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Respirology (Carlton, Vic.) Mar 2024
Topics: Humans; Omalizumab; Enterotoxins; Asthma; Anti-Asthmatic Agents; Immunoglobulin E
PubMed: 38296607
DOI: 10.1111/resp.14663 -
Vaccines Dec 2023The 80+ existing autoimmune disorders (ADs) affect billions with little prevention or treatment options, except for temporary symptomatic management, leading to enormous... (Review)
Review
The 80+ existing autoimmune disorders (ADs) affect billions with little prevention or treatment options, except for temporary symptomatic management, leading to enormous human suffering and a monumental financial burden. The autoantibodies formed in most ADs have been identified, allowing the development of novel anti-idiotypic antibodies to mute the autoantibodies using vaccines. Nucleoside vaccines have been successfully tested as antigen-specific immunotherapies (ASI), with mRNA technology offering multi-epitope targeting to mute multiple autoantibodies. This paper proposes using mRNA technology to produce anti-idiotypic antibodies with broad effectiveness in preventing and treating them. This paper delves into the state-of-the-art mRNA design strategies used to develop novel ASIs by selecting appropriate T cell and B cell epitopes to generate anti-idiotypic antibodies. The low cost and fast development of mRNA vaccines make this technology the most affordable for the global control of ADs.
PubMed: 38276668
DOI: 10.3390/vaccines12010009 -
Journal of Virology Feb 2024Vaccination is the most effective method to protect humans and animals from diseases. Anti-idiotype vaccines are safer due to their absence of pathogens. However, the...
Vaccination is the most effective method to protect humans and animals from diseases. Anti-idiotype vaccines are safer due to their absence of pathogens. However, the commercial production of traditional anti-idiotype vaccines using monoclonal and polyclonal antibodies (mAb and pAb) is complex and has a high failure rate. The present study designed a novel, simple, low-cost strategy for developing anti-idiotype vaccines with nanobody technology. We used porcine circovirus type 2 (PCV2) as a viral model, which can result in serious economic loss in the pig industry. The neutralizing mAb-1E7 (Ab1) against PCV2 capsid protein (PCV2-Cap) was immunized in the camel. And 12 nanobodies against mAb-1E7 were screened. Among them, Nb61 (Ab2) targeted the idiotype epitope of mAb-1E7 and blocked mAb-1E7's binding to PCV2-Cap. Additionally, a high-dose Nb61 vaccination can also protect mice and pigs from PCV2 infection. Epitope mapping showed that mAb-1E7 recognized the NINDFL of PCV2-Cap and NYNDFLG of Nb61. Subsequently, the mAb-3G4 (Ab3) against Nb61 was produced and can neutralize PCV2 infection in the PK-15 cells. Structure analysis showed that the amino acids of mAb-1E7 and mAb-3G4 respective binding to PCV2-Cap and Nb61 were also similar on the amino acids sequences and spatial conformation. Collectively, our study first provided a strategy for producing nanobody-based anti-idiotype vaccines and identified that anti-idiotype nanobodies could mimic the antigen on amino acids and structures. Importantly, as more and more neutralization mAbs against different pathogens are prepared, anti-idiotype nanobody vaccines can be easily produced against the disease with our strategy, especially for dangerous pathogens.IMPORTANCEAnti-idiotype vaccines utilize idiotype-anti-idiotype network theory, eliminating the need for external antigens as vaccine candidates. Especially for dangerous pathogens, they were safer because they did not contact the live pathogenic microorganisms. However, developing anti-idiotype vaccines with traditional monoclonal and polyclonal antibodies is complex and has a high failure rate. We present a novel, universal, simple, low-cost strategy for producing anti-idiotype vaccines with nanobody technology. Using a neutralization antibody against PCV2-Cap, a nanobody (Ab2) was successfully produced and could mimic the neutralizing epitope of PCV2-Cap. The nanobody can induce protective immune responses against PCV2 infection in mice and pigs. It highlighted that the anti-idiotype vaccine using nanobody has a very good application in the future, especially for dangerous pathogens.
Topics: Animals; Humans; Mice; Capsid Proteins; Circoviridae Infections; Circovirus; Epitopes; Single-Domain Antibodies; Swine; Viral Vaccines
PubMed: 38271227
DOI: 10.1128/jvi.01650-23 -
Respiratory Medicine Mar 2024For patients with moderate-to-severe persistent allergic asthma, omalizumab is approved for subcutaneous administration according to a recommended dosing table based on...
For patients with moderate-to-severe persistent allergic asthma, omalizumab is approved for subcutaneous administration according to a recommended dosing table based on weight and total immunoglobulin E (IgE) level. The aim of this analysis was to assess asthma outcomes including quality of life in patients with allergic asthma initiated on omalizumab in the PROSPERO trial; patients were stratified by where their IgE and body weight fell on the approved dosing table. Patient groups were defined as Inside Dosing Table: patients whose IgE and weight fell within the approved dosing table (n = 506); Insufficient Data to Recommend a Dose: patients who fell into the section of the approved dosing table where not enough clinical data were available to make dosing recommendations (n = 72); and Outside Dosing Table: patients who fell outside the approved dosing table due to baseline IgE and/or weight (n = 209). Overall, asthma and quality of life outcomes were improved after omalizumab initiation for both patients who fall within the recommended dosing table or those who fall outside the recommended dosing table. Our results suggest that omalizumab treatment may be effective in a wide range of patients with moderate-to-severe allergic asthma. ClinicalTrials.gov identifier NCT01922037.
Topics: Humans; Omalizumab; Anti-Asthmatic Agents; Quality of Life; Antibodies, Monoclonal, Humanized; Immunoglobulin E; Asthma
PubMed: 38253245
DOI: 10.1016/j.rmed.2024.107537 -
Frontiers in Genetics 2023A phylogenetic conservation analysis of Trop-2 across vertebrate species showed a high degree of sequence conservation, permitting to explore multiple models as...
A phylogenetic conservation analysis of Trop-2 across vertebrate species showed a high degree of sequence conservation, permitting to explore multiple models as pre-clinical benchmarks. Sequence divergence and incomplete conservation of expression patterns were observed in mouse and rat. Primate Trop-2 sequences were found to be 95%-100% identical to the human sequence. Comparative three-dimension primate Trop-2 structures were obtained with AlphaFold and homology modeling. This revealed high structure conservation of Trop-2 (0.66 ProMod3 GMQE, 0.80-0.86 ± 0.05 QMEANDisCo scores), with conservative amino acid changes at variant sites. Primate cDNAs were cloned and transfectants for individual ORF were shown to be efficiently recognized by humanized anti-Trop-2 monoclonal antibodies (Hu2G10, Hu2EF). Immunohistochemistry analysis of (rhesus monkey) tissues showed Trop-2 expression patterns that closely followed those in human tissues. This led us to test Trop-2 targeting in (cynomolgus monkey) Intravenously injected Hu2G10 and Hu2EF were well tolerated from 5 to 10 mg/kg. Neither neurological, respiratory, digestive, urinary symptoms, nor biochemical or hematological toxicities were detected during 28-day observation. Blood serum pharmacokinetic (PK) studies were conducted utilizing anti-idiotypic antibodies in capture-ELISA assays. Hu2G10 (t = 6.5 days) and Hu2EF (t = 5.5 days) were stable in plasma, and were detectable in the circulation up to 3 weeks after the infusion. These findings validate primates as reliable models for Hu2G10 and Hu2EF toxicity and PK, and support the use of these antibodies as next-generation anti-Trop-2 immunotherapy tools.
PubMed: 38250577
DOI: 10.3389/fgene.2023.1297367 -
Sensors & Diagnostics Jan 2024Concentration-therapeutic efficacy relationships have been observed for several therapeutic monoclonal antibodies (TmAb), where low circulating levels can result in...
Concentration-therapeutic efficacy relationships have been observed for several therapeutic monoclonal antibodies (TmAb), where low circulating levels can result in ineffective treatment and high concentrations can cause adverse reactions. Rapid therapeutic drug monitoring (TDM) of TmAb drugs would provide the opportunity to adjust an individual patient's dosing regimen to improve treatment results. However, TDM for immunotherapies is currently limited to centralised testing methods with long sample-collection to result timeframes. Here, we show four point-of-care (PoC) TmAb biosensors by combining anti-idiotypic Affimer proteins and NanoBiT split luciferase technology at a molecular level to provide a platform for rapid quantification (<10 minutes) for four clinically relevant TmAb (rituximab, adalimumab, ipilimumab and trastuzumab). The rituximab sensor performed best with 4 pM limit of detection (LoD) and a quantifiable range between 8 pM-2 nM with neglectable matrix effects in serum up to 1%. After dilution of serum samples, the resulting quantifiable range for all four sensors falls within the clinically relevant range and compares favourably with the sensitivity and/or time-to-result of current ELISA standards. Further development of these sensors into a PoC test may improve treatment outcome and quality of life for patients receiving immunotherapy.
PubMed: 38249540
DOI: 10.1039/d3sd00126a -
Clinical and Experimental Medicine Jan 2024Despite conventional glucocorticoid and antifungal therapy, acute exacerbation and hospitalization occur frequently in patients with allergic bronchopulmonary...
Despite conventional glucocorticoid and antifungal therapy, acute exacerbation and hospitalization occur frequently in patients with allergic bronchopulmonary aspergillosis (ABPA). Whether omalizumab is an effective and safe treatment for adult patients with ABPA complicating asthma. Patients with ABPA complicating asthma who were treated with omalizumab from October 2019 to May 2023 were collected from five tertiary hospitals and evaluated. The frequencies of acute exacerbation and hospitalization; the number of eosinophils; the total IgE levels; and the average monthly medical dosages after 3, 6, and 12 months of omalizumab treatment were analysed, and the data before and after treatment (up to one year) were compared. The efficacy and safety of omalizumab treatment were assessed. In total, 26 patients were enrolled. The average monthly glucocorticoid dosage significantly decreased (median 0 vs. 24 mg/m) after 6 months of omalizumab treatment compared with 3 months; 73.68% of patients discontinued glucocorticoids after ≤ 12 months of treatment. Similarly, the average monthly dosage of antifungal agents was significantly decreased (median 0 vs. 3.49 g/m) after 12 months of treatment compared with 3 months. The average monthly glucocorticoid dosage (median 213.75 vs. 65.42 mg/m, P = 0.002) and the frequency of acute exacerbation (median 0.94 vs. 0.44 events, P = 0.033) were considerably reduced after omalizumab treatment. Omalizumab is effective in reducing the frequency of acute exacerbation and the necessary dosage of glucocorticoids in adult patients with ABPA complicating asthma. Patient age and BMI may affect the efficacy of treatment.
Topics: Adult; Humans; Anti-Allergic Agents; Aspergillosis, Allergic Bronchopulmonary; Asthma; China; Glucocorticoids; Omalizumab
PubMed: 38240869
DOI: 10.1007/s10238-023-01267-y -
Therapeutic Advances in Respiratory... 2024With the rise of targeted treatments for asthma, treatment with omalizumab is a new option. (Meta-Analysis)
Meta-Analysis
BACKGROUND
With the rise of targeted treatments for asthma, treatment with omalizumab is a new option.
OBJECTIVES
To assess the improvement of pulmonary function with additional omalizumab treatment in patients (⩾6 years old) with moderate-to-severe allergic asthma.
DATA SOURCES AND METHODS
Observational studies of randomized controlled trials of add-on omalizumab for the treatment of patients with moderate-to-severe allergic asthma, published from the establishment till August 2022, were retrieved from WAN FANG DATA, PubMed, CNKI, Embase, Cochrane, and Web of Science databases. Data extraction and quality evaluation were performed on the literature that met the inclusion criteria, using RevMan 5.3 to analyze the data.
RESULTS
A total of 11 randomized controlled clinical trials were included, involving a total of 3578 patients with asthma, 1856 patients in the omalizumab group, and 1722 patients in the control group. The improvement in Forced expiratory volume in 1 s as a percentage of predicted normal and Forced expiratory volume in 1 s was more pronounced in the omalizumab-treated group [MD = 3.91, 95% confidence interval (CI): 1.89-5.94, = 0.0002; MD = 0.09, 95% CI: 0.05-0.13, < 0.0001], while the improvement in Morning Peak expiratory flow rate was not statistically different between the two groups (MD = 3.64, 95% CI: -22.17-29.45, = 0.78).
CONCLUSION
Additional omalizumab treatment showed some improvement in lung function in patients with moderate-to-severe asthma.
TRIAL REGISTRATION
PROSPERO ID:CRD42022378498.
Topics: Humans; Anti-Asthmatic Agents; Asthma; Forced Expiratory Volume; Lung; Omalizumab; Treatment Outcome
PubMed: 38235607
DOI: 10.1177/17534666231221771 -
Research and Practice in Thrombosis and... Nov 2023Emicizumab is a bispecific humanized monoclonal antibody that shortens the activated partial thromboplastin time (aPTT), making aPTT-based tests unreliable.
BACKGROUND
Emicizumab is a bispecific humanized monoclonal antibody that shortens the activated partial thromboplastin time (aPTT), making aPTT-based tests unreliable.
OBJECTIVES
To evaluate the efficacy of a mixture of 2 anti-idiotype monoclonal antibodies (anti-emi) in neutralizing emicizumab in samples from persons with hemophilia A treated with emicizumab.
METHODS
Fifty samples from persons with hemophilia A treated with emicizumab were analyzed for aPTT and factor VIII procoagulant activity; FVIII inhibitor titer was measured using Nijmegen-Bethesda assay in 50 plasma samples of additional patients (positive for FVIII inhibitor) treated with emicizumab. FVIII procoagulant activity and inhibitor titer were measured using 1-stage (Actin FS, Siemens) and chromogenic assays with bovine regents (Factor VIII Chromogenic Assay, Siemens). Emicizumab concentration was measured by modified a 1-stage assay calibrated with a drug-specific calibrator (r Diagnostics Inc). All the tests were performed on Sysmex CS-2400 (Sysmex) before and after the addition of anti-emi (Chugai Pharmaceutical).
RESULTS
Emicizumab concentrations measured after neutralization were <1.6 μg/mL in all samples. FVIII levels were >480 IU/dL with an aPTT of <30.8 seconds in all samples before neutralization and were <1 IU/dL with an aPTT of >70 seconds after adding anti-emi. FVIII inhibitor resulted in a false negative result in 44 of 50 samples measured with the 1-stage assay before neutralization. A good correlation (r = 0.98) was found between inhibitor titer measured using the chromogenic (insensitive to emicizumab) and 1-stage assays after neutralization.
CONCLUSION
The anti-emi antibodies were shown to completely neutralize emicizumab, making samples pretreated with anti-emi analyzable with the 1-stage assay.
PubMed: 38193066
DOI: 10.1016/j.rpth.2023.102260 -
Acta Dermato-venereologica Jan 2024Solar urticaria is a rare photodermatosis with several unknown pathogenic, clinical and therapeutic aspects. This study analysed the clinical and therapeutic features of...
Solar urticaria is a rare photodermatosis with several unknown pathogenic, clinical and therapeutic aspects. This study analysed the clinical and therapeutic features of a long-term follow-up solar urticaria cohort, with a focus on omalizumab management and outcomes, and characterized omalizumab response with the use of the high-affinity immunoglobulin E (IgE) receptor (FcεRI) and the Urticaria Control Test. An observational, unicentric, ambispective study was conducted from 2007 to 2023. Solar urticaria was diagnosed in 41 patients with a median follow-up of 60 months. Thirteen patients were prescribed omalizumab, with a median treatment time of 48 months. A significant decrease in FcεRI baseline levels and subsequent median increase in Urticaria Control Test was evidenced after omalizumab prescription in all patients. Drug survival at 48 months was at 88.9%. Omalizumab stepping-down protocol led to sustained omalizumab discontinuation in only 1 patient. Median basal Urticaria Control Test was lower (p < 0.01) in patients who were prescribed omalizumab and in patients without remission. This study contributes to our knowledge of omalizumab outcomes in real-life clinical practice and highlights the pathogenic importance of IgE-mediated pathways in solar urticaria, where FcεRI emerges as a possible biomarker of omalizumab response.
Topics: Humans; Urticaria, Solar; Follow-Up Studies; Omalizumab; Urticaria; Immunoglobulin E
PubMed: 38189220
DOI: 10.2340/actadv.v104.25576