They can be used not only for the short-term prevention of SARS-COV-2 infection, but also for the treatment of corona virus disease 2019 (COVID-19), showing important application value. At present, the research and development of SARS-CoV-2 neutralizing antibody has made its rapid progress in China and abroad. Many antibody drugs have entered clinical trials and been put into emergency use. This article mainly summarizes targets of SARS-CoV-2 neutralizing antibody, screening technologies, drug development progresses and problems to be concerned.
As one of the fastest-growing immunotherapies in recent years, CAR-T cell therapy has demonstrated good efficacy and tolerable safety profiles in hematological malignancies, whereas their clinical utility in solid tumors is still limited by poor efficacy and safety profiles. This article starts with a brief introduction of commercial CAR-T products with their clinical performance as the basis of regulatory approval and their ongoing life cycle management, followed by a discussion of most popular targets, such as CD19, BCMA, HER2 and GPC3. Challenges as well as current progress with regards to improving efficacy and durability of response and managing toxicity are also discussed.
As the first mRNA-based COVID-19 vaccine received Emergency Use Authorization (EUA) in 2020, its great safety profile and high protection efficacy has been well demonstrated. As a result of its unique advantage in the mechanism of action, mRNA can effectively trigger strong humoral and cellular immune response. Of note, many other prophylactic or therapeutic mRNA vaccines developed for preventing different infectious diseases or treatment of cancer are under clinical trial investigations. mRNA-based protein supplementation and gene therapy also begin to emerge. There will be bigger stage for the development of mRNA technology-based products, posing a revolutionary effect in the field of biopharmaceuticals.
To compare the correlation between the results of SARS-CoV-2 neutralizing antibody colloidal gold test cards prepared by two different principles and the SARS-CoV-2 pseudovirus neutralization experiment, and to evaluate the feasibility of the neutralizing antibody colloidal gold test card for the SARS-CoV-2 neutralizing antibody detection in different populations.
Two kinds of SARS-CoV-2 neutralizing antibody colloidal gold test cards using double antigen sandwich method (manufacturer A) and competitive blocking method (manufacturers B) were used to detect the samples with SARS-CoV-2 neutralizing antibody titers. Detection sensitivity and the correlation between the two methods and the neutralization experiment were compared. The intravenous human immunoglobulin and specific immunoglobulin prepared before the outbreak of COVID-19 epidemic were detected to investigate the specificity of the eligible test card. In order to determine whether there is a hook effect, individual immunized plasma samples of high ELISA titers were tested with series of dilutions and original dilution. Single post-immunized plasma samples were detected with different ELISA titers, the positive rates were determined and the color changes were observed. Single post-immunized plasma samples were screened in the low-dilution area of ELISA according to chromaticity of 120NT50 and 300NT50 on the colorimetric card to prepare pooled plasma. The results were compared with the currently used indirect ELISA method.
The detection limits of manufacturers A and B for the first-generation NIBSC international standard 20/136 (anti-SARS-CoV-2 human immunoglobulin international standard) were 0.612 5 and 5 IU·mL-1, respectively. The results of different titers of pooled plasma (both of post-immunization with SARS-CoV-2 vaccine and COVID-19 convalescence plasma) have a good correlation with the neutralizing antibody titer. The post-immunization plasma with high ELISA dilutions (above 10 000) did not show hook effect. The positive rate of individual plasma of different ELISA dilution levels reached 100% when the dilution was above 160, and the uniformity of the chromaticity was higher when the dilution level was above 640. The overall chromaticity became darker as the ELISA dilution increased. The chromaticities of Ppool 120NT50 and Ppool 300NT50 screened according to the colorimetric chart were close to the neutralizing antibody titers.
The correlation between the results of the manufacturer A neutralizing antibody test card using the dual antigen sandwich method to detect SARS-CoV-2 neutralizing antibody in convalescent plasma and post-immunization plasma and the titer of the pseudovirus neutralization experiment is better than that of the manufacturer B product using the competitive inhibition method and indirect ELISA. And the color brightness of the detection line is positively correlated with the level of neutralizing antibody, which can be used for preliminary screening of neutralizing antibody in different populations.
To confirm the efficacy of human rabies immunoglobulin (HRIG).
Animal experiments was used to show the protection effect of the neutralizing antibody contained in HRIG on living animals to neutralize rabies virus in vivo. The function of neutralizing antibody contained in HRIG to neutralize and protect cells was evaluated by cytology experiments in vitro.
The survival rate of mice was 0 in 0.006 and 0.003 IU·mL-1 groups, 16.7% in 0.012 IU·mL-1 group, 41.7% in 0.024 IU·mL-1 group, 75.0% in 0.048 IU·mL-1 group, and 100% in 0.095, 0.190 and 0.380 IU·mL-1 groups. The inhibition rate of virus-infected cells was 100% in 0.317 and 0.951 IU·mL-1, 99% in 0.106 IU·mL-1, 58% in 0.035 IU·mL-1, close to 0 in 0.012 IU·mL-1. The degree of HRIG reducing viral infectivity decreases as the concentration of neutralizing antibodies decreasing.
HRIG can neutralize the virus effectively in vivo and in vitro, and has a good dose-response relationship.
To develop a sandwich ELISA method for detection of N protein in SARS-CoV-2 inactivated vaccine, and to further validate and primarily apply it for N protein qutification.
The indirect ELISA method was used to assess the affinity of different anti-N protein antibodies by coating the recombinant N protein. Then the sandwich ELISA system was set up by using antibodies rN003 and rN002 as the capture and detection antibody, respectively. Also, the method for fully lysing virus to release all the N protein was confirmed. Validation of linear range, accuracy, precision, intermediate precision, specificity and LLD were obtained, and N protein content in 6 batches of SARS-CoV-2 inactivated vaccine was determined using this method.
N protein content has good linearty within the concentration range of 0.018~0.75 μg·mL-1 (R2>0.98), with the recovery of 80%~120% and CV <10%. N protein concentrations for 6 batches of samples accounted for 10%~20% of the total protein. All samples showed a good uniformity.
The sandwich ELISA method for detection of N protein in SARS-CoV-2 inactivated vaccine was successfully developed with good linearty, accuracy, precision, intermediate precision, selectivity, and sensitivity, which can satisfy the N protein detection of SARS-CoV-2 inactivated vaccine.
To analyze the safety risks of blood products during the COVID-19 pandemic, and to study the emergency countermeasures of the World Health Organization (WHO), the US FDA (FDA) and the Plasma Protein Therapeutics Association (PPTA) to ensure the safety of blood products during the COVID-19 pandemic, in order to suggest improvements for blood product regulation in China in response to public health emergencies. This article uses literature review, comparative research and descriptive research methods to analyze the existing problems of blood product regulation in response to public health emergencies during the COVID-19 pandemic. When responding to sudden epidemic situations or infectious public health emergencies, Chinese government regulatory agencies should strengthen communication and cooperation with blood product manufacturers, industry associations, and professional consulting teams, providing timely scientific industry guidelines to give a full play as the role of industry associations so as to ensure the safety of blood products on the market.
To Explore and analyze the patent dance system related to the registration of biological products in the United States, domestic and foreign documents were consulted. The background of the US “Biologics Product Price Competition and Innovation Act” was reviewed, and the reasons, characteristics, and the challenges of system implementation were analyzed regarding the design of biological product patent dance system that is different from the chemical drug patent linkage. The patent dance system is based on good faith negotiation between the original research company of biological products and the biosimilar drug company. The scope of patent litigation is determined by the patent information exchange process. At the same time, two different stages are designed to enter the patent litigation, in order to speed up the similar biological products coming into the market, so as to improve the public accessibility.
Herpes zoster and its complications postherpetic neuralgia seriously affects the quality of life for patients, and brings significant disease burden to the society. At present, since there is no effective drug for the treatment of herpes zoster, vaccination is still the best approach to prevent herpes zoster and its complications. There is no domestic herpes zoster preventive vaccine authorized in China until now, so there is still unmet demands from market. Combined with the general technical requirements by clinical trials of vaccine, considering classification and characteristics of herpes zoster preventive vaccines in China, the key points that should be considered in clinical evaluation of herpes zoster preventive vaccine will be analyzed and summarized in this article, so as to provide references for domestic clinical trials and studies.
In recent years, increasing number of oncolytic virus drugs have entered clinical study. Administration approach mainly involves intratumoral, intravenous, intracranial intra-arberial, and so on. Among them, indications for intraperitoneal administration of oncolytic virus mostly include malignant pleural effusion, malignant pleural mesothelioma, and thoracic/abdominal cancer. Due to the inherent characteristics of the administration approach, the absorption of intra-cavity administration is slower than that by intravenous, and the pleural injection requires an indwelling catheter. The efficacy of intraperitoneal administration greatly varies among different oncolytic virus products and indications. Among them, pleural administration for malignant pleural effusion shows good efficacy, while the efficacy of intra-cavity administration for malignant pleural mesothelioma and ovarian cancer is unclear. Due to limited participants in relevant clinical study, the safety and efficacy need further verification by confirming clinical trials.
Cell therapy products (CTPs) have the potential of tumor formation risks, i.e., tumorigenicity, oncogenicity and tumor-enhancement. Since the final stem cell therapy products derived from human embryonic stem cells and human induced pluripotent stem cells may contain undifferentiated hPSCs, malignant transformed cells/mutations and genetic instability, they have the highest risk of tumorigenicity. Tumorigenicity and oncogenicity risk of CTPs may be largely increased in genetically modified stem cells, that express foreign genes (such as various growth factors), as well as the oncogene activated by insertion mutations of genetically modified viral vectors (such as retroviruses and lentiviruses). While terminally differentiated somatic cell products have lower risk of tumorigenicity. During recent years, increasing number of cell therapy products have entered the clinical application, the tumor formation risk of which is a safety issue that is concerned by product developers and regulatory authorities. This article introduces the concepts of tumorigenicity, oncogenicity and tumor-enhancement of CTPs, providing a comprehensive overview of the current evaluation methods in vitro and in vivo, as well as the general considerations for risk assessment of tumorigenicity and oncogenicity of CTPs.
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