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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 -
The New England Journal of Medicine Mar 2013Many patients with chronic idiopathic urticaria (also called chronic spontaneous urticaria) do not have a response to therapy with H-antihistamines, even at high doses.... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Many patients with chronic idiopathic urticaria (also called chronic spontaneous urticaria) do not have a response to therapy with H-antihistamines, even at high doses. In phase 2 trials, omalizumab, an anti-IgE monoclonal antibody [corrected] that targets IgE and affects mast-cell and basophil function, has shown efficacy in such patients.
METHODS
In this phase 3, multicenter, randomized, double-blind study, we evaluated the efficacy and safety of omalizumab in patients with moderate-to-severe chronic idiopathic urticaria who remained symptomatic despite H-antihistamine therapy (licensed doses). We randomly assigned 323 patients to receive three subcutaneous injections, spaced 4 weeks apart, of omalizumab at doses of 75 mg, 150 mg, or 300 mg or placebo, followed by a 16-week observation period. The primary efficacy outcome was the change from baseline in a weekly itch-severity score (ranging from 0 to 21, with higher scores indicating more severe itching).
RESULTS
The baseline weekly itch-severity score was approximately 14 in all four study groups. At week 12, the mean (±SD) change from baseline in the weekly itch-severity score was -5.1±5.6 in the placebo group, -5.9±6.5 in the 75-mg group (P=0.46), -8.1±6.4 in the 150-mg group (P=0.001), and -9.8±6.0 in the 300-mg group (P<0.001). Most prespecified secondary outcomes at week 12 showed similar dose-dependent effects. The frequency of adverse events was similar across groups. The frequency of serious adverse events was low, although the rate was higher in the 300-mg group (6%) than in the placebo group (3%) or in either the 75-mg or 150-mg group (1% for each).
CONCLUSIONS
Omalizumab diminished clinical symptoms and signs of chronic idiopathic urticaria in patients who had remained symptomatic despite the use of approved doses of H-antihistamines. (Funded by Genentech and Novartis Pharma; ClinicalTrials.gov number, NCT01292473.).
Topics: Adolescent; Adult; Aged; Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Humanized; Child; Chronic Disease; Double-Blind Method; Female; Humans; Intention to Treat Analysis; Male; Middle Aged; Omalizumab; Pruritus; Severity of Illness Index; Urticaria; Young Adult
PubMed: 23432142
DOI: 10.1056/NEJMoa1215372 -
Frontiers in Immunology 2019The promise of idiotype-based therapeutics has been disappointing forcing a new look at the concept and its potential to generate an effective approach for... (Review)
Review
The promise of idiotype-based therapeutics has been disappointing forcing a new look at the concept and its potential to generate an effective approach for immunotherapy. Here, the idiotype network theory is revisited with regard to the development of efficacious anti-idiotype vaccines. The experience of polyclonal anti-Idiotype reagents in animal models as well as an understanding of the immune response in humans lends to the proposition that polyclonal anti-Idiotype vaccines will be more effective compared to monoclonal-based anti-Idiotype vaccines. This novel strategy can be adapted in Biotech-standard production of therapeutic antibodies.
Topics: Animals; Antibodies, Anti-Idiotypic; Biomarkers; Humans; Immunoglobulin Idiotypes; Immunomodulation; Immunotherapy; Protein Binding; Treatment Outcome; Vaccines
PubMed: 31031777
DOI: 10.3389/fimmu.2019.00808 -
Paediatric Drugs Dec 2014Omalizumab is a recombinant humanized monoclonal antibody that reduces levels of circulating immunoglobulin E (IgE) and expression of IgE high-affinity receptors on mast... (Review)
Review
Omalizumab is a recombinant humanized monoclonal antibody that reduces levels of circulating immunoglobulin E (IgE) and expression of IgE high-affinity receptors on mast cells and basophils, interrupting the subsequent allergic inflammatory cascade. Current indications for treatment with omalizumab in pediatric patients are clearly defined and are confined to moderate-to-severe uncontrolled allergic asthma and chronic spontaneous urticaria (CSU). Any other prescription can only be off label. Data available from clinical trials conducted in children suggest that omalizumab is clinically effective and generally well tolerated. Given its mechanism of action, recent reports have suggested its possible clinical use in other IgE-mediated disorders, such as allergic rhinitis, food allergy, and anaphylaxis. In recent years, several studies have also investigated the possible applications of omalizumab in a number of non IgE-mediated diseases. The aim of the present review is to assess all applications of omalizumab as therapy in the pediatric population. The approved indications--allergic asthma and CSU--are reviewed. Moreover, further potential applications of omalizumab are discussed in both IgE-mediated and non-IgE-mediated diseases.
Topics: Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Humanized; Asthma; Child; Food Hypersensitivity; Humans; Immunoglobulin E; Omalizumab; Quality of Life; Urticaria
PubMed: 25404353
DOI: 10.1007/s40272-014-0107-z -
Toxins Dec 2020The use of synthetic antibody libraries and phage displays provides an efficient and robust method for the generation of antibodies against a wide range of targets with...
The use of synthetic antibody libraries and phage displays provides an efficient and robust method for the generation of antibodies against a wide range of targets with highly specific binding properties. As the in vitro selection conditions can be easily controlled, these methods enable the rapid generation of binders against difficult targets such as toxins and haptens. In this study, we used deoxynivalenol mycotoxin as a target to generate anti-idiotype-antibodies with unique binding properties from synthetic antibody libraries. The binding of the selected anti-idiotype antibodies can be efficiently inhibited with the addition of free isoforms of deoxynivalenol. The antibody was consecutively used to develop deoxynivalenol-specific ELISA and TRF-immunoassays, which can detect deoxynivalenol and two of the most common metabolic isoforms in the range of 78-115 ng/mL.
Topics: Antibodies, Anti-Idiotypic; Cell Surface Display Techniques; Immunoassay; Mycotoxins
PubMed: 33379255
DOI: 10.3390/toxins13010018 -
Journal of Immunological Methods Apr 2020The recent identification of human monoclonal antibodies with broad and potent neutralizing activity against HIV-1 (bnAbs) has resulted in substantial efforts to develop...
The recent identification of human monoclonal antibodies with broad and potent neutralizing activity against HIV-1 (bnAbs) has resulted in substantial efforts to develop these molecules for clinical use in the prevention and treatment of HIV-1 infection. As with any protein therapeutic drug product, it is imperative to have qualified assays that can accurately detect and quantify anti-drug antibodies (ADA) that may develop in patients receiving passive administration of HIV-1 bnAbs. Here, we have optimized and qualified a functional assay to assess the potential of ADA to inhibit the neutralizing function of HIV-1 bnAbs. Using a modified version of the validated TZM-bl HIV-1 neutralization assay, murine anti-idiotype antibodies were utilized to optimize and evaluate parameters of linearity, range, limit of detection, specificity, and precision for measuring inhibitory ADA activity against multiple HIV-1 bnAbs that are in clinical development. We further demonstrate the utility of this assay for detecting naturally occurring ADA responses in non-human primates receiving passive administration of human bnAbs. This functional assay format complements binding-antibody ADA strategies being developed for HIV-1 bnAbs, and when utilized together, will support a multi-tiered approach for ADA testing that is compliant with Good Clinical Laboratory Practice (GCLP) procedures and FDA guidance.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Murine-Derived; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans; Mice; Neutralization Tests
PubMed: 31917969
DOI: 10.1016/j.jim.2020.112736 -
PLoS Pathogens May 2015
Review
Topics: Animals; Antibodies, Anti-Idiotypic; Humans; Immunity; Mumps; Mumps virus; Treatment Outcome; Vaccines
PubMed: 25951183
DOI: 10.1371/journal.ppat.1004791 -
PloS One 2016Vaccination with proteins mimicking GD2 that is highly expressed on neuroblastoma (NB) cells is a promising strategy in treatment of NB, a pediatric malignancy with poor...
Vaccination with proteins mimicking GD2 that is highly expressed on neuroblastoma (NB) cells is a promising strategy in treatment of NB, a pediatric malignancy with poor prognosis. We previously showed efficacy of ganglidiomab in vivo, a murine anti-idiotype (anti-Id) IgG1. In order to tailor immune responses to variable regions, we generated a new human/mouse chimeric anti-Id antibody (Ab) ganglidiximab by replacing murine constant fragments with corresponding human IgG1 regions. DNA sequences encoding for variable regions of heavy (VH) and light chains (VL) were synthesized by RT-PCR from total RNA of ganglidiomab-producing hybridoma cells and further ligated into mammalian expression plasmids with coding sequences for constant regions of human IgG1 heavy and light chains, respectively. We established a stable production cell line using Chinese hamster ovarian (CHO) cells co-transfected with two expression plasmids driving the expression of either ganglidiximab heavy or light chain. After purification from supernatants, anti-idiotypic characteristics of ganglidiximab were demonstrated. Binding of ganglidiximab to anti-GD2 Abs of the 14.18 family as well as to NK-92tr cells expressing a GD2-specific chimeric antigen receptor (scFv(ch14.18)-zeta) was shown using standard ELISA and flow cytometry analysis, respectively. Ganglidiximab binding affinities to anti-GD2 Abs were further determined by surface plasmon resonance technique. Moreover, binding of anti-GD2 Abs to the nominal antigen GD2 as well as GD2-specific Ab-mediated cytotoxicity (ADCC, CDC) was competitively inhibited by ganglidiximab. Finally, ganglidiximab was successfully used as a protein vaccine in vivo to induce a GD2-specific humoral immune response. In summary, we report generation and characterization of a new human/mouse chimeric anti-Id Ab ganglidiximab for active immunotherapy against NB. This Ab may be useful to tailor immune responses to the paratope regions mimicking GD2 overexpressed in NB.
Topics: Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Antibody Affinity; CHO Cells; Cancer Vaccines; Cricetinae; Cricetulus; Cytotoxicity, Immunologic; Humans; Immunotherapy, Active; Killer Cells, Natural; Mice; Neuroblastoma
PubMed: 26967324
DOI: 10.1371/journal.pone.0150479 -
Human Vaccines & Immunotherapeutics Oct 2017The prevalence of IgE mediated food allergy is an increasing public health concern. The current standard of treatment is strict avoidance of the offending food(s). There... (Review)
Review
The prevalence of IgE mediated food allergy is an increasing public health concern. The current standard of treatment is strict avoidance of the offending food(s). There are no FDA approved treatments for food allergy. This review will provide an overview of strategies currently under investigation for the treatment of food allergy. The main focus of research has been directed at various forms of immunotherapy, including oral, sublingual and epicutaneous delivery routes. While oral immunotherapy (OIT) has shown the greatest promise for efficacy in terms of amount of protein that can be ingested, it has also demonstrated less tolerability and a less favorable safety profile as compared to sublingual immunotherapy (SLIT) and epicutaneous immunotherapy (EPIT), which offers the least protection but has the best safety and tolerability profile. Investigation is also underway for modified antigens that may be used for immunotherapy and for adjuncts that may help facilitate immunotherapy, including biologics such as anti-IgE therapy, and also probiotics. There are also a number of preclinical concepts that are being evaluated to manipulate the antigens and/or the immune system that may one day be translatable to patients.
Topics: Administration, Sublingual; Allergens; Animals; Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Desensitization, Immunologic; Food Hypersensitivity; Humans; Immunoglobulin E; Medicine, Chinese Traditional; Mice; Omalizumab; Probiotics; Sublingual Immunotherapy
PubMed: 28846472
DOI: 10.1080/21645515.2017.1359363 -
Cancer Immunology, Immunotherapy : CII Jun 2013Immunotherapy targeting disialoganglioside GD(2) emerges as an important treatment option for neuroblastoma, a pediatric malignancy characterized by poor outcome. Here,...
PURPOSE
Immunotherapy targeting disialoganglioside GD(2) emerges as an important treatment option for neuroblastoma, a pediatric malignancy characterized by poor outcome. Here, we report the induction of a GD(2)-specific immune response with ganglidiomab, a new anti-idiotype antibody to anti-GD(2) antibodies of the 14.18 family.
EXPERIMENTAL DESIGN AND RESULTS
Ganglidiomab was generated following immunization of Balb/c mice with 14G2a, and splenocytes were harvested to generate hybridoma cells. Clones were screened by ELISA for mouse antibody binding to hu14.18. One positive clone was selected to purify and characterize the secreted IgG protein (κ, IgG(1)). This antibody bound to anti-GD(2) antibodies 14G2a, ch14.18/CHO, hu14.18, and to immunocytokines ch14.18-IL2 and hu14.18-IL2 as well as to NK-92 cells expressing scFv(ch14.18)-zeta receptor. Binding of these anti-GD(2) antibodies to the nominal antigen GD(2) as well as GD(2)-specific lysis of neuroblastoma cells by NK-92-scFv(ch14.18)-zeta cells was competitively inhibited by ganglidiomab, proving GD(2) surrogate function and anti-idiotype characteristics. The dissociation constants of ganglidiomab from anti-GD(2) antibodies ranged from 10.8 ± 5.01 to 53.5 ± 1.92 nM as determined by Biacore analyses. The sequences of framework and complementarity-determining regions of ganglidiomab were identified. Finally, we demonstrated induction of a GD(2)-specific humoral immune response after vaccination of mice with ganglidiomab effective in mediating GD(2)-specific killing of neuroblastoma cells.
CONCLUSION
We generated and characterized a novel anti-idiotype antibody ganglidiomab and demonstrated activity against neuroblastoma.
Topics: Amino Acid Sequence; Animals; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal; Base Sequence; Binding, Competitive; Cancer Vaccines; Cell Line, Tumor; Gangliosides; Humans; Kinetics; Mice; Molecular Sequence Data; Neuroblastoma; Protein Binding; Sequence Alignment
PubMed: 23591980
DOI: 10.1007/s00262-013-1413-y