Biomarker Predictors of Clinical Efficacy of the Anti-IgE Biologic Omalizumab in Severe Asthma in Adults: Results of the SoMOSA Study.

Background: The anti-IgE monoclonal antibody omalizumab is widely used for severe asthma. This study aimed to identify biomarkers that predict clinical improvement during 1 year of omalizumab treatment. Methods: One-year open-label Study of Mechanisms of action of Omalizumab in Severe Asthma (SoMOSA) involving 216 patients with severe (Global Initiative for Asthma step 4/5) uncontrolled atopic asthma (at least two severe exacerbations in the previous year) taking high-dose inhaled corticosteroids and long-acting ß-agonists with or without maintenance oral corticosteroids. It had two phases: 0-16 weeks, to assess early clinical improvement by Global Evaluation of Therapeutic Effectiveness (GETE); and 16-52 weeks, to assess late responses based on ⩾50% reduction in exacerbations or mOCS dose. All participants provided samples (exhaled breath, blood, sputum, urine) before and after 16 weeks of omalizumab treatment. Measurements and Main Results: A total of 191 patients completed phase 1; 63% had early improvement. Of 173 who completed phase 2, 69% had reduced exacerbations by ⩾50% and 57% (37 of 65) taking mOCSs had reduced their dose by ⩾50%. The primary outcomes 2,3-dinor-11-ß-PGF2α, GETE score, and standard clinical biomarkers (blood and sputum eosinophils, exhaled nitric oxide, serum IgE) did not predict either clinical response. Five volatile organic compounds and five plasma lipid biomarkers strongly predicted the ⩾50% reduction in exacerbations (receiver operating characteristic areas under the curve of 0.780 and 0.922, respectively) and early responses (areas under the curve of 0.835 and 0.949, respectively). In an independent cohort, gas chromatography/mass spectrometry biomarkers differentiated between severe and mild asthma. Conclusions: This is the first discovery of omics biomarkers that predict improvement in asthma with biologic agent treatment. Prospective validation and development for clinical use is justified.

Clinical implications of anti-idiotype antibodies in COVID-19.

Idiotype-based therapeutics have failed to deliver their promise, necessitating rethinking of the concept and its potential to develop a viable immunotherapy method. The idiotype based hypothesis is discussed in this paper in order to produce effective anti-idiotype vaccinations. Polyclonal anti-idiotype reagents have been shown to be more successful in animal models, and a better understanding of the immune response in humans supports the idea that polyclonal anti-idiotype vaccines will be more effective than monoclonal-based anti-idiotype vaccines. This innovative approach can be used to produce therapeutic antibodies in a Biotech-standard manner. The idiotype network has been tweaked in the lab to provide protection against a variety of microbiological diseases. Antibodies to image-idiotype antigens, both internal and non-internal, can elicit unique immune responses to antigens. The current outbreak of severe acute respiratory syndrome 2 (SARS-2) has presented a fantastic chance to use idiotype/anti-idiotype antibodies as a protective regimen, which might be used to treat COVID-19 patients. The development of various effective vaccinations has been crucial in the pandemic's management, but their effectiveness has been limited. In certain healthy people, the development of viral variations and vaccinations can be linked to rare off-target or hazardous effects, such as allergic responses, myocarditis and immune-mediated thrombosis and thrombocytopenia. Many of these occurrences are most likely immune-mediated. The current analysis reveals successful idiotype/anti-idiotype antibody uses in a variety of viral illnesses, emphazising their importance in the COVID-19 pandemic.

Profiling Serum Cytokines and Anticytokine Antibodies in Psoriasis Patients.

Cytokines like IL-17A have been consistently found to be elevated in psoriatic lesional skin, and therapeutic antibodies to IL-17 have demonstrated efficacy in treating psoriatic skin and joint disease. However, results about the circulating cytokines in psoriasis patients remained controversial. Anticytokine autoantibodies (ACAAs) were detected in various autoimmune diseases but remained largely unknown in psoriasis. We aimed to investigate the serum levels of cytokines and ACAAs in psoriasis patients. The study included 44 biologics-naive psoriasis patients and 40 healthy controls. Serum cytokines and the corresponding autoantibodies were measured by multiplex bead-based technology. The bioactivity of serum IL-17A was determined by IL-8 production in primary keratinocytes. Herein, we found serum levels of IL-12B (median: 6.16 vs. 9.03, p = 0.0194) and Th17 cytokines (IL-17A: median: 0.32 vs. 1.05, p = 0.0026; IL-22: median: 4.41 vs. 4.41, p = 0.0120) were increased in psoriasis patients. More interestingly, bioactive IL-17A was identified in a proportion of patients and positively correlated with disease severity. A few of cytokines were closely associated with each other and formed into a distinct panel in psoriasis. Of 13 anticytokine antibodies, anti-IL-22 was moderately lower (median: 262.8 vs.190.5, p = 0.0418), and anti-IL-15 was slightly higher (median: 25.5 vs. 30.5, p = 0.0069) in psoriasis than controls. None of ACAAs was related to disease severity. Consequently, the ratios of antibodies to cytokines varied with the pattern of cytokines. In summary, our finding suggested that the levels of circulating bioactive IL-17A were associated with disease activity in psoriasis patients. In contrast, the titers of ACAAs were not significantly altered nor correlated with disease severity. However, the functionality of ACAAs remains to be further demonstrated in vitro in future studies.

The significance of antiglobulin (Coombs) test reactivity in patients with COVID-19.

Previous case reports have described patients with COVID-19-associated autoimmune hemolytic anemia (AIHA), and cold agglutinin disease (CAD) which is characterized by a positive direct antiglobulin (DAT) or "Coombs" test, yet the mechanism is not well understood. To investigate the significance of Coombs test reactivity among COVID-19 patients, we conducted a retrospective study on hospitalized COVID-19 patients treated at NMC Royal Hospital between 15 April and 30 May 2020. There were 27 (20%) patients in the Coombs-positive group and 108 (80%) in the Coombs-negative group. The cold agglutinin titer was examined in 22 patients due to symptoms suggestive of cold agglutinin disease, and all tested negative. We demonstrated a significant association with reactive Coombs test results in univariate analysis through clinical findings such as ICU admission rate, the severity of COVID-19, and several laboratory findings such as CRP, D-dimer, and hemoglobin levels lactate dehydrogenase, and RDW-CV. However, only hemoglobin levels and disease severity had a statistically significant association in multivariate analysis. A possible explanation of COVID-19-associated positive Coombs is cytokine storm-induced hyperinflammation, complement system activation, alterations of RBCs, binding of SARS-CoV-2 proteins to hemoglobin or its metabolites, and autoantibody production. Coombs-positive patients were tested for hemolysis using indirect bilirubin, consumed haptoglobin, and/or peripheral smear that ruled out any evidence of hemolysis. Understanding this etiology sheds new light on RBC involvement as a pathophysiological target for SARS-CoV-2 by interfering with their function; consequently, therapies capable of restoring RBC function, such as erythrocytapheresis, could be repurposed for the treatment of worsening severe and critical COVID-19.

Ceftriaxone versus antistaphylococcal antibiotics for definitive treatment of methicillin-susceptible Staphylococcus aureus infections: a systematic review and meta-analysis.

Optimal therapy for methicillin-susceptible Staphylococcus aureus (MSSA) infections is unclear. Current standard of care consists of antistaphylococcal antibiotics (ASAs) such as nafcillin, oxacillin and cefazolin. Ceftriaxone has been evaluated due to its advantage as a once-daily outpatient regimen. However, questions remain regarding its efficacy compared with ASAs. We aimed to conduct a review and synthesis of available literature for outcomes of patients treated with ceftriaxone or ASAs for MSSA infections. We searched Cochrane Central Register of Controlled Trials, Embase Ovid, MEDLINE Ovid, Scopus and Web of Science (1990 to June 2021). Risk of bias for cohort studies was assessed by the Newcastle-Ottawa scale. We pooled risk ratios (RRs) using the DerSimonian-Laird random-effects model for outcomes of those receiving ceftriaxone versus ASAs. Heterogeneity was assessed by the I2 index. From 459 identified studies, 7 were included in the quantitative synthesis totalling 1640 patients. Definitive therapy with ceftriaxone was associated with a lower risk of toxicity requiring therapy alteration (RR 0.49, 95% CI 0.27-0.88; I2 = 0%). There was no difference in terms of 90-day all-cause mortality (RR 0.93, 95% CI 0.46-1.88; I2 = 9%), hospital readmission (RR 0.96, 95% CI 0.57-1.64; I2 = 0%) or infection recurrence (RR 1.04, 95% CI 0.63-1.72; I2 =0%). Current evidence suggests there is no difference in efficacy between ceftriaxone and ASAs for MSSA infection, with a lower risk of toxicity with ceftriaxone. Within the limitations of available retrospective studies, ceftriaxone is a consideration for definitive therapy of MSSA infection. [Trial registration: PROSPERO ID: CRD42021259086].

The clinical efficacy and safety of anti-IgE therapy in recessive dystrophic epidermolysis bullosa.

The treatment of recessive dystrophic epidermolysis bullosa (RDEB) remains challenging. Elevated IgE levels have previously been reported in several RDEB patients. In this prospective, single-centre, open intervention study, elevated IgE levels were seen in 11 out of 12 patients with intense pruritus, and the patients with elevated IgE levels received anti-IgE therapy every 4 weeks for at least three cycles. Compared with the baseline, 10 patients with RDEB had good clinical outcomes with enhanced wound healing, a reduction in Birmingham (epidermolysis bullosa) EB severity score by 15%, a reduction in affected body surface area by 23.3%, amelioration of skin inflammation, and an increase in type VII collagen deposition by 13.1-fold. All the patients had a good tolerance to anti-IgE therapy. Furthermore, patients with higher IgE levels tended to have higher disease severity and more favorable clinical outcomes. Our report also suggested the potential role of IgE in the pathogenesis of inflammatory conditions associated with RDEB. (ChiCTR1900021437).

Anti-GD2 IgA kills tumors by neutrophils without antibody-associated pain in the preclinical treatment of high-risk neuroblastoma.

BACKGROUND: The addition of monoclonal antibody therapy against GD2 to the treatment of high-risk neuroblastoma led to improved responses in patients. Nevertheless, administration of GD2 antibodies against neuroblastoma is associated with therapy-limiting neuropathic pain. This severe pain is evoked at least partially through complement activation on GD2-expressing sensory neurons. METHODS: To reduce pain while maintaining antitumor activity, we have reformatted the approved GD2 antibody ch14.18 into the IgA1 isotype. This novel reformatted IgA is unable to activate the complement system but efficiently activates leukocytes through the FcαRI (CD89). RESULTS: IgA GD2 did not activate the complement system in vitro nor induced pain in mice. Importantly, neutrophil-mediated killing of neuroblastoma cells is enhanced with IgA in comparison to IgG, resulting in efficient tumoricidal capacity of the antibody in vitro and in vivo. CONCLUSIONS: Our results indicate that employing IgA GD2 as a novel isotype has two major benefits: it halts antibody-induced excruciating pain and improves neutrophil-mediated lysis of neuroblastoma. Thus, we postulate that patients with high-risk neuroblastoma would strongly benefit from IgA GD2 therapy.

Novel Approaches in the Inhibition of IgE-Induced Mast Cell Reactivity in Food Allergy.

Allergy is an IgE-dependent type-I hypersensitivity reaction that can lead to life-threatening systemic symptoms such as anaphylaxis. In the pathogenesis of the allergic response, the common upstream event is the binding of allergens to specific IgE, inducing cross-linking of the high-affinity FcεRI on mast cells, triggering cellular degranulation and the release of histamine, proteases, lipids mediators, cytokines and chemokines with inflammatory activity. A number of novel therapeutic options to curb mast cell activation are in the pipeline for the treatment of severe allergies. In addition to anti-IgE therapy and allergen-specific immunotherapy, monoclonal antibodies targeted against several key Th2/alarmin cytokines (i.e. IL-4Rα, IL-33, TSLP), active modification of allergen-specific IgE (i.e. inhibitory compounds, monoclonal antibodies, de-sialylation), engagement of inhibitory receptors on mast cells and allergen-specific adjuvant vaccines, are new promising options to inhibit the uncontrolled release of mast cell mediators upon allergen exposure. In this review, we critically discuss the novel approaches targeting mast cells limiting allergic responses and the immunological mechanisms involved, with special interest on food allergy treatment.

COL4A3 is degraded in allergic asthma and degradation predicts response to anti-IgE therapy.

BACKGROUND: Asthma is a heterogeneous syndrome substantiating the urgent requirement for endotype-specific biomarkers. Dysbalance of fibrosis and fibrolysis in asthmatic lung tissue leads to reduced levels of the inflammation-protective collagen 4 (COL4A3). OBJECTIVE: To delineate the degradation of COL4A3 in allergic airway inflammation and evaluate the resultant product as a biomarker for anti-IgE therapy response. METHODS: The serological COL4A3 degradation marker C4Ma3 (Nordic Bioscience, Denmark) and serum cytokines were measured in the ALLIANCE cohort (paediatric cases/controls: n=134/n=35; adult cases/controls: n=149/n=31). Exacerbation of allergic airway disease in mice was induced by sensitising to ovalbumin (OVA), challenge with OVA aerosol and instillation of poly(cytidylic-inosinic). Fulacimstat (chymase inhibitor; Bayer) was used to determine the role of mast cell chymase in COL4A3 degradation. Patients with cystic fibrosis (n=14) and cystic fibrosis with allergic bronchopulmonary aspergillosis (ABPA; n=9) as well as patients with severe allergic uncontrolled asthma (n=19) were tested for COL4A3 degradation. Omalizumab (anti-IgE) treatment was assessed using the Asthma Control Test. RESULTS: Serum levels of C4Ma3 were increased in asthma in adults and children alike and linked to a more severe, exacerbating allergic asthma phenotype. In an experimental asthma mouse model, C4Ma3 was dependent on mast cell chymase. Serum C4Ma3 was significantly elevated in cystic fibrosis plus ABPA and at baseline predicted the success of the anti-IgE therapy in allergic, uncontrolled asthmatics (diagnostic OR 31.5). CONCLUSION: C4Ma3 levels depend on lung mast cell chymase and are increased in a severe, exacerbating allergic asthma phenotype. C4Ma3 may serve as a novel biomarker to predict anti-IgE therapy response.

Omalizumab response in patients with asthma by number and type of allergen.

BACKGROUND: The anti-immunoglobulin E therapy, omalizumab, improves asthma control and reduces exacerbations in patients with moderate-to-severe allergic asthma. However, it has been suggested that omalizumab should be reserved for highly allergic patients with multiple allergen sensitivities or perennial-only sensitivities. OBJECTIVE: To examine impact of allergy burden, including number and type of allergen sensitivities, on omalizumab response in a real-world setting. METHODS: This post hoc analysis evaluated a subset of omalizumab-treated patients from the Prospective Observational Study to Evaluate Predictors of Clinical Effectiveness in Response to Omalizumab (NCT01922037) who had completed 13 allergen assessments (N=478). Patients were classified by allergen burden (nonsensitized, 1, 2-4, or ≥5 allergen sensitivities) and type of allergen (nonsensitized, seasonal, perennial, or both). Outcome measures included exacerbation rate vs previous year and improvements in lung function and Asthma Quality of Life Questionnaire (AQLQ). RESULTS: Comparable adjusted exacerbation rates were observed after omalizumab initiation, regardless of number or type of allergen sensitizations (0.56-0.85/y). Improvements in forced expiratory volume in 1 second from baseline at months 6 (0.03-0.09 L) and 12 (-0.08 to 0.08 L) were also similar across subgroups. Least squares mean change in AQLQ from baseline at months 6 (1.0-1.2) and 12 (1.1-1.4) was comparable across patient subgroups, and similar percentages of patients achieved AQLQ minimal clinically important difference of at least a 0.5-point improvement at month 6 (71%-75%), which was maintained or improved to month 12 (71%-89%). In all analyses, 95% confidence intervals overlapped. CONCLUSION: Overall findings suggest that patients with allergic asthma achieved comparable improvements across distinct outcome measures after omalizumab therapy in a real-world setting, regardless of number and type of allergen sensitizations. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01922037.

IGF-1R anti-idiotypic antibody antagonist exhibited anti-ovarian cancer bioactivity and reduced cisplatin resistance.

Ovarian cancer is the most deadly gynecological malignant tumor in the world today. Previous studies have shown that insulin-like growth factor-1 receptor (IGF-1R) is closely related to the occurrence and development of ovarian cancer, and ovarian cancer cells endogenously express high IGF-1R. Therefore, IGF-1R could be used as a target for ovarian cancer treatment. In the past, the strategy for preparing IGF-1R antagonists was to use IGF-1R antibody and small-molecule inhibitor. In the current research, we use a new method to prepare IGF-1R antagonists. We prepared a series of IGF-1 internal imaging anti-idiotypic antibodies by anti-idiotypic antibody strategy. After a series of screening and identification, one of the anti-idiotypic antibodies (B003-2A) was selected for further evaluation, and the results showed that B003-2A could not only inhibit the binding of IGF-1 to IGF-1R but also inhibit the signaling mediated by IGF-1R. Further work showed that B003-2A inhibited the proliferation of ovarian cancer cells in vivo and in vitro. In addition, the current study also indicates that B003-2A could enhance the sensitivity of cisplatin in cisplatin-resistant ovarian cancer cell lines. In summary, our research shows that B003-2A can be used to treat ovarian cancer. The current study also laid the foundation for the development of IGF-1R antagonist.

Establishment of a pigmented murine model abundant with characteristics of retinal vein occlusion.

Retinal vein occlusion (RVO) is a vascular disease that represents characteristic retinal hemorrhage and dilated retinal veins. Despite its clinical importance, its pathogenesis remains largely unknown because of limited opportunities to acquire human retinal samples. Therefore, an animal model that reproduces the clinical features of RVO patients is required for further investigation. In this study, we established a pigmented murine RVO model that reproduced characteristic fundus appearances similar to human RVO findings. Retinal edema in this model was observed in both optical coherence tomography and histological analysis, which is a clinically important outcome. With quantitative real-time PCR analysis on retinal samples, we revealed that the mRNA level of vascular endothelial growth factor (VEGF) increased in the retina induced RVO. Moreover, this retinal edema was reduced by intravitreal injection of anti-VEGF antibody. These results were consistent with human clinical knowledge and suggested that this model could be a useful tool for research into new therapeutic approaches.

An Omalizumab Biobetter Antibody With Improved Stability and Efficacy for the Treatment of Allergic Diseases.

The critical role of IgE in allergic diseases is well-documented and clinically proven. Omalizumab, a humanized anti-IgE antibody, was the first approved antibody for the treatment of allergic diseases. Nevertheless, omalizumab still has some limitations, such as product instability and dosage restriction in clinical application. In this study, we attempted to develop an omalizumab biobetter antibody with the potential to overcome its limitations. We removed two aspartic acid isomerization hotspots in CDRs of omalizumab to improve antibody candidate's stability. Meanwhile, several murine amino acids in the framework region of omalizumab were replaced with human source to reduce the potential immunogenicity. Yeast display technology was then applied to screen antibody candidates with high binding affinity to IgE. Moreover, YTE mutation in Fc fragment was introduced into the candidates for extending their serum half-life. A lead candidate, AB1904Am15, was screened out, which showed desired biophysical properties and improved stability, high binding affinity and elevated potency in vitro, prolonged half-life in human FcRn transgenic mouse, and enhanced in vivo efficacy in cynomolgus monkey asthma model. Overall, our study developed a biobetter antibody of omalizumab, AB1904Am15, which has the potential to show improved clinical benefit in the treatment of allergic diseases.

Current and Future Monoclonal Antibodies in the Treatment of Atopic Dermatitis.

Atopic dermatitis is a common immunologic skin disease. Mild atopic dermatitis can be managed with emollients and topical therapies such as low potency topical steroids, which have a favorable safety profile. Severe atopic dermatitis, in contrast, is a challenging disease to treat. Topical therapies are typically inadequate for control of severe atopic dermatitis. When topical therapies fail, the mainstay of therapy for severe atopic dermatitis has traditionally been phototherapy or off-label use of systemic immunosuppressant treatment, yet systemic immunosuppressants all have significant potential toxicities, drug interactions, and contraindications, requiring close monitoring. Targeted biologics are therefore attractive treatment options for topical therapy-refractory cases of atopic dermatitis, with the potential to offer effective, safer treatment of uncontrolled atopic dermatitis. Dupilumab, as the only biologic therapy currently FDA-approved for atopic dermatitis, is effective for many patients, but there is need for continuing study of additional biologic therapies to address the needs of diverse patients with uncontrolled atopic dermatitis.

Development of a novel insulin receptor (IR) antagonist that exhibits anti-breast tumor activity.

Many reports have indicated that the insulin receptor (IR) causes tumorigenesis and the development of breast cancer. It has been considered a potential target for treating IR-related tumors. Traditionally, there are two categories of insulin receptor (IR) antagonists, they are small molecule antagonists and anti-IR antibodies. Here, we describe a new method (anti-idiotypic antibody strategy) for the development of IR antagonist. Hybridoma technology was employed to design and identify a series of anti-idiotypic antibodies against insulin. After repeated screening and identification, an anti-idiotypic antibody against IR (AK98) was obtained. Analysis through competitive ELISA and competitive receptor binding indicated that AK98 mimicked the receptor binding epitope of insulin. The interaction between AK98 and IR was determined using indirect immunofluorescence, immunoelectron microscopy, and Immunoprecipitation-Western (IP-WB). Further research using a tumor cell model revealed that AK98 inhibited insulin-IR binding and IR-mediated intracellular signaling pathways. Conclusively, the main purpose of this paper is that we proposed a new method (anti-idiotypic antibody strategy) to develop the insulin receptor (IR) antagonist (AK98), and a series of experiments showed that the anti-idiotypic antibody (AK98) exhibited good antagonistic activity against IR. This work suggests that the anti-idiotypic antibody may be a potential strategy to develop IR antagonists that can be used in treating breast cancer.

Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids.

The novel coronavirus, SARS-CoV2, can cause a potentially fatal disease, COVID-19, in humans. Here, we will provide an overview of therapeutic options for COVID-19. Plasma from patients recovered from COVID-19 that contains antibodies against SARS-CoV2 has shown promising results in patients with severe COVID-19. Also, IVIG, combined with moderate-dose of corticosteroids, might improve patient outcomes. Evidence links COVID-19 to variable degrees of inflammation. Studies show that the use of corticosteroids might accelerate recovery from COVID-19. There are, however, no controlled clinical trials that show whether the use of corticosteroids can reduce COVID-19-related death. Also, the pro-inflammatory cytokine IL6 is the best-documented cytokine in COVID-19 correlated with severity, criticality, viral load, and prognosis of patients with COVID-19. Tocilizumab, a monoclonal antibody against IL6, could confer clinical benefit in patients with high IL6 levels. Essential elements that process SARS-CoV2 cell entry and specific characteristics that allow SARS-CoV2 to escape the immune system have the potential as targets for COVID-19 therapy.

Combined IMIG and immune Ig attenuates inflammatory colitis in mice.

BACKGROUND: Using a combination of homologous and heterologous (mouse/human) polyclonal anti-idiotypic Igs and immune Igs in BALB/c mice we have previously reported attenuation of allergic type responses following OVA immunization. We have now investigated attenuation of an inflammatory colitis in C57BL/6 mice receiving dextran sodium sulfate (DSS) in their drinking water, using additional treatment of DSS-exposed mice with combined human Igs, commercial IVIG (given IM, hence hereafter IMIG) as a source of pooled anti-idiotype Ig, and human anti-Tet as immune Ig. METHODS: Acute or chronic colitis was induced by DSS in groups of C57BL/6 mice. Mice also received weekly immunotherapy with im injections of polyclonal immune Ig, polyclonal anti-idiotype Ig, or the combined Igs, for a total of 5 injections, beginning with DSS treatment or after 2 cycles of DSS. Weight loss and mortality were monitored daily, and the extent of colitis was determined further using colonic length measurement, and by ELISA measurement of inflammatory cytokines in supernatants from colonic explant cultures. RESULTS: Mice developed colitis in both the acute and chronic models with loss of body weight, shortened colon lengths, and increased expression of inflammatory cytokines in colonic tissue. Loss of body weight, and inflammatory cytokine production, was attenuated only in chronic colitis, and only after combined IMIG and immune Ig treatment, and not in groups receiving only IMIG or immune Ig alone. CONCLUSION: Heterologous combinations of polyclonal IMIG and immune Ig can attenuate inflammatory colitis in mice. Given the described efficacy of this treatment for allergic desensitization, we hypothesize this methodology may have widespread clinic utility.