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Frontiers in Immunology 2022Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous disease of the skin. First-line treatment of systemic corticosteroids may cause serious...
BACKGROUND
Bullous pemphigoid (BP) is the most common autoimmune subepidermal bullous disease of the skin. First-line treatment of systemic corticosteroids may cause serious adverse events. Rituximab, omalizumab, and dupilumab should be explored as alternative treatment options to improve outcomes.
OBJECTIVE
To systematically review the rituximab, omalizumab, and dupilumab treatment outcomes in bullous pemphigoid.
METHODS
A PubMed, Embase, Web of Science, and Cochrane library search were conducted on March 10, 2022. A total of 75 studies were included using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
RESULTS
Use of rituximab (n=122), omalizumab (n=53) and dupilumab (n=36) were reported in 211 patients with BP. Rituximab led to complete remission in 70.5% (n=86/122) and partial remission in 23.8% (n=29/122) of patients within 5.7 months, with a recurrence rate of 20.5% (n=25/122). 9.0% (n=11/122) of patients died and infection (6.6%, n=8/122) was the most common adverse event. Omalizumab led to complete remission in 67.9% (n=36/53) and partial remission in 20.8% (n=11/53) of patients within 6.6 months, with a recurrence rate of 5.7% (n=3/53). 1.9% (n=1/53) of patients died and thrombocytopenia (1.9%, n=1/53) was observed as the most common adverse event. Dupilumab led to complete remission in 66.7% (n=24/36) and partial remission in 19.4% (n=7/36) of patients within 4.5 months of treatment without any reported adverse events, with a recurrence rate of 5.6% (n=2/36).
CONCLUSIONS
Rituximab, omalizumab, and dupilumab have similar clinical benefits for BP patients. However, rituximab resulted in higher recurrence rates, adverse events, and mortality rates.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022316454.
Topics: Antibodies, Monoclonal, Humanized; Humans; Omalizumab; Pemphigoid, Bullous; Rituximab; Treatment Outcome
PubMed: 35769474
DOI: 10.3389/fimmu.2022.928621 -
Expert Opinion on Investigational Drugs Mar 2022Across the globe, chronic urticaria (CU), i.e. chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CINDU), is common, long-persisting and difficult to... (Review)
Review
INTRODUCTION
Across the globe, chronic urticaria (CU), i.e. chronic spontaneous urticaria (CSU) and chronic inducible urticaria (CINDU), is common, long-persisting and difficult to manage. Still, at least one-fifth is not sufficiently controlled by guideline-recommended treatment with H1-antihistamines and add-on therapy with the anti-IgE monoclonal antibody omalizumab.
AREAS COVERED
Using PubMed, ClinicalTrials.gov, Congress websites, and websites of the manufacturers, this review explored the pipeline, namely anti-IgE-, anti-cytokine-, anti-receptor biologics, and small molecules, in clinical development for CU.
EXPERT OPINION
The CU pipeline is promising. While three omalizumab biosimilars are investigated, the assumed early approval of ligelizumab will expand the effective and safe anti-IgE approach observed with omalizumab. For other anti-IgEs like UB-221, the development is behind. Data are too limited so far to clearly define the role of anti-cytokine and anti-cytokine receptor biologics such as dupilumab, tezepelumab, mepolizumab, benralizumab, and CDX-0159, of which only dupilumab is actually investigated in phase 3. Among three selective oral BTK inhibitors, remibrutinib, rilzabrutinib, and fenebrutinib, the development of remibrutinib is most advanced (phase 3). As the pipeline addresses different targets, study results will give deeper insights into the pathomechanisms of CU. Hopefully, in the next future additional approved and also more targeted approaches will be available.
Topics: Anti-Allergic Agents; Biosimilar Pharmaceuticals; Chronic Disease; Chronic Urticaria; Humans; Omalizumab; Urticaria
PubMed: 35166638
DOI: 10.1080/13543784.2022.2042513 -
Frontiers in Immunology 2020Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug... (Review)
Review
Monoclonal antibodies (mAbs) are a crucial asset for human health and modern medicine, however, the repeated administration of mAbs can be highly immunogenic. Drug immunogenicity manifests in the generation of anti-drug antibodies (ADAs), and some mAbs show immunogenicity in up to 70% of patients. ADAs can alter a drug's pharmacokinetic and pharmacodynamic properties, reducing drug efficacy. In more severe cases, ADAs can neutralize the drug's therapeutic effects or cause severe adverse events to the patient. While some contributing factors to ADA formation are known, the molecular mechanisms of how therapeutic mAbs elicit ADAs are not completely clear. Accurate ADA detection is necessary to provide clinicians with sufficient information for patient monitoring and clinical intervention. However, ADA assays present unique challenges because both the analyte and antigen are antibodies, so most assays are cumbersome, costly, time consuming, and lack standardization. This review will discuss aspects related to ADA formation following mAb drug administration. First, we will provide an overview of the prevalence of ADA formation and the available diagnostic tools for their detection. Next, we will review studies that support possible molecular mechanisms causing the formation of ADA. Finally, we will summarize recent approaches used to decrease the propensity of mAbs to induce ADAs.
Topics: Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibody Formation; Antibody Specificity; Epitopes; Humans; Immunoassay; Risk Factors
PubMed: 33013848
DOI: 10.3389/fimmu.2020.01951 -
Annals of Allergy, Asthma & Immunology... Jul 2023To review the safety and efficacy of anti-immunoglobulin E (IgE) monotherapy or as an adjunct to oral immunotherapy (OIT) in the treatment of IgE-mediated food allergy. (Review)
Review
OBJECTIVE
To review the safety and efficacy of anti-immunoglobulin E (IgE) monotherapy or as an adjunct to oral immunotherapy (OIT) in the treatment of IgE-mediated food allergy.
DATA SOURCES
Literature searches were performed using the Excerpta Medica dataBASE, Medline, Scopus, and PubMed Central to identify articles in English related to food allergy and anti-IgE therapies, including omalizumab and ligelizemab.
STUDY SELECTIONS
Original research articles reviewed include interventional studies, retrospective and prospective observational studies, peer-reviewed reviews, and systematic reviews. Data were reviewed and summarized.
RESULTS
Here, we discuss the current anti-IgE therapies being studied as a potential treatment option for food allergy. We also review trial design, safety, and efficacy data on the use of anti-IgE therapies as monotherapy or in combination with OIT for food allergies. Finally, we discuss clinical trials in progress using omalizumab and ligelizumab and highlight important clinical considerations.
CONCLUSION
Over the past 20 years, substantial progress has been made in understanding the potential role of anti-IgE therapies for food allergy. Anti-IgE therapies seem to be a promising option that may increase reaction dose thresholds and decrease time to reach OIT maintenance and OIT dosing-related reactions. Two phase 3 trials are currently in progress studying anti-IgE potential monotherapy for the treatment of peanut and multifood allergies. It is important for clinicians to be aware of these emerging treatment options.
Topics: Humans; Omalizumab; Immunoglobulin E; Desensitization, Immunologic; Retrospective Studies; Administration, Oral; Food Hypersensitivity; Allergens; Observational Studies as Topic
PubMed: 37031775
DOI: 10.1016/j.anai.2023.03.030 -
Nature Medicine Jul 2020Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans, and block liver transduction and vector readministration; thus, they...
Neutralizing antibodies to adeno-associated virus (AAV) vectors are highly prevalent in humans, and block liver transduction and vector readministration; thus, they represent a major limitation to in vivo gene therapy. Strategies aimed at overcoming anti-AAV antibodies are being studied, which often involve immunosuppression and are not efficient in removing pre-existing antibodies. Imlifidase (IdeS) is an endopeptidase able to degrade circulating IgG that is currently being tested in transplant patients. Here, we studied if IdeS could eliminate anti-AAV antibodies in the context of gene therapy. We showed efficient cleavage of pooled human IgG (intravenous Ig) in vitro upon endopeptidase treatment. In mice passively immunized with intravenous Ig, IdeS administration decreased anti-AAV antibodies and enabled efficient liver gene transfer. The approach was scaled up to nonhuman primates, a natural host for wild-type AAV. IdeS treatment before AAV vector infusion was safe and resulted in enhanced liver transduction, even in the setting of vector readministration. Finally, IdeS reduced anti-AAV antibody levels from human plasma samples in vitro, including plasma from prospective gene therapy trial participants. These results provide a potential solution to overcome pre-existing antibodies to AAV-based gene therapy.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Neutralizing; Antibodies, Viral; Capsid; Dependovirus; Endopeptidases; Genetic Therapy; Genetic Vectors; Humans; Immunoglobulin G; Liver; Mice
PubMed: 32483358
DOI: 10.1038/s41591-020-0911-7 -
International Journal of Molecular... Mar 2024The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic... (Review)
Review
The basis of our current understanding of allergies begins with the discovery of IgE in the mid-1960s. The whole theory of the physiology and pathophysiology of allergic diseases, including rhinitis and asthma, dates from that period. Among the key regions of IgE identified were the FAB (fragment antigen binding) portion that has the ability to capture allergens, and the Cε3 domain, through which IgE binds to its membrane receptor. It was then postulated that blocking IgE at the level of the Cε3 domain would prevent it from binding to its receptor and thus set in motion the allergic cascade. This was the beginning of the development of omalizumab, a monoclonal antibody with an anti-IgE effect. In this article, we review the pathophysiology of allergic disease and trace the clinical development of omalizumab. We also review the benefits of omalizumab treatment that are apparently unrelated to allergies, such as its effect on immunity and bronchial remodeling.
Topics: Humans; Omalizumab; Antibodies, Monoclonal, Humanized; Asthma; Hypersensitivity; Immunoglobulin E
PubMed: 38474304
DOI: 10.3390/ijms25053056 -
Advances in Therapy Nov 2023Patients with uncontrolled, allergic severe asthma may be prescribed biologic therapies to reduce exacerbations and improve disease control. Randomized controlled trials... (Review)
Review
Patients with uncontrolled, allergic severe asthma may be prescribed biologic therapies to reduce exacerbations and improve disease control. Randomized controlled trials (RCTs) of these therapies have differed in design, with varying results overall and by baseline blood eosinophil count (BEC). This study describes published annualized asthma exacerbation rate (AAER) reductions from RCTs in patients with allergic severe asthma, overall and by baseline BEC category. A literature search was performed to identify published phase 3 RCT data of US Food and Drug Administration-approved biologics for severe asthma in patients with severe, uncontrolled asthma and confirmed sensitization to perennial aeroallergens. Analyses focused on AAER reduction versus placebo in the overall population and/or in those with an elevated or low BEC at baseline or screening. Baseline serum total immunoglobulin E levels varied between RCT populations. In patients with allergic severe asthma across all BEC categories, data were available for tezepelumab, dupilumab, benralizumab and omalizumab only; the greatest AAER reduction was observed with tezepelumab. In patients with allergic severe asthma and BECs of ≥ 260 cells/µL or ≥ 300 cells/μL, AAER reductions were observed with all biologics (tezepelumab, dupilumab, mepolizumab, benralizumab and omalizumab); the greatest AAER reduction was observed with tezepelumab and the smallest AAER reduction was observed with omalizumab. In patients with allergic severe asthma and BECs of < 260 cells/µL or < 300 cells/μL (regardless of historical BEC), an AAER reduction was observed with tezepelumab but not with benralizumab or omalizumab. Differential mechanisms of action may explain the differences in results observed between biologics. Among patients with allergic severe asthma, the efficacy of biologics in RCTs varied considerably overall and by BEC. Tezepelumab was the only biologic to demonstrate AAER reductions consistently across all subgroups. These differences can inform provider treatment decisions when selecting biologic treatments for patients with allergic severe asthma.
Topics: Humans; Eosinophils; Omalizumab; Anti-Asthmatic Agents; Asthma; Biological Products
PubMed: 37698716
DOI: 10.1007/s12325-023-02647-2 -
Blood May 2021B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because...
B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies have shown efficacy in relapsed/refractory multiple myeloma (RRMM). Because the non-human originated antigen-targeting domain may limit clinical efficacy, we developed a fully human BCMA-specific CAR, CT103A, and report its safety and efficacy in a phase 1 trial. Eighteen consecutive patients with RRMM, including 4 with prior murine BCMA CAR exposures, were enrolled. CT103A was administered at 1, 3, and 6 × 106 CAR-positive T cells/kg in the dose-escalation phase, and 1 × 106 CAR-positive T cells/kg in the expansion cohort. The overall response rate was 100%, with 72.2% of the patients achieving complete response or stringent complete response. For the 4 murine BCMA CAR-exposed patients, 3 achieved stringent complete response, and 1 achieved a very good partial response. At 1 year, the progression-free survival rate was 58.3% for all cohorts and 79.1% for the patients without extramedullary myeloma. Hematologic toxicities were the most common adverse events; 70.6% of the patients experienced grade 1 or 2 cytokine release syndromes. No immune effector cell-associated neurotoxicity syndrome was observed. To the cutoff date, CAR transgenes were detectable in 77.8% of the patients. The median CAR transgene persistence was 307.5 days. Only 1 patient was positive for the anti-drug antibody. Altogether, CT103A is safe and highly active in patients with RRMM and can be developed as a promising therapy for RRMM. Patients who relapsed from prior murine BCMA CAR T-cell therapy may still benefit from CT103A. This trial was registered at http://www.chictr.org.cn as #ChiCTR1800018137.
Topics: Adult; Afibrinogenemia; Aged; Animals; Antibodies, Anti-Idiotypic; Antineoplastic Agents; B-Cell Maturation Antigen; Combined Modality Therapy; Drug Resistance, Neoplasm; Female; Hematologic Diseases; Humans; Immunity, Humoral; Immunotherapy, Adoptive; Leukemia, Plasma Cell; Male; Mice; Middle Aged; Multiple Myeloma; Receptors, Chimeric Antigen; Remission Induction; Single-Chain Antibodies; Transgenes
PubMed: 33512480
DOI: 10.1182/blood.2020008936 -
Frontiers in Immunology 2024The VH6-1 class of antibodies includes some of the broadest and most potent antibodies that neutralize influenza A virus. Here, we elicit and isolate anti-idiotype...
The VH6-1 class of antibodies includes some of the broadest and most potent antibodies that neutralize influenza A virus. Here, we elicit and isolate anti-idiotype antibodies against germline versions of VH6-1 antibodies, use these to sort human leukocytes, and isolate a new VH6-1-class member, antibody L5A7, which potently neutralized diverse group 1 and group 2 influenza A strains. While its heavy chain derived from the canonical IGHV6-1 heavy chain gene used by the class, L5A7 utilized a light chain gene, IGKV1-9, which had not been previously observed in other VH6-1-class antibodies. The cryo-EM structure of L5A7 in complex with Indonesia 2005 hemagglutinin revealed a nearly identical binding mode to other VH6-1-class members. The structure of L5A7 bound to the isolating anti-idiotype antibody, 28H6E11, revealed a shared surface for binding anti-idiotype and hemagglutinin that included two critical L5A7 regions: an FG motif in the third heavy chain-complementary determining region (CDR H3) and the CDR L1 loop. Surprisingly, the chemistries of L5A7 interactions with hemagglutinin and with anti-idiotype were substantially different. Overall, we demonstrate anti-idiotype-based isolation of a broad and potent influenza A virus-neutralizing antibody, revealing that anti-idiotypic selection of antibodies can involve features other than chemical mimicry of the target antigen.
Topics: Humans; Influenza A virus; Antibodies, Viral; Antibodies, Neutralizing; Antibodies, Anti-Idiotypic; Hemagglutinin Glycoproteins, Influenza Virus; Influenza, Human; Animals; Immunoglobulin Heavy Chains
PubMed: 38873606
DOI: 10.3389/fimmu.2024.1399960 -
The British Journal of Dermatology Jan 2024
Topics: Humans; Omalizumab; Pemphigoid, Bullous; Retrospective Studies; Anti-Allergic Agents; Immunoglobulin E
PubMed: 37939788
DOI: 10.1093/bjd/ljad432