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Monoclonal antibodies (mAbs) that target the P-amyloid peptide (Aβ) are important Alzheimer's disease research tools and are now being used as Alzheimer's disease therapies. Conformation-specific mAbs that target oligomeric and fibrillar Aβ assemblies are of particular interest, as these assemblies are associated with Alzheimer's disease pathogenesis and progression. This paper reports the generation of rabbit mAbs against two different triangular trimers derived from Aβ. These antibodies are the first mAbs generated against Aβ oligomer mimics in which the high-resolution structures of the oligomers are known. We describe the isolation of the mAbs using single B-cell sorting of peripheral blood mononuclear cells (PBMCs) from immunized rabbits, the selectivity of the mAbs for the triangular trimers, the immunoreactivity of the mAbs with aggregated Aβ42, and the immunoreactivity of the mAbs in brain tissue from the 5xFAD Alzheimer's disease mouse model. The characterization of these mAbs against structurally defined trimers derived from Aβ enhances understanding of antibody-amyloid recognition and may benefit the development of diagnostics and immunotherapies in Alzheimer's disease.

BackgroundOutpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration.MethodsACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days.ResultsA total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA ConclusionsWhile safe, the BMS mAbs delivered subcutaneously were not effective at treating COVID-19 at low risk for progression. The lack of clinically significant activity may relate to the pharmacokinetics of subcutaneous administration of mAbs.

Objective Background Methods Results Conclusions To assess changes in real‐world use of acute and preventive medications for migraine over a 12‐month follow‐up period in the United States following initiation of the anti‐calcitonin gene‐related peptide (CGRP) pathway monoclonal antibody (mAb) erenumab.Early assessments of real‐world use of acute and preventive medications for migraine after initiation of erenumab have been limited to 6 months of follow‐up.This retrospective cohort study used data from the IQVIA open‐source longitudinal prescription (LRx) and medical (Dx) claims databases. Adult patients with an initial claim (index date) for erenumab between May 2018 and April 2020 were identified.Among 201,176 patients who met inclusion criteria, the mean (standard deviation [SD]) age was 47.5 (13.8) years and 85.6% (n = 172,153) were female. Most patients used one or more acute (88.4%; n = 177,795) and one or more traditional preventive (86.1%; n = 173,225) medications during the 12‐month pre‐index period. Adherence to erenumab (proportion of days covered [PDC] ≥0.80) was 40.2% (n = 80,927) with an overall mean (SD) PDC of 0.60 (0.34). Among all patients, 70.0% (n = 140,809) discontinued erenumab. After accounting for 24.7% (n = 49,720) of patients who restarted erenumab, discontinuation without reinitiation was observed in 45.3% (n = 91,089) of total patients. Switching to a different anti‐CGRP pathway mAb was observed in 13.1% (n = 26,446) of total patients. Among 177,795 patients with pre‐index use of one or more acute migraine medication class, 86.5% (n = 153,788) had post‐index use of the same class, and 56.7% (87,134/153,788) of them discontinued one or more class of acute medication in the 12‐month follow‐up period. Similarly, among 173,225 patients with pre‐index use of one or more traditional migraine preventive medication class, 67.7% (n = 117,274) had post‐index use of the same class, and 46.7% (54,790/117,274) of them discontinued one or more class of traditional preventive medication in the 12‐month follow‐up period.In this long‐term study, we observed the discontinuation of both acute and preventive medications for migraine post‐erenumab initiation. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is one of the deadliest cancers worldwide, mainly due to late diagnosis. Therefore, there is an urgent need for novel diagnostic approaches to identify the disease as early as possible. We have developed a diagnostic assay for pancreatic cancer based on the detection of naturally occurring tumor associated autoantibodies against Mucin‐1 (MUC1) using engineered glycopeptides on nanoparticle probes. We used a structure‐guided approach to develop unnatural glycopeptides as model antigens for tumor‐associated MUC1. We designed a collection of 13 glycopeptides to bind either SM3 or 5E5, two monoclonal antibodies with distinct epitopes known to recognize tumor associated MUC1. Glycopeptide binding to SM3 or 5E5 was confirmed by surface plasmon resonance and rationalized by molecular dynamics simulations. These model antigens were conjugated to gold nanoparticles and used in a dot‐blot assay to detect autoantibodies in serum samples from pancreatic cancer patients and healthy volunteers. Nanoparticle probes with glycopeptides displaying the SM3 epitope did not have diagnostic potential. Instead, nanoparticle probes displaying glycopeptides with high affinity for 5E5 could discriminate between cancer patients and healthy controls. Remarkably, the best‐discriminating probes show significantly better true and false positive rates than the current clinical biomarkers CA19‐9 and carcinoembryonic antigen (CEA). [ABSTRACT FROM AUTHOR]

As a heterogeneous disease, breast cancer (BC) has been characterized by the uncontrolled proliferation of mammary epithelial cells. The tumor microenvironment (TME) also contains inflammatory cells, fibroblasts, the extracellular matrix (ECM), and soluble factors that all promote BC progression. In this sense, the macrophage migration inhibitory factor (MIF), a pleiotropic pro-inflammatory cytokine and an upstream regulator of the immune response, enhances breast tumorigenesis through escalating cancer cell proliferation, survival, angiogenesis, invasion, metastasis, and stemness, which then brings tumorigenic effects by activating key oncogenic signaling pathways and inducing immunosuppression. Against this background, this review was to summarize the current understanding of the MIF pathogenic mechanisms in cancer, particularly BC, and address the central role of this immunoregulatory cytokine in signaling pathways and breast tumorigenesis. Furthermore, different inhibitors, such as small molecules as well as antibodies (Abs) or small interfering RNA (siRNA) and their anti-tumor effects in BC studies were examined. Small molecules and other therapy target MIF. Considering MIF as a promising therapeutic target, further clinical evaluation of MIF-targeted agents in patients with BC was warranted. [ABSTRACT FROM AUTHOR]

Expressed on the surface of CD8+ T cells, the CD8 co-receptor is a key component of the T cells that contributes to antigen recognition, immune cell maturation, and immune cell signaling. While CD8 is widely recognized as a costimulatory molecule for conventional CD8+ αβ T cells, recent reports highlight its multifaceted role in both adaptive and innate immune responses. In this review, we discuss the utility of CD8 in relation to its immunomodulatory properties. We outline the unique structure and function of different CD8 domains (ectodomain, hinge, transmembrane, cytoplasmic tail) in the context of the distinct properties of CD8αα homodimers and CD8αβ heterodimers. We discuss CD8 features commonly used to construct chimeric antigen receptors for immunotherapy. We describe the molecular interactions of CD8 with classical MHC-I, non-classical MHCs, and Lck partners involved in T cell signaling. Engineered and naturally occurring CD8 mutations that alter immune responses are discussed. The applications of anti-CD8 monoclonal antibodies (mABs) that target CD8 are summarized. Finally, we examine the unique structure and function of several CD8/mAB complexes. Collectively, these findings reveal the promising immunomodulatory properties of CD8 and CD8 binding partners, not only to uncover basic immune system function, but to advance efforts towards translational research for targeted immunotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Monoclonal antibodies (mAbs) play a pivotal role in disease diagnosis as well as immunotherapy interventions. Traditional monoclonal antibody generation relies on animal immunization procedures predominantly involving mice; however, recent advances in in-vitro expression methodologies have enabled large-scale production suitable for both industrial applications as well as scientific investigations. Methods: In this study, two mAbs against H7 subtype avian influenza viruses (AIV) were sequenced and analyzed, and the DNA sequences encoding heavy chain (HC) and light chain (LC) were obtained and cloned into pCHO-1.0 expression vector. Then, the HC and LC expression plasmids were transfected into CHO-S cells to establish stable cell lines expressing these mAbs using a two-phase selection scheme with different concentrations of methotrexate and puromycin. Recombinant antibodies were purified from the cell culture medium, and their potential applications were evaluated using hemagglutination inhibition (HI), western blotting (WB), confocal microscopy, and enzyme-linked immunosorbent assay (ELISA). Results: The results indicated that the obtained recombinant antibodies exhibited biological activity similar to that of the parent antibodies derived from ascites and could be used as a replacement for animal-derived mAbs. A kinetic analysis of the two antibodies to the AIV HA protein, conducted using surface plasmon resonance (SPR), showed concordance between the recombinant and parental antibodies. Discussion: The data presented in this study suggest that the described antibody production protocol could avoid the use of experimental animals and better conform to animal welfare regulations, and provides a basis for further research and development of mAbs-based diagnostic products. [ABSTRACT FROM AUTHOR]

The diagnosis of mycobacterial infections, including both the Mycobacterium tuberculosis complex (MTBC) and non-tuberculous mycobacteria (NTM), poses a significant global medical challenge. This study proposes a novel approach using immunochromatographic (IC) strip tests for the simultaneous detection of MTBC and NTM. Traditional methods for identifying mycobacteria, such as culture techniques, are hindered by delays in distinguishing between MTBC and NTM, which can affect patient care and disease control. Molecular methods, while sensitive, are resource-intensive and unable to differentiate between live and dead bacteria. In this research, we developed unique monoclonal antibodies (mAbs) against Ag85B, a mycobacterial secretory protein, and successfully implemented IC strip tests named 8B and 9B. These strips demonstrated high concordance rates with conventional methods for detecting MTBC, with positivity rates of 93.9% and 85.9%, respectively. For NTM detection, the IC strip tests achieved a 63.2% detection rate compared to culture methods, considering variations in growth rates among different NTM species. Furthermore, this study highlights a significant finding regarding the potential of MPT64 and Ag85B proteins as markers for MTBC detection. In conclusion, our breakthrough method enables rapid and accurate detection of both MTBC and NTM bacteria within the BACTEC MGIT system. This approach represents a valuable tool in clinical settings for distinguishing between MTBC and NTM infections, thereby enhancing the management and control of mycobacterial diseases. Key points: • Panel of mAbs for differentiating MTB versus NTM • IC strips for diagnosing MTBC and NTM after the BACTEC MGIT • Combined detection of MTP64 and Ag85B enhances diagnostic accuracy [ABSTRACT FROM AUTHOR]

Summary The immunosuppressive treatment of immune‐mediated thrombotic thrombocytopenic purpura (iTTP) in patients with intolerance or refractoriness to the B‐cell depleting monoclonal antibody rituximab remains debated. Daratumumab, a plasma cell‐directed monoclonal antibody targeting CD38, represents a therapeutic option, but data are scarce. The French Thrombotic Microangiopathies Reference Center conducted a nationwide survey on iTTP patients treated with daratumumab. Nine episodes from seven patients were identified. Treatment was administered for A Disintegrin And Metalloproteinase with ThromboSpondin‐1 motifs, 13th member (ADAMTS13) relapses while patients were otherwise in clinical response (N = 8), or during the acute phase of the disease following rituximab intolerance (N = 1). Patients have received a median of three previous therapeutic lines. ADAMTS13 activity improved in eight cases following daratumumab administration, including three cases where ADAMTS13 normalized. ADAMTS13 relapses occurred in three patients; in two cases, retreatment with daratumumab was successful. Median ADAMTS13 relapse‐free survival was not reached; 12‐month ADAMTS13 relapse‐free survival was 56%. Daratumumab‐related adverse events occurred in five cases and were non‐severe infusion‐related reactions in all cases. These results suggest that daratumumab may be an effective treatment option for iTTP patients with intolerance or refractoriness to rituximab. [ABSTRACT FROM AUTHOR]

Background and objectives: About a quarter of migraine cases among women have menstrual migraine (MM), which is usually more severe, longer lasting, and less responsive to treatment than typical migraine. Randomized controlled trials (RCTs) have evaluated the efficacy of several medication in the acute and preventive treatment of MM; this meta-analysis compared the effectiveness of these treatments. Methods: We conducted systematic searches in the Cochrane Central Register of Controlled Trials, MEDLINE, and Embase databases. The primary outcomes of acute treatment trials were pain relief at 2 and 24 h after treatment compared with placebo or another treatment. The three endpoints we checked for studying MM prevention were: no recurrence of headaches each month, a 50% reduction in monthly migraine days from baseline, and a decrease in the mean number of headache days per month. Results: Out of 342 studies, 26 RCTs met the criteria. Triptans, combined with or without other analgesics, were superior to placebo in providing pain relief in the acute treatment and prevention of MM. Among the treatments, sumatriptan and lasmiditan demonstrated superior pain relief at 2 h (OR: 4.62) and 24 h (OR: 4.81). Frovatriptan exhibited effectiveness in preventing headache recurrence, whereas galcanezumab and erenumab displayed significant preventive benefits in reducing headache days per month. Conclusion: Sumatriptan and lasmiditan are effective first-line treatments for acute MM. For prevention, frovatriptan may be the more effective of triptans. Compared with triptans, CGRP monoclonal antibodies, here including erenumab and galcanezumab, are more effective in reducing headache days, and therefore, in preventing MM. [ABSTRACT FROM AUTHOR]

Background Methods Results Conclusion Accurate conflict of interest (COI) information is essential for promoting transparency and trust in research. We aim to assess COI disclosure patterns in monoclonal antibodies (MABs) research for chronic rhinosinusitis with nasal polyposis (CRSwNP) using the Open Payments Database (OPD).Studies on FDA‐approved MABs for CRSwNP (dupilumab, omalizumab, mepolizumab) published between 2019 and 2021 with at least one US author were identified through PubMed. Industry‐reported payments from the manufacturers (Sanofi, Regeneron, Genentech, Novartis, and GlaxoSmithKline) between 2018 and 2021 in OPD's General Payments category were collected. Authors were cross‐checked against OPD metadata using a previously published ChatGPT‐based algorithm. Additionally, this novel algorithm analyzed COI statements for relevant author‒company specific disclosures, identifying disclosed and undisclosed payments made 3‒15 months prior to publication.A total of 214 unique authors from 76 studies were included. Of 30 articles that received at least one relevant payment, 21 (70%) were found to have an undisclosed COI, with a mean total undisclosed payment of $4890 and a median of $10,331. Fifty‐six authors had relevant OPD payments and 40 (71.4%) authors did not declare a potential COI. Interestingly, 158 authors had no relevant payments and 62 (39.2%) declared a potential COI. Author order was not significantly associated with potential under‐ or over‐disclosure.This study characterizes COI disclosure patterns in rhinosinusitis‐relevant MABs research using a novel automated approach. Given the discrepancy between disclosures and industry‐reported payments, our findings suggest a need for improved disclosure education and practices. [ABSTRACT FROM AUTHOR]

A 48-year-old female presented to the emergency department with severe fatigue. Admission laboratory test results were hemoglobin 6.6 g/dL, platelet count 287,000/μL, and white blood cell count 25,200/μL. Lactate dehydrogenase was elevated at 898 U/L, haptoglobin was markedly decreased (< 31 mg/dL), indirect bilirubin was elevated (5.3 mg/dL), and the absolute reticulocyte count was low at 0.0050/μL. A sample was sent to the immunohematology reference laboratory. The direct antiglobulin test immunoglobulin G was negative; C3 was 1+. All cells were reactive at immediate spin phase, indirect antiglobulin testing (IAT) with polyethylene glycol, with low ionic strength saline, neat, prewarm, and in the solid phase. All cells were nonreactive at IAT-ficin. Additional testing included a cold antibody titer that was 1:4096 and thermal amplitude studies demonstrating reactivity of 2+ at 37°C. These results were consistent with a clinically significant anti-Pr and cold agglutinin disease (CAD). Although rituximab is effective in autoimmune hemolytic anemia, this may take weeks. The patient was treated with pegcetacoplan, a pegylated peptide that targets C3 inhibiting hemolysis. The patient was discharged on day 29 with a hemoglobin of 8 g/dL. This is a report of one of the first patients successfully treated with pegcetacoplan for CAD. [ABSTRACT FROM AUTHOR]

Objectives To evaluate 1-year bimekizumab efficacy in PsA from the patient perspective using the 12-item PsA Impact of Disease (PsAID-12) questionnaire. Methods BE OPTIMAL (NCT03895203; biologic DMARD [bDMARD]-naïve), BE COMPLETE (NCT03896581; inadequate response/intolerance to TNF inhibitors [TNFi-IR]) and BE VITAL (NCT04009499; open-label extension) assessed bimekizumab 160 mg every 4 weeks in patients with PsA. Post hoc analyses of patient-reported disease impact, assessed by the PsAID-12 questionnaire, are reported to 1 year (collected to Week 40 in BE COMPLETE). Results Overall, 1,112 total patients were included (698 bimekizumab, 414 placebo). Rapid improvements observed with bimekizumab treatment at Week 4 continued to Week 16 and were sustained to 1 year. At 1 year, mean (SE) change from baseline in PsAID-12 total score was comparable between bimekizumab-randomized patients and patients who switched to bimekizumab at Week 16 (bDMARD-naïve bimekizumab –2.3 [0.1], placebo/bimekizumab –2.2 [0.1]; TNFi-IR bimekizumab –2.5 [0.1], placebo/bimekizumab –2.2 [0.2]). Proportions of bimekizumab-randomized patients achieving clinically meaningful within-patient improvement (≥3-point decrease from baseline) at Week 16 were sustained to 1 year (bDMARD-naïve 49.0%; TNFi-IR 48.5%) and were similar for placebo/bimekizumab patients (bDMARD-naïve 44.4%; TNFi-IR 40.6%). Across studies and arms, 35.3% to 47.8% of patients had minimal or no symptom impact at 1 year. Improvements were observed to 1 year across all single-item domains, including pain, fatigue and skin problems. Conclusion Bimekizumab treatment resulted in rapid and sustained clinically meaningful improvements in disease impact up to 1 year in bDMARD-naïve and TNFi-IR patients with PsA. Trial registration BE OPTIMAL: NCT03895203; BE COMPLETE: NCT03896581; BE VITAL: NCT04009499 (ClinicalTrials.gov) [ABSTRACT FROM AUTHOR]

Objective To investigate the safety and efficacy of subcutaneous tocilizumab (SC-TCZ) treatment in a long-term extension (LTE) of clinical trials in polyarticular or systemic juvenile idiopathic arthritis (pJIA or sJIA). Methods Patients with pJIA or sJIA from two open-label, 52-week phase 1b core trials of SC-TCZ who had adequate response per investigator assessment entered the LTE and continued SC-TCZ treatment according to body weight–based dosing regimens until commercial availability or up to 5 years. Pharmacokinetics, pharmacodynamics, and efficacy were assessed for up to 3 years, and safety for up to 5 years in the LTE. Results Forty-four patients with pJIA and 38 patients with sJIA entered the LTE. Tocilizumab trough concentrations were maintained within the range expected to provide clinical benefit (mean values: pJIA, ∼10 μg/ml; sJIA, ∼75 μg/ml over 3 years). Pharmacodynamic parameters (interleukin-6, soluble interleukin-6 receptor, erythrocyte sedimentation rate, C-reactive protein) were maintained throughout the LTE at levels achieved in the core trials. Inactive disease per American College of Rheumatology provisional criteria was reported for 90% (17/19) and 53% (8/15) of patients with pJIA and 91% (10/11) and 92% (12/13) of patients with sJIA in the <30 and ≥30 kg body weight groups, respectively. Serious adverse events in the LTE were reported in six patients with pJIA (13.6%; five serious infections) and five patients with sJIA (13.2%; one serious infection). Conclusion Patients with pJIA or sJIA experienced long-term disease control with SC-TCZ treatment. Long-term safety was consistent with the known tocilizumab safety profile. Clinical trial registration clinicaltrials.gov, NCT02165345 [ABSTRACT FROM AUTHOR]

OBJECTIVE Comparing the utility of the anti-human serum amyloid A (SAA)-specific monoclonal and polyclonal antibodies assays (LZ-SAA) with the pure monoclonal anti-human antibody assays (VET-SAA) during clinical practice in primary care hospital populations by measuring SAA measurement in healthy and diseased domestic cats. ANIMALS 52 healthy and 185 diseased client-owned cats. METHODS SAA concentration was measured using different LZ-SAA and VET-SAA measurements for healthy and various diseased cats. Sensitivity, specificity, and accuracy were calculated for each disease. RESULTS VET-SAA has higher sensitivity than LZ-SAA for the most common diseases presenting to primary care veterinary hospitals, including chronic kidney disease, tumors, and gingivostomatitis. Our results reveal the capability of detecting low SAA concentrations in healthy and diseased cats using VET-SAA in contrast to LZ-SAA, which found elevations of SAA concentrations only in diseased cats. CLINICAL RELEVANCE Our findings indicate that switching to the new VET-SAA instead of the conventional LZ-SAA will likely enhance the diagnostic performance in primary care veterinary hospitals. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic raised concern amongst clinicians that disease-modifying therapies (DMT), particularly anti-CD20 monoclonal antibodies (mAb) and fingolimod, could worsen COVID-19 in people with multiple sclerosis (pwMS). This study aimed to examine DMT prescribing trends pre- and post-pandemic onset. Methods: A multi-centre longitudinal study with 8,771 participants from MSBase was conducted. Two time periods were defined: pre-pandemic (March 11 2018–March 10 2020) and post-pandemic onset (March 11 2020–11 March 2022). The association between time and prescribing trends was analysed using multivariable mixed-effects logistic regression. DMT initiation refers to first initiation of any DMT, whilst DMT switches indicate changing regimen within 6 months of last use. Results: Post-pandemic onset, there was a significant increase in DMT initiation/switching to natalizumab and cladribine [(Natalizumab-initiation: OR 1.72, 95% CI 1.39–2.13; switching: OR 1.66, 95% CI 1.40–1.98), (Cladribine-initiation: OR 1.43, 95% CI 1.09–1.87; switching: OR 1.67, 95% CI 1.41–1.98)]. Anti-CD20mAb initiation/switching decreased in the year of the pandemic, but recovered in the second year, such that overall odds increased slightly post-pandemic (initiation: OR 1.26, 95% CI 1.06–1.49; Switching: OR 1.15, 95% CI 1.02–1.29. Initiation/switching of fingolimod, interferon-beta, and alemtuzumab significantly decreased [(Fingolimod-initiation: OR 0.55, 95% CI 0.41–0.73; switching: OR 0.49, 95% CI 0.41–0.58), (Interferon-gamma-initiation: OR 0.48, 95% CI 0.41–0.57; switching: OR 0.78, 95% CI 0.62–0.99), (Alemtuzumab-initiation: OR 0.27, 95% CI 0.15–0.48; switching: OR 0.27, 95% CI 0.17–0.44)]. Conclusions: Post-pandemic onset, clinicians preferentially prescribed natalizumab and cladribine over anti-CD20 mAbs and fingolimod, likely to preserve efficacy but reduce perceived immunosuppressive risks. This could have implications for disease progression in pwMS. Our findings highlight the significance of equitable DMT access globally, and the importance of evidence-based decision-making in global health challenges. [ABSTRACT FROM AUTHOR]

Objective: We examined whether the combined use of telemedicine and self‐injection could improve patient satisfaction. Background: For patients with migraine, the use of calcitonin gene‐related peptide ‐pathway targeting monoclonal antibodies is associated with concerns, such as the burden of doctor visits and anxiety around self‐injection. Methods: At four institutions, patients with migraines who used self‐injectable calcitonin gene‐related peptide ‐pathway targeting monoclonal antibodies attempted telemedicine, and web‐based questionnaires and interviews were conducted thereafter. Results: Of the 26 participants, 58% felt that telemedicine helped with self‐injections and 65% wanted to continue using the combination. The average time required per doctor visit was reduced from 158 to 31 min, and the median from 86 to 18 min. The benefits included reduced burden (46%), ease of schedule adjustment (35%), and lower anxiety levels (19%). Conclusion: Although there are issues with telemedicine usage, including the burden on healthcare professionals or lower reimbursement points, the combination of self‐injection of calcitonin gene‐related peptide ‐pathway targeting monoclonal antibodies and telemedicine is effective in improving the experience of patients have migraines. [ABSTRACT FROM AUTHOR]

Background and Aims: Guillain‐Barré syndrome (GBS) is an acute, self‐limited, immune‐mediated peripheral neuropathy. Current treatments for GBS include intravenous immunoglobulin (IVIg) and plasma exchange, which may not sufficiently benefit severely affected patients. This study evaluated the efficacy and safety of eculizumab add‐on therapy to IVIg (standard‐of‐care treatment) in patients with severe GBS. Methods: This phase 3, multicenter, double‐blind, randomized, placebo‐controlled clinical trial (NCT04752566), enrolled Japanese adults (age ≥ 18 years) with severe GBS (Hughes functional grade [FG] score FG3 or FG4/FG5 within 2 weeks of onset of GBS). Participants were randomized 2:1 to receive intravenous infusion of eculizumab or placebo (once weekly for 4 weeks) with IVIg treatment with 20 weeks of follow‐up. Primary efficacy endpoint was the time to first reach FG score ≤1 (able to run). Key secondary endpoints were proportion of participants achieving FG ≤1 at weeks 8 and 24 and FG improvement ≥3 at week 24. Pharmacodynamic analysis of serum free C5 concentration over time was performed. Safety was evaluated. Results: The analysis included 57 participants (eculizumab, n = 37; placebo, n = 20). Primary endpoint was not achieved (hazard ratio, 0.9; 95% CI, 0.45–1.97; p =.89). Key secondary endpoints did not reach statistical significance. Serum C5 concentration was reduced by 99.99% at 1 h postdose and sustained to week 5 but returned to baseline at the end of follow‐up period. No new safety signals for eculizumab were identified. Interpretation: Although well tolerated, eculizumab treatment did not show significant effects on motor function recovery compared to placebo in patients with GBS. [ABSTRACT FROM AUTHOR]

This article discusses the high attrition rate of oncology drugs, which leads to increased costs for drug developers. The success rate for oncology drugs is relatively low, with only 1 in 20 new chemical entities receiving approval. The primary reasons for drug attrition have shifted from inappropriate pharmacokinetics to a lack of efficacy and safety. Strategies to reduce attrition include careful selection of animal models and biomarkers during early drug development stages, as well as the use of biologics, which have a higher success rate. The article also analyzes the factors contributing to drug failure and discusses potential measures to mitigate attrition, such as investment in paradigm-shifting drugs and the use of biomarkers. A survey was conducted to gather insights from experts and clinical professionals on the attrition of oncology drugs. The article highlights the increasing trend of discontinued oncology drugs and the factors that contribute to drug attrition. The number of failed drugs has doubled in the past 8 years and is projected to triple by 2023. Half of the discontinued drugs occur in Phase 1 trials, indicating that attrition can happen early in development. Reasons for drug attrition include lack of efficacy, safety issues, strategic considerations, and unspecified concerns. Small molecules have a higher attrition rate compared to biologics, and certain cancer types, such as lung cancer, have a higher number of discontinued drugs. Financial considerations also play a significant role in drug development. The study examines the factors contributing to the high attrition [Extracted from the article]

Advances in biomarker-based diagnostic modalities, recent approval of anti-amyloid monoclonal antibodies for early Alzheimer's disease (AD; mild cognitive impairment or mild dementia due to AD) and late-stage clinical development of other disease-modifying therapies for AD necessitate a significant paradigm shift in the early detection, diagnosis and management of AD. Anti-amyloid monoclonal antibodies target the underlying pathophysiological mechanisms of AD and have demonstrated a significant reduction in the rate of clinical decline in cognitive and functional outcome measures in patients with early AD. With growing recognition of the benefit of early interventions in AD, an increasing number of people may seek diagnosis for their subjective cognitive problems in an already busy medical system. Various factors such as limited examination time, lack of expertise for cognitive assessment and limited access to specialized tests can impact diagnostic accuracy and timely detection of AD. To overcome these challenges, a new model of care will be required. In this paper, we provide practical guidance for institutional readiness for anti-amyloid therapies for early AD in Asia, in terms of best practices for identifying eligible patients and diagnosing them appropriately, safe administration of anti-amyloid monoclonal antibodies and monitoring of treatment, managing potential adverse events such as infusion reactions and amyloid-related imaging abnormalities, and cross-disciplinary collaboration. Education and training will be the cornerstone for the establishment of new pathways of care for the identification of patients with early AD and delivery of anti-amyloid therapies in a safe and efficient manner to eligible patients. [ABSTRACT FROM AUTHOR]

Purpose: To describe, compare similarity of pharmacokinetic (PK), pharmacodynamic (PD) and efficacy of SB12 and reference eculizumab (ECU) and find clinically significant covariate relationships. Methods: The PK, PD (terminal complement activity) and efficacy (LDH) data of SB12 and ECU were obtained from 289 subjects from phase I and phase III studies. One- and two-compartment PK models with first-order elimination were evaluated for SB12 and ECU. For PD and efficacy, both direct and indirect models were tested. The impact of covariates on PK, PD and efficacy parameters was assessed. Relationship between PK/PD and PD/efficacy was characterized. This modeling was performed using NONMEM version 7.4 (Icon Development Solutions, Ellicott City, MD, USA). Results: The two-compartment model adequately described the PK of SB12 and ECU, and the subject's weight was chosen as a clinically significant covariate affecting drugs' clearance and central volume of distribution. Treatment group was not a significant covariate affecting clearance. The direct response model using inhibitory sigmoid Emax and sigmoid Emax relationship well described the PK/PD relationship and PD/efficacy relationship of SB12 and ECU, respectively. Through this modeling, the relationships between PK, PD and efficacy were characterized. There were no differences in PK, PD and efficacy parameters between SB12 and ECU in pooled populations of healthy subjects and paroxysmal nocturnal haemoglobinuria (PNH) patients. Conclusion: The population modeling showed PK, PD and efficacy similarities between SB12 and ECU in pooled population of healthy subjects and PNH patients, supporting the totality of evidence on biosimilarity for SB12. [ABSTRACT FROM AUTHOR]

The article analyses data on the occurrence of hematological abnormalities in severe acute respiratory syndrome 2 infection. Among these hematological abnormalities, the majority of patients develop a hypercoagulable state associated with thromboembolic complications and poor prognosis. Approximately one-third of patients with severe acute respiratory syndrome 2 infection are diagnosed with mild to severe thrombocytopenia. Another hematological autoimmune disease observed in patients with coronavirus disease 2019 is autoimmune hemolytic anemia. A clinical case with the development of autoimmune hemolytic anemia in the setting of coronavirus infection was described. The diagnosis was based on the presence of anemia, reticulocytosis, a significant decrease in haptoglobin levels, and a positive antiglobulin test (Coombs test). Given the comorbidity, the risks of adverse effects of severe coronavirus disease were high, despite this, it was possible to achieve clinical and hematological remission of autoimmune hemolytic anemia by prescribing pathogenetic therapy with anti-CD-20 monoclonal antibody (rituximab), recombinant erythropoietin and glucocorticoid hormones. This clinical case demonstrates the possibility of successful treatment of patients with severe hemolytic anemia. Special attention should be paid to the discrepancy between the severity of the condition and objective data. This case demonstrates the need for a more in-depth approach to each patient with anemia associated with coronavirus disease infection, namely, in the presence of anemic syndrome, it is imperative to include a full range of laboratory tests. [ABSTRACT FROM AUTHOR]

In vivo clearance mechanisms of therapeutic monoclonal antibodies (mAbs) encompass both target-mediated and target-independent processes. Two distinct determinants of overall mAb clearance largely separate of target-mediated influences are non-specific cellular endocytosis and subsequent pH-dependent mAb recycling mediated by the neonatal Fc receptor (FcRn), where inter-mAb variability in the efficiency of both processes is observed. Here, we implemented a functional cell-based FcRn recycling assay via Madin-Darby canine kidney type II cells stably co-transfected with human FcRn and its light chain β2-microglobulin. Next, a series of pH-dependent internalization studies using a model antibody demonstrated proper function of the human FcRn complex. We then applied our cellular assays to assess the contribution of both FcRn and non-specific interactions in the cellular turnover for a panel of 8 clinically relevant mAbs exhibiting variable human pharmacokinetic behavior. Our results demonstrate that the interplay of non-specific endocytosis rates, pH-dependent non-specific interactions, and engagement with FcRn all contribute to the overall recycling efficiency of therapeutic monoclonal antibodies. The predictive capacity of our assay approach was highlighted by successful identification of all mAbs within our panel possessing clearance in humans greater than 5 mL/day/kg. These results demonstrate that a combination of cell-based in vitro assays can properly resolve individual mechanisms underlying the overall in vivo recycling efficiency and non-target mediated clearance of therapeutic mAbs. [ABSTRACT FROM AUTHOR]

Uveal melanoma (UM) is genetically a distinct tumor compared to cutaneous melanoma (CM), and due to its low mutational burden, it is far less perceptible to the immune system. Thus, treatments that have revolutionized the treatment of CM remain widely inefficient in metastatic UM or only demonstrate effectiveness in a small subpopulation of patients. To this end, the therapeutic benefit of immune checkpoint blockade is very limited and may come at the expense of severe immune-related adverse events that could potentially affect all organ systems. Notably, tebentafusp, an entirely novel class of anti-cancer drugs, has received official authorization for the treatment of metastatic UM. It is the first agent that demonstrated a survival advantage in a randomized controlled trial of metastatic UM patients. Despite the survival benefit and approval, the restriction of tebentafusp to HLA-A*02:01-positive patients and the low objective response rate indicate the persistent need for additional therapies. Thus, liver-directed therapies are commonly used for tumor control of hepatic metastases and represent a central pillar of the daily management of liver-dominant disease. Further, promising data from targeted therapies independent of MEK-inhibitors, such as the combination of darovasertib and crizotinib, raise hope for additional options in metastatic UM in the future. This narrative review provides a timely and comprehensive overview of the current treatment landscape for metastatic UM. [ABSTRACT FROM AUTHOR]

The article examines the relationship between biologic treatments for psoriasis and the risk of developing depression, based on a retrospective analysis of U.S. administrative claims data. Topics include the reduced incidence of depression among patients using biologics compared to conventional treatments, the relative risk reduction associated with different classes of biologics, and the implications of these findings for future treatment strategies.

Summary: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months on bone mineral density, taking into account prior therapies. Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. Introduction: In Switzerland, romosozumab is administered to high-risk osteoporosis patients. Our study aimed to assess the effect of romosozumab on bone mineral density (BMD), taking into account prior therapies. Methods: This multicentre, prospective cohort study measured the effect of romosozumab for 12 months in patients in a nationwide Swiss osteoporosis registry. BMD and bone turnover marker (P1NP and CTX) changes were measured and compared between pre-treated and treatment naïve patients. Results: Ninety-nine patients (92 women and 7 men, median age 71 years [65, 76]) were enrolled from January 2021 to December 2023. Among them, 22 had no prior treatment before romosozumab, while 77 had previous therapy (including 23 with a history of prior teriparatide therapy), with a median duration of 6 years [4, 11] of cumulative antiresorptive treatment. Over 12 months, romosozumab led to BMD changes of 10.3% [7.5, 15.5] at the lumbar spine, 3.1% [1.1, 5.8] at the total hip and 3.1% [0.5, 5.3] at the femoral neck, indicating notable variability. Significantly lower BMD responses were observed in pre-treated patients, with the duration of prior antiresorptive therapy inversely associated with BMD increases at the lumbar spine and hip. Other predictors of BMD changes at the total hip included baseline T-scores at the hip, body mass index and baseline CTX level, while the BMD response at the lumbar spine was associated with the lumbar spine T-score at baseline, age and baseline CTX level. Conclusion: Prior antiresorptive therapy blunted the BMD response to romosozumab, and the duration was correlated with BMD changes at both the lumbar spine and total hip. [ABSTRACT FROM AUTHOR]

Objective: The objective of this systematic review and meta-analysis was to determine whether patients with episodic (EM) or chronic migraine (CM), who were treated with anti-CGRP antibodies, showed a reversal from medication overuse (MO) or medication overuse headache (MOH) status at their baseline to non-overuse status. Furthermore, this study aimed to establish which acute headache medication (AHM) categories responded more effectively to anti-CGRP antibodies. Methods: A systematic search was conducted in the PubMed database for relevant studies from January 2013 to September 2023. We included phase three randomized controlled trials to examine the role of anti-CGRP antibodies in patients with EM or CM and their MO status. A meta-analysis was conducted to find the association between anti-CGRP antibodies and the number of EM and CM patients with MO or MOH at baseline that reverted to non-MO status or below the MOH threshold. Results: The initial search yielded a total of 345 studies. After removing duplicates and screening with inclusion criteria, 5 studies fulfilled our conditions. Each study reviewed the response to changes in the MO status of patients after receiving anti-CGRP antibodies, including eptinezumab, fremanezumab, galcanezumab, and erenumab, compared to placebo. Our study analyzed three AHM categories: triptans, simple analgesics, and multiple drugs. The overall relative risk (RR) was 1.44 (95% CI, 1.31 to 1.59; p < 0.001). The RRs for triptans, simple analgesics, and multi-drug groups were 1.71 (95% CI, 1.53 to 1.91; p < 0.001), 1.10 (95% CI, 0.83 to 1.47; p = 0.5), and 1.29 (95%CI 1.14 to 1.46; p < 0.001) respectively. Conclusion: The meta-analysis has shown that anti-CGRP antibodies were statistically significant in transitioning from MO or MOH status to non-MO status or below the MOH threshold (RR = 1.44) for all included studies and all AHM categories except for simple analgesics. Patients from the triptan group had the highest RR of 1.71 with a p-value < 0.001, while the simple analgesics group had an RR of 1.10, however, with a p-value > 0.05. Interestingly, this analysis can be interpreted as that anti-CGRP antibodies might not be effective in reducing simple analgesics use in EM or CM patients. Further studies are needed to investigate these matters. [ABSTRACT FROM AUTHOR]

Respiratory syncytial virus (RSV) and rotavirus infections are long-standing infectious diseases that affect children worldwide. RSV and rotavirus were first discovered in clinical specimens in 1955 and 1973, respectively. From their discovery to the present day, significant progress has been made in understanding these two infections. The introduction of a simple and rapid antigen diagnostic test into clinical settings in the 1990s offered new insight into the clinical characteristics and epidemiology of these infections. Regarding therapeutics, symptomatic treatments have remained the mainstay; however, prophylactic humanized anti-RSV monoclonal antibodies have been developed and advances in structural biology may allow for more effective human anti-RSV monoclonal antibodies and novel RSV vaccines to be developed soon. For rotavirus, two vaccines have been licensed and broadly applied over the past 10 years, which have been successful clinically and have changed the epidemiology of rotavirus infections in Japan. [ABSTRACT FROM AUTHOR]

Background Xeligekimab (GR1501) is a fully human monoclonal antibody that selectively neutralizes interleukin (IL)-17A and has shown potential efficacy in treating moderate-to-severe psoriasis in preliminary trials. Objectives To evaluate the efficacy and safety of xeligekimab in Chinese patients with moderate-to-severe psoriasis. Methods A total of 420 Chinese patients were randomized to 200 mg xeligekimab every 2 weeks (n = 281) or placebo (n = 139) for the first 12 weeks, followed by an extension of the treatment schedule to xeligekimab every 4 weeks for a further 40 weeks. Efficacy was assessed by evaluating achievement of Physician Global Assessment (PGA) 0/1 and 75%, 90% and 100% improvement in Psoriasis Area and Severity Index (PASI 75, PASI 90 and PASI 100, respectively). The safety profile was also evaluated. Results At week 12, PASI 75, PASI 90 and PASI 100 were achieved in 90.7%, 74.4% and 30.2% of patients in the xeligekimab group vs. 8.6%, 1.4% and 0% of patients in the placebo group, respectively. PGA 0/1 was achieved in 74.4% patients in the xeligekimab group and 3.6% of patients in the placebo group. PASI 75 and PGA 0/1 were maintained until week 52. No unexpected adverse events were recorded. Conclusions Xeligekimab showed high efficacy and was well tolerated in Chinese patients with moderate-to-severe plaque psoriasis. [ABSTRACT FROM AUTHOR]

Mogamulizumab is a first‐in‐class IgG1k monoclonal antibody that selectively targets the chemokine receptor type 4. The drug has received Food and Drug administration authorisation for mycosis fungoides and Sézary syndrome following failure of at least one previous course of systemic therapy and now is available in Europe. One of the most common treatment‐related side effects observed has been the mogamulizumab‐associated rash (MAR), which affects up to a quarter of patients and is the most frequent adverse event leading to drug discontinuation. The aim of this study is to perform a systematic review of the literature on patients diagnosed with MAR and other mogamulizumab‐related cutaneous events to describe the clinical and histological characteristics, the management in clinical practice and to assess whether these events have prognostic implications. In total, 2073 records were initially identified through a literature search, 843 of which were duplicates. After screening for eligibility and inclusion criteria, 49 articles reporting mogamulizumab‐associated cutaneous events were included. Totally, 1516 patients were retrieved, with a slight male prevalence as for the available data (639 males and 570 females, i.e. 52.9% vs. 47.1%). Regarding the reported clinicopathological findings of the cutaneous reactions, the five most common patterns were spongiotic/psoriasiform dermatitis (22%), eruptions characterized by the presence of papules and/or plaques (16.1%), cutaneous granulomatosis (11.4%), morbilliform or erythrodermic dermatitis (9.4%) and photodermatitis (7.1%). Our results highlight how the majority of the reported cutaneous adverse events on mogamulizumab are of mild‐to‐moderate entity and generally manageable in clinical practice, though prompt recognition is essential and case‐by‐case assessment should be recommended. Future research will need to focus on the MAR prognostic implications and to identify genomic and molecular markers for a more rapid and accurate diagnosis. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies are attractive therapeutic agents in a wide range of human disorders that bind specifically to their target through their complementary‐determining regions (CDRs). Small proteins with structurally preserved CDRs are promising antibodies mimetics. In this in silico study, we presented new antibody mimetics against the cancer marker epidermal growth factor receptor (EGFR) created by the CDRs grafting technique. Ten potential graft acceptor sites that efficiently immobilize the grafted CDR loops were selected from three small protein scaffolds using a computer. The three most involved CDR loops in antibody‐receptor interactions extracted from panitumumab antibody against the EGFR domain III crystal structure were then grafted to the selected scaffolds through the loop randomization technique. The combination of three CDR loops and 10 grafting sites revealed that three of the 36 combinations showed specific binding to EGFR DIII by binding energy calculations. Thus, the present strategy and selected small protein scaffolds are promising tools in the design of new binders against EGFR with high binding energy. [ABSTRACT FROM AUTHOR]

Objective To review how different classes of immunosuppressants affect wound healing. Data Sources A literature search was conducted in PubMed, Google Scholar, and the University of Calgary Health Sciences Library. Study Selection The researchers initially screened article titles using key words such as "immunosuppressive medication," "wound healing," and "immunosuppression." Articles in which the title and/or abstract contained these key words, that addressed wound healing related to immunosuppressant medications, and were published after 2000 were included in the review. When human data were not available for an immunosuppressant (class), animal studies were included. Data Extraction The 61 included articles underwent full text review and summarization. Data Synthesis: All included studies were summarized descriptively including immunosuppressive mechanism of action, study participants or subjects, and evidence of effects on wound healing. Conclusions Corticosteroids and mechanistic target of rapamycin inhibitors most consistently demonstrate detrimental effects on wound healing. For other classes of immunosuppressants, evidence is limited with varying effects on wound healing described. Larger, high-quality studies are required to better understand the effects of immunosuppressants, including those with new mechanisms of action, to identify those with the most impact on wound healing. [ABSTRACT FROM AUTHOR]

Eosinophilic Esophagitis is a widely-recognized immune-mediated esophagus disease with distinct clinical and histopathological features, exhibiting an increased global incidence. Therapeutic options encompass either dietary measures or pharmacological approaches, including proton pump inhibitors and topical corticosteroids. The use of monoclonal antibodies is currently under comprehensive evaluation, with a plethora of ongoing clinical trials designed to determine their clinical efficacy. The present case report demonstrates an exceptional case of refractory Eosinophilic Esophagitis, unresponsive to conventional treatment, achieving both clinical and histopathological remission subsequent to initiation of benralizumab treatment. Concurrently, our case underscores the necessity for continued research in the field of monoclonal antibodies for their use as a future treatment approach against Eosinophilic Esophagitis. [ABSTRACT FROM AUTHOR]

Introduction: This study evaluated the pharmacokinetic (PK) equivalence between BP02 (a proposed trastuzumab biosimilar) and the reference trastuzumab approved in the EU (EU-trastuzumab) and the US (US-trastuzumab). Methods: In this phase 1, double-blind, parallel-group trial, 111 healthy male volunteers were randomized 1:1:1 to receive a single 6-mg/kg intravenous infusion of BP02, EU-trastuzumab, or US-trastuzumab and were evaluated for 78 days. Serum drug concentration–time data were analyzed by non-compartmental methods. The PK similarity of BP02 to the two reference products, and between EU-trastuzumab and US-trastuzumab, was determined using the standard 80–125% bioequivalence criteria. Results: Baseline demographics for the 111 subjects with evaluable pharmacokinetics were similar across all treatment groups. PK profiles were similar for the three products. The 90% confidence intervals (CIs) for the ratios of area under the serum concentration–time curve (AUC) from the time of dosing to infinity (AUC0-inf), AUC from the time of dosing until the time of the last quantifiable concentration (AUC0-t), and peak serum concentration of trastuzumab (Cmax) were within 80% to 125% for all three pairwise comparisons. Adverse events (AEs) were similar across all arms, with treatment-related AEs reported by 73.0%, 73.0%, and 89.2% of the subjects in the BP02, EU-trastuzumab, and US-trastuzumab groups, respectively. The most common AEs were headache, infusion-related reactions, and upper-respiratory-tract infections. Four subjects—three in the US-trastuzumab group and one in the BP02 group—discontinued the study due to AEs. All post-dose samples except for two tested negative for anti-drug antibodies. Conclusion: This study demonstrates the PK similarity among BP02, EU-trastuzumab, and US-trastuzumab. The safety and immunogenicity profiles observed for the three products in this study are consistent with previous reports for trastuzumab. Trial Registration: ANZCTR number: ACTRN12621000573853. [ABSTRACT FROM AUTHOR]

Introduction: Biological monoclonal antibodies play a pivotal role in cancer treatment, with biosimilars significantly enhancing their accessibility. In Brazil's ethnically diverse setting, real-world evidence is crucial for assessing the effectiveness and applicability of these therapies in routine clinical practice. Methods: We performed a multicentric, observational, prospective real-world study on biosimilar trastuzumab-dkst for adjuvant treatment of early HER2-positive breast cancer in Brazilian patients. Data were collected using a case-report form. Results: Of the 176 recruited, we present data from the first 59 patients (mean age 51.7 ± 12.9 years) who had completed treatment with trastuzumab-dkst. The mean time from diagnosis to the first adjuvant treatment with trastuzumab-dkst was 5.5 ± 2.7 months. Of the patients, 59% of patients achieved at least a 30-month follow-up. The 31.7-month invasive disease-free survival rate (IDFS) was 94.5% (95% CI 83.9–98.2%) and median IDFS was not achieved, since only three patients had invasive disease recurrence. The overall survival rate was 100% until the last assessment. The observed adverse events were similar to those presented by other studies using biosimilar or reference trastuzumab. Four serious adverse events (8.5%) were observed. A reduction in left ventricular ejection fraction of at least 10% was observed in 16.9% of participants. There was no treatment interruption, and three participants (5.1%) had their trastuzumab-dkst dose reduced. Conclusion: Our study reinforces the existing pivotal data, underscoring the real-world efficacy and safety of biosimilar trastuzumab-dkst in the adjuvant treatment for early HER2-positive breast cancer. The preliminary long-term effectiveness and safety data we present further validate trastuzumab-dkst's role as a cost-saving alternative in oncological care. These findings have important implications for improving patient access to crucial treatments and for the more efficient use of healthcare resources. ClinicalTrials.gov Registration: NCT03892655. [ABSTRACT FROM AUTHOR]

Gantenerumab is a monoclonal antibody targeting amyloid β protein (Aβ) in early Alzheimer's disease (AD). The authors sought to evaluate gantenerumab safety and efficacy in early AD patients. MEDLINE, Embase, and Cochrane databases were systematically searched until 2 December 2023. Data were examined using the Mantel–Haenszel method and 95% confidence intervals (CIs). Meta-regression analysis was conducted to evaluate a possible link between baseline Clinical Dementia Rating Scale – Sum of Boxes (CDR-SB) and amyloid-related imaging abnormalities (ARIA) at follow-up. R, version 4.2.3, was used for statistical analysis. A total of 4 RCTs and 2848 patients were included, of whom 1580 (55%) received subcutaneous gantenerumab. Concerning clinical scores, the placebo group achieved better rates of change in the Disease Assessment Scale (ADAS-Cog13) (SMD −0.11; 95% CI −0.19– −0.03; p = 0.008569; I2 = 0%). Gantenerumab was strongly associated with the occurrence of ARIA-E and ARIA-H: (19.67% vs. 2.31%; RR 9.46; 95% CI 5.55–16.11; p = <0.000001; I2 = 10%) and (21.95% vs. 12.38%; RR 1.79; 95% CI 1.50–2.13; p = <0.000001; I2 = 0%), respectively. In this meta-analysis, consistent results suggest that gantenerumab is not safe and efficient for early AD, showing no improvement in clinical scores for AD and being associated with the occurrence of ARIA-E and ARIA-H. [ABSTRACT FROM AUTHOR]

Background: Pyodermatitis-pyostomatitis vegetans (PPV) is a rare mucocutaneous disease characterized by multiple pustules and it is considered a marker for inflammatory bowel disease (IBD). The oral manifestations of this condition are referred to as pyostomatitis vegetans (PSV). Purpose: To investigate which features could help in establishing the diagnosis of PSV, with or without cutaneous lesions, based on information retrieved from all cases of PSV described in the literature. A case of PV from the authors was also included in the analysis. Methods: An electronic search was undertaken, last updated in August 2022. Inclusion criteria included publications reporting cases of PSV, with the diagnosis confirmed by the pathological examination of oral or skin lesions, and presence of IBD. Results/Conclusions: Sixty-two publications with 77 cases of PSV and an associated IBD were included. Features that are helpful in establishing the diagnosis of PSV are snail track appearance of oral lesions, an associated IBD (which is not always symptomatic), evidence of intraepithelial clefting on microscopic examination of oral lesions, and peripheral blood eosinophilia. A gold standard for the management of PSV does not exist and high-level evidence is limited. There is no established therapeutic protocol for PSV and management primarily consists of topical and/or systemic corticosteroids, antirheumatic drugs (sulfasalazine, mesalazine), monoclonal antibody (infliximab, adalimumab) immunosuppressives (azathioprine, methotrexate), antibiotics (dapsone), or a combination of these. The risk of recurrence of oral lesions is considerable when the medication dose is decreased or fully interrupted. [ABSTRACT FROM AUTHOR]

Objective: To review the efficacy and safety of eculizumab for prevention and treatment of antibody-mediated rejection (AMR) in lung transplant recipients (LTRs). Data Sources: A literature search of PubMed and the Cochrane Controlled Trials Register (2007 to mid-October 2023) was performed using the following search terms: eculizumab, complement inhibitor, solid organ transplant, lung transplant, and AMR. Study Selection and Data Extraction: All relevant English-language studies were reviewed and considered. Data Synthesis: Eculizumab, a monoclonal antibody that binds complement protein C5 to inhibit its cleavage and subsequent generation of the membrane attack complex, is currently approved to treat paroxysmal nocturnal hemoglobinuria, atypical hemolytic uremic syndrome, generalized myasthenia and neuromyelitis optica spectrum disorder. Given the role of antibodies directed against donor antigens that are produced by allospecific B-cells and plasma cells in AMR, eculizumab is being investigated for use within this indication. Three case reports have described the successful use of eculizumab for the prevention and treatment of AMR in LTRs. Given this lack of robust data, evidence for the use of eculizumab in other solid organ transplant recipients is of increased value. Early experiences from a single center's use of eculizumab in LTRs are also described. Relevance to Patient Care and Clinical Practice: Lung transplant is a recognized treatment for end-stage lung disease, though complications posttransplant can be associated with significant morbidity and mortality. While prevention and management of AMR remains a substantial challenge without comprehensive guidance from societal guidelines, recently published literature may be helpful to guide clinical practice using alternative treatment options. However, this remains an area of great clinical importance, given the impact of AMR on long-term allograft function. Conclusions: Optimizing use of current therapies, as well as identifying and advancing novel therapeutic modalities such as eculizumab, are vital for the improvement of AMR prevention and treatment in LTRs to extend long-term allograft function and survival. [ABSTRACT FROM AUTHOR]

Nipah virus (NiV) is a zoonotic emergent paramyxovirus that can cause severe encephalitis and respiratory infections in humans, with a high fatality rate ranging from 40% to 75%. Currently, there are no approved human vaccines or antiviral drugs against NiV. Here, we designed a ferritin-based self-assembling nanoparticle displaying the NiV G head domain on the surface (NiV G-ferritin) and assessed immune responses elicited by the soluble NiV G head domain (NiV sG) or NiV G-ferritin. Immunization with NiV G-ferritin or NiV sG conferred complete protection against lethal NiV challenge without detection of viral RNA in Syrian golden hamsters. Compared to NiV sG, NiV G-ferritin induced significantly faster, broader, and higher serum neutralizing responses against three pathogenic henipaviruses (NiV-Malaysia, NiV-Bangladesh, and Hendra virus). Moreover, NiV G-ferritin induced a durable neutralizing immunity in mice as antisera potently inhibited NiV infection even after six months of the third immunization. Additionally, we isolated a panel of 27 NiV G-binding monoclonal antibodies (mAbs) from NiV G-ferritin immunized mice and found that these mAbs targeted four distinct antigenic sites on NiV G head domain with two sites that have not been defined previously. Notably, 25 isolated mAbs have potent neutralizing activity with 50% inhibitory concentrations less than 10 ng/mL against NiV pseudovirus. Collectively, these findings provide new insights into the immunogenicity of NiV G protein and reveal that NiV G-ferritin is a safe and highly effective vaccine candidate against Nipah virus infection. [ABSTRACT FROM AUTHOR]

Gynecologic cancer is a critical concern in the field of women's health, and traditional treatment methods have demonstrated limited efficacy for certain advanced and recurrent gynecologic cancers. In recent years, antibody–drug conjugate (ADC) therapy, as an emerging targeted approach, has gained increasing attention as a research hotspot. This review aims to elucidate the structure and mechanism of ADC drugs and explore their application and clinical research progress in gynecologic cancers such as ovarian cancer, cervical cancer, and endometrial cancer. [ABSTRACT FROM AUTHOR]

KRAS belongs to a family of small GTPases that act as binary switches upstream of several signalling cascades, controlling proliferation and survival of cells. Mutations in KRAS drive oncogenesis, especially in pancreatic, lung, and colorectal cancers (CRC). Although historic attempts at targeting mutant KRAS with small molecule inhibitors have proven challenging, there are recent successes with the G12C, and G12D mutations. However, clinically important RAS mutations such as G12V, G13D, Q61L, and A146T, remain elusive drug targets, and insights to their structural landscape is of critical importance to develop novel, and effective therapeutic concepts. We present a fully open, P-loop exposing conformer of KRAS G13D by X-ray crystallography at 1.4–2.4 Å resolution in Mg2+-free phosphate and malonate buffers. The G13D conformer has the switch-I region displaced in an upright position leaving the catalytic core fully exposed. To prove that this state is druggable, we developed a P-loop-targeting monoclonal antibody (mAb). The mAb displayed high-affinity binding to G13D and was shown using high resolution fluorescence microscopy to be spontaneously taken up by G13D-mutated HCT 116 cells (human CRC derived) by macropinocytosis. The mAb inhibited KRAS signalling in phosphoproteomic and genomic studies. Taken together, the data propose novel druggable space of G13D that is reachable in the cellular context. It is our hope that these findings will stimulate attempts to drug this fully open state G13D conformer using mAbs or other modalities. [ABSTRACT FROM AUTHOR]

African swine fever (ASF) is a highly fatal infectious disease in pigs, caused by the African swine fever virus (ASFV). It is characterized by short disease duration and high morbidity and mortality. In August 2018, ASF was first reported in China and it subsequently spread rapidly throughout the country, causing serious economic losses for the Chinese pig industry. Early detection plays a critical role in preventing and controlling ASF because there is currently no effective vaccine or targeted therapeutic medication available. Additionally, identifying conserved protective antigenic epitopes of ASFV is essential for the development of diagnostic reagents. The E165R protein, which is highly expressed in the early stages of ASFV infection, can serve as an important indicator for early detection. In this study, we successfully obtained high purity soluble prokaryotic expression of the E165R protein. We then utilized the purified recombinant E165R protein for immunization in mice to prepare monoclonal antibodies (mAbs) using the hybridoma fusion technique. After three subclonal screens, we successfully obtained three mAbs against ASFV E165R protein in cells named 1B7, 1B8, and 10B8. Through immunofluorescence assay (IFA) and Western blot, we confirmed that the prepared mAbs specifically recognize the baculovirus-expressed E165R protein. By using overlapping truncated E165R protein and overlapping peptide scanning analysis, we tentatively identified two novel linear B cell epitopes (13EAEAYYPPSV22 and 55VACEHMGKKC64) that are highly conserved in genotype I and genotype II of ASFV. Thus, as a detection antibody, it has the capability to detect ASFV across a wide range of genotypes, providing valuable information for the development of related immunodiagnostic reagents. [ABSTRACT FROM AUTHOR]

This document provides a comprehensive list of references and citations for articles and studies related to the use of trastuzumab emtansine and trastuzumab deruxtecan in the treatment of HER2-positive/mutated malignancies. The articles cover various topics, including the mechanism of action of trastuzumab, the safety profile of trastuzumab-based antibody-drug conjugates, and the evolving therapeutic landscape of trastuzumab-drug conjugates. This resource is valuable for library patrons conducting research on these specific topics. [Extracted from the article]

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) and hospital admissions in early childhood. Recent advancements in novel preventive therapies, including extended half‐life monoclonal antibodies and antenatal vaccination, have afforded new opportunities to significantly reduce the burden of this infection. Nirsevimab is a novel monoclonal antibody that provides sustained protection against RSV for at least 5 months among newborns and young children. It has received regulatory approval in numerous countries and is being implemented across various settings. Two pivotal Phase 3 trials (MELODY, HARMONIE) demonstrated significant reductions in RSV‐associated LRTI hospitalisations following nirsevimab administration, with treatment efficacy of 62.1% and 83.2%. Emerging real‐world data from early adopters of nirsevimab corroborates these findings. Studies from Spain, Luxembourg, France and the USA report effectiveness rates between 82% and 90% in preventing RSV‐associated hospitalisations among infants entering their first RSV season. Current implementation strategies for nirsevimab have primarily focused on seasonal administration for all infants, aligned to local RSV seasons, and often include catch‐up doses for those born before the season begins. Available cost‐effectiveness analyses indicate that while nirsevimab offers significant potential public health benefits, its adoption must carefully consider economic factors such as treatment costs, implementation strategies tailored to local viral epidemiology, and logistics for vaccine delivery. Overall, nirsevimab presents a promising opportunity to alleviate the burden of severe RSV infections in young children. However, ongoing surveillance and refinements in implementation strategies are crucial to optimise its impact and ensure sustainability across diverse health‐care settings. [ABSTRACT FROM AUTHOR]

AbstractPseudomonas cocovenenans subsp. farinofermentans is a pathogenic bacterium that causes the poisoning of fermented rice products. Its isomeric products, bongkrekic acid (BA) and isobongkrekic acid (IBA), have become popular research topics. In this study, we developed a heterologous-coating strategy for high-sensitivity indirect competitive enzyme-linked immunoassay (icELISA) for BA and IBA using monoclonal antibodies (mAbs). The optimized procedure exhibited an IC50 of 5.49 ng/mL, a limit of detection of 0.99 ng/mL, and a linear range from 2.12 to 14.21 ng/mL. Notably, this method exhibited negligible cross-reactivity to other small toxins, and the recoveries of the samples, including rice noodles, Auricularia auricula, and flat rice noodles, ranged from 92.0%–111.9%, 105.6%–115.0%, and 83.2%–109.0%, respectively, with coefficients of variation below 12%. A comparison of the recoveries of high-performance liquid chromatography-mass spectrometry (HPLC-MS) and icELISA demonstrated that the developed approach provides good accuracy and reliability. Overall, the simple preparation of IBA combined with the suitability of icELISA for high-throughput analysis is efficient and cost-effective, making it suitable for routine screening of food. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)–namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib–from the perspective of the Chinese health care system. Methods: The York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis. Results: Compared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows: secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used. Conclusion: Targeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics. [ABSTRACT FROM AUTHOR]

Antibodies are used in many areas of biomedical and clinical research, but many of these antibodies have not been adequately characterized, which casts doubt on the results reported in many scientific papers. This problem is compounded by a lack of suitable control experiments in many studies. In this article we review the history of the ‘antibody characterization crisis’, and we document efforts and initiatives to address the problem, notably for antibodies that target human proteins. We also present recommendations for a range of stakeholders – researchers, universities, journals, antibody vendors and repositories, scientific societies and funders – to increase the reproducibility of studies that rely on antibodies. [ABSTRACT FROM AUTHOR]

High-affinity and specific agents are widely applied in various areas, including diagnostics, scientific research, and disease therapy (as drugs and drug delivery systems). It takes significant time to develop them. For this reason, development of high-affinity agents extensively utilizes computer methods at various stages for the analysis and modeling of these molecules. The review describes the main affinity and specific agents, such as monoclonal antibodies and their fragments, antibody mimetics, aptamers, and molecularly imprinted polymers. The methods of their obtaining as well as their main advantages and disadvantages are briefly described, with special attention focused on the molecular modeling methods used for their analysis and development. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic immune-mediated inflammatory disease which can induce progressive disability if not properly treated early. Over the last 20 years, the improvement of knowledge on the pathogenesis of the disease has made available several drugs targeting key elements of the pathogenetic process, which now represent the preferred treatment option after the failure of first-line therapy with conventional drugs such as methotrexate (MTX). To this category of targeted drugs belong anti-cytokine or cell-targeted biological agents and more recently also Janus kinase inhibitors (JAKis). In the absence to date of specific biomarkers to guide the therapeutic choice in the context of true precision medicine, the choice of the first targeted drug after MTX failure is guided by treatment cost (especially after the marketing of biosimilar products) and by the clinical characteristics of the patient (age, sex, comorbidities and compliance) and the disease (presence or absence of autoantibodies and systemic or extra-articular manifestations), which may influence the efficacy and safety profile of the available products. This viewpoint focuses on the decision-making process underlying the personalized approach to RA therapy and will analyse the evidence in the literature supporting the choice of individual products and in particular the differential choice between biological drugs and JAKis. [ABSTRACT FROM AUTHOR]