Human IgG1 Monoclonal Antibody Research Articles

Immuno-PET Imaging of EGFR with 64Cu-NOTA Panitumumab in Subcutaneous and Metastatic Nonsmall Cell Lung Cancer Xenografts.

Objective: About 65-90% of nonsmall cell lung cancer (NSCLC) express the epithelial growth factor receptor (EGFR) as a transmembrane protein that is activated by binding of specific ligands, including epidermal growth factor and transforming growth factor α (TGFα). Identifying EGFR as an oncogene has led to the development of anticancer therapeutics directed against EGFR, including the full-length human IgG2 monoclonal antibody panitumumab. The main goal of the present study was to investigate 64Cu-labeled panitumumab with immuno-PET in subcutaneous and metastatic EGFR-positive NSCLC xenografts. Methods: Bifunctional chelating agent 2-S-(4-isothiocyanatobenzyl)-1,4,7-triazacyclo-nonane-1,4,7-triacetic acid (NOTA-NCS) was attached to panitumumab. The number of chelators per panitumumab was determined using matrix-assisted laser desorption/ionization (MALDI) mass spectroscopy. The incorporation efficiency of 64Cu into NOTA-panitumumab was measured by using radio-TLC. EGFR-expressing epithelial-like H1299-luc+ NSCLC cells were used for in vitro and in vivo experiments. Cell uptake of [64Cu]Cu-NOTA-panitumumab was measured in the presence and absence of panitumumab. Subcutaneous and metastatic H1299-luc tumor models were grown in male NSG mice. The presence of tumors at lung and metastatic sites was analyzed by [18F]FLT PET. Immuno-PET with [64Cu]Cu-NOTA-panitumumab was performed as static PET imaging at 2, 24, and 48 h postinjection in both tumor models. Proof-of-target was confirmed by blocking experiments with panitumumab. Detailed ex vivo biodistribution experiments were performed in both animal tumor models to confirm biodistribution profiles obtained by immuno-PET imaging. Results: MALDI analysis confirmed the attachment of ∼1.5 NOTA per antibody. Radiolabeling efficiency with [64Cu]CuCl2 was 93.8 ± 5.7% and a molar activity of 0.65 MBq/μg. Cellular uptake studies with [64Cu]Cu-NOTA-panitumumab in H1299 cells demonstrated increasing uptake over time, reaching 29.1 ± 2.9% radioactivity(Bq)/mg protein (n = 3) and plateauing at 45 min. Addition of 25 μg of panitumumab reduced radioligand uptake to 1.22 ± 0.06% radioactivity/mg protein (n = 3). PET imaging revealed high uptake of [64Cu]Cu-NOTA-panitumumab in subcutaneous tumors: Standardized uptake values (SUV)mean reached 4.70 ± 0.42 and 5.37 ± 0.40 (n = 5) after 24 and 48 h postinjection, respectively. Administration of 1 mg panitumumab reduced tumor uptake significantly to 1.94 ± 0.22 and 1.66 ± 0.08 (n = 4; p < 0.001). In the metastatic model, the following SUVmean were analyzed from liver and lung lesions: 5.55 ± 0.34 and 6.28 ± 0.46 (both n = 23 lesions from 6 mice) after 24 and 48 h postinjection, which was also significantly reduced to 2.53 ± 0.39 and 2.31 ± 0.15 (both n = 16 lesions from 4 mice; p < 0.001) after injection of 1 mg panitumumab. Detailed ex vivo biodistribution confirmed immuno-PET analysis in both models. Panitumumab reduced radioactivity uptake into subcutaneous tumors from 11.01 ± 0.72 (n = 4) to 3.67 ± 0.33% ID/g (n = 5; p < 0.001), and in metastatic liver lesions from 29.44 ± 8.14 (n = 4) to 8.35 ± 1.30% ID/g (n = 5; p < 0.001), respectively. Conclusions: [64Cu]Cu-NOTA-panitumumab was successfully used for immuno-PET imaging of EGFR-expressing subcutaneous and metastatic NSCLC tumors. This result represents the basis for developing radiotheranostics for targeting EGFR in cancers and for selecting the right patients for the right treatment at the right time.

The impact of tildrakizumab on quality of life in patients suffering from moderate-to-severe psoriasis: a 36-week prospective, monocentric, real-life, observational study.

Psoriasis may significantly impact on patients' health related quality of life (HRQoL). Clinical assessment has been combined with HRQoL scores to evaluate the ways that cutaneous disease is a burden to patients. Tildrakizumab is a humanized IgG1 monoclonal antibody targeting interleukin-23 p19 and is approved for the management of moderate-to-severe plaque psoriasis. The aim of our study was to evaluate the impact of tildrakizumab treatment on psychological field in patients affected by moderate-to-severe plaque psoriasis. a 36-weeks observational study was carried out enrolling psoriasis patients who initiated treatment with tildrakizumab 100 mg. DLQI and Skindex-16 questionnaire were administered at baseline, week 12, week 24 and week 36. PASI, BSA and pruritus (p)-VAS were also assessed at baseline and at each follow-up. A total of 34 patients were enrolled. Baseline PASI and BSA score were 28.4±5.6 and 38.8±21.4, respectively. Similarly, the impact of psoriasis on HRQoL was collected (DLQI: 26.4±3.2, Skindex-16: 68±5.8, p-VAS: 8.2). Clinical improvement was assessed since week 12 (PASI: 12.4±4.2; BSA: 16.5±7.3), continuing to week 24 (PASI: 4.2±2.8; BSA: 6.1±3.1) and 36 (PASI: 3.6±3.2; BSA: 4.2±1.37). Clinical improvement was accompanied by an improvement in quality of life at week 16 (DLQI: 15.5±2.9; Skindex-16: 28.2±4.2; p-VAS: 3.8) , 24 (DLQI: 8.2±1.4, Skindex-16: 16.2; p-VAS: 2.6) and 36 (DLQI: 3.1±2.4; Skindex-16: 9.3±2.8; p-VAS: 2.8). Our study also confirmed the safety of tildrakizumab in real life settings, with no treatment discontinuation for inefficacy or adverse events reported during the study. our results confirm tildrakizumab as an effective option for the improvement of psoriasis patients' HRQoL.

Post-marketing safety of tralokinumab: a real-world pharmacovigilance study based on the FDA adverse event reporting system

ABSTRACT Background Tralokinumab is a fully human IgG4 monoclonal antibody targeting IL-13, used for treating atopic dermatitis. This study analyzed tralokinumab-related adverse drug events by mining the Food and Drug Administration Adverse Event Reporting System (FAERS) database to provide a safety reference for clinical application. Methods Adverse drug event reports from Q1 2022 to Q2 2024 were extracted from the FAERS database. After standardizing the data, various signal detection methods were used for analysis, including ROR, PRR, BCPNN, and MGPS. Results A total of 1,820 reports of adverse events (AEs) with tralokinumab as the primary suspected drug were identified. 70 preferred terms (PTs) met the criteria across four signal detection methods, involving 11 system organ classes (SOCs). These included known adverse reactions like conjunctivitis and injection site reactions, and signals not previously reported in clinical trials, such as eye pruritus, dry eye, eye swelling, pneumonia pneumococcal, and cutaneous T-cell lymphoma. Most AEs occurred within one month of initiating tralokinumab treatment. Conclusions Based on the FAERS database, this study comprehensively and systematically analyzed AE signals in tralokinumab treatment. The results enhance the understanding of tralokinumab’s safety and serve as valuable references for reducing the risk of adverse reactions during clinical use.

Efficacy and Safety of Inebilizumab, an Anti-CD19 Monoclonal Antibody, for the Treatment of Neuromyelitis Optica Spectrum Disorder: Based on the N-MOmentum Trial

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathic disease of the central nervous system characterized by severe optic neuritis and transverse myelitis. The antibody against aquaporin 4 (AQP4), a water channel mainly expressed in astrocytes, is specific to NMOSD and may be detected in >70% of all cases. Inebilizumab is a humanized IgG1 monoclonal antibody against CD19. Anti-AQP4 antibodies are produced by CD19-positive plasmablasts, and inebilizumab administration significantly reduces the number of CD19-positive B cells and has therapeutic effects on NMOSD. The efficacy and safety of inebilizumab have been verified in the N-MOmentum trial, an international double-blind, placebo-controlled phase II/III study, in which Japanese patients also participated. Inebilizumab was approved for the treatment of NMOSD with AQP4-IgG in Japan in March 2021. In this review, we summarize the efficacy and safety of inebilizumab in the treatment of NMOSD and, focus on findings from the primary and additional analyses of the N-MOmentum trial. These results suggest that inebilizumab is effective and safe in preventing the recurrence of NMOSD in populations with different backgrounds and that long-term treatment with inebilizumab is beneficial.

Phase I–II study of OBI-888, a humanized monoclonal IgG1 antibody against the tumor-associated carbohydrate antigen Globo H, in patients with advanced solid tumors

Phase I–II study of OBI-888, a humanized monoclonal IgG1 antibody against the tumor-associated carbohydrate antigen Globo H, in patients with advanced solid tumors

Population Pharmacokinetics of Xeligekimab: An Anti-IL-17A Monoclonal Antibody, in Patients with Moderate to Severe Plaque Psoriasis.

Xeligekimab, a recombinant fully human IgG4 monoclonal antibody, has been strategically developed to target IL-17A and is presently in the developmental phase for treating moderate to severe plaque psoriasis. This study aims to investigate the pharmacokinetic profile of Xeligekimab, utilizing data derived from clinical trials specifically conducted in Chinese patients. The study conducted a population pharmacokinetic (PopPK) analysis involving 614 patients with plaque psoriasis. Examined covariates encompassed demographics, baseline laboratory tests, anti-drug antibodies (ADA), injection site, and disease-related baseline characteristics. Model evaluation utilized goodness-of-fit, prediction-corrected visual prediction check, and bootstrap methods. The clinical significance of covariates statistically associated with Xeligekimab was assessed through simulation analysis. The PopPK model of Xeligekimab demonstrated characteristics of a two-compartment model with first-order absorption and linear elimination. Inter-individual variability (IIV) was estimated for clearance and volume of distribution. For a typical plaque psoriasis patient, the estimated values for absorption rate constant (Ka), apparent clearance (CL/F), central compartment volume (Vc/F), peripheral compartment volume (Vp/F), and inter-compartmental clearance (Q/F) was 0.225 per day, 2.223 L/day, 4.02 L, 4.13 L, and 1.11 L/day, respectively. The estimated IIV for CL/F and Vc/F was 25.8% and 49.8%, respectively. The elimination half-life (t1/2) was approximately 28.5 days. CL/F was significantly influenced by factors such as body weight, age, gender, and baseline total protein. Vc/F was significantly influenced by body weight, age, gender, and baseline albumin. However, the clinical relevance of these covariate effects on exposure parameters was determined to be limited.

Advances in Understanding and Managing Alzheimer's Disease: From Pathophysiology to Innovative Therapeutic Strategies.

Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by the presence of amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles, leading to cognitive and physical decline. Representing the majority of dementia cases, AD poses a significant burden on healthcare systems globally, with onset typically occurring after the age of 65. While most cases are sporadic, about 10% exhibit autosomal forms associated with specific gene mutations. Neurofibrillary tangles and Aβ plaques formed by misfolded tau proteins and Aβ peptides contribute to neuronal damage and cognitive impairment. Currently, approved drugs, such as acetylcholinesterase inhibitors and N-methyl D-aspartate receptor agonists, offer only partial symptomatic relief without altering disease progression. A promising development is using lecanemab, a humanized IgG1 monoclonal antibody, as an immune therapeutic approach. Lecanemab demonstrates selectivity for polymorphic Aβ variants and binds to large soluble Aβ aggregates, providing a potential avenue for targeted treatment. This shift in understanding the role of the adaptive immune response in AD pathogenesis opens new possibilities for therapeutic interventions aiming to address the disease's intricate mechanisms. This review aims to summarize recent advancements in understanding Alzheimer's disease pathophysiology and innovative therapeutic approaches, providing valuable insights for both researchers and clinicians.

A Randomized Placebo-Controlled Trial of Leronlimab in Mild-To-Moderate COVID-19

PurposeEarly in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19. MethodsThe TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14). FindingsOverall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%). ImplicationsAt the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.ClinicalTrials.gov number, NCT04343651 https://classic.clinicaltrials.gov/ct2/show/NCT04343651

The KEYVIBE program: vibostolimab and pembrolizumab for the treatment of advanced malignancies.

Vibostolimab, a humanized IgG1 monoclonal antibody, blocks the interaction between TIGITand its ligands, preventing the immunosuppressive effects of TIGIT. The addition of vibostolimab to the PD-1 inhibitor pembrolizumab has shown promising antitumor activity, warranting further exploration of vibostolimab as a potential therapeutic option. The KEYVIBE program consists of nine trials that will evaluate the safety and efficacy of vibostolimab monotherapy and vibostolimab-based combination therapy in advanced solid tumors and hematological malignancies. These studies will also evaluate coformulated immunotherapy addressing issues that occur with the sequential administration of immunotherapy. The KEYVIBE program will provide further insight into the clinical utility of vibostolimab-based therapy across multiple indications and various stages of disease.

Efficacy and safety of bintrafusp alfa in 2 phase I expansion cohorts with advanced HCC.

Simultaneous inhibition of the TGF-β and programmed cell death 1 ligand 1 pathways provides a potential novel treatment approach. Bintrafusp alfa, a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII (a TGF-β "trap") fused to a human IgG1 monoclonal antibody blocking programmed cell death 1 ligand 1, was evaluated in patients with advanced HCC. In this global, open-label, phase I study (NCT02517398), patients with programmed cell death 1 ligand 1-unselected HCC who failed or were intolerant to ≥1 line of sorafenib received bintrafusp alfa 1200mg every 2 weeks in a dose-escalation (n = 38) or dose-expansion (n = 68) cohort until confirmed progression, unacceptable toxicity, or trial withdrawal. The primary endpoint was the best overall response per Response Evaluation Criteria in Solid Tumors version 1.1 by an independent review committee. Secondary endpoints included investigator-assessed best overall response, safety, and pharmacokinetics. Median follow-up times (range) were 41.4 (39.8-44.2) and 38.6 (33.5-39.7) months in the dose-escalation and dose-expansion cohorts, respectively. The objective response rate was below the prespecified 20% objective response rate threshold set to evaluate the efficacy of bintrafusp alfa in both cohorts (10.5% and 8.8%, respectively). Median overall survival and progression-free survival, respectively, were 13.8 and 1.5 months in the dose-escalation cohort and 13.5 and 1.4 months in the dose-expansion cohort. Treatment-related adverse events occurred in 78.9% and 64.7% of patients in the respective cohorts (grade ≥3 in 18.4% and 25.0% of patients). Bintrafusp alfa showed moderate clinical activity and a safety profile consistent with previous studies of bintrafusp alfa in patients with advanced HCC.

Updated efficacy of anti-TROP2 ADC ESG401 for first-line metastatic TNBC in phase 1b study.

2 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to SN-38, with a Drug-Antibody Ratio of 8 and a stable cleavable linker, demonstrated preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report presents updated results from the first-line mTNBC cohort of the Phase Ib trial and results from patients with brain metastases. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Apr 7th, 2024), 24 pts in the cohort received ≥1 dose of ESG401. Median age was 53 years (range: 33-73), 33.3% were ECOG 0, 25.0% were de novo stage IV, 70.8% had visceral disease (8.3% brain, 33.3% liver, 50.0% lung). Updated efficacy results are shown in the Table. Thirteen pts (68.4% of 19 efficacy evaluable pts) remained on treatment, with the longest on-treatment duration being 10.3 mons. Median PFS has not been reached. Two pts in this cohort had brain metastases, with one achieving a complete intracranial response and an overall response of PR, and the other demonstrating overall PR with a -13.8% reduction in brain lesion size. Totally 16 pts with brain metastases were enrolled in the entire Phase Ia/1b trials, for these pts, the best overall intracranial response rate was 31%, with an intracranial disease control rate of 75%, while the corresponding overall response rate and disease control rate were 50% and 69%, respectively. The response of intracranial lesions to the treatment is consistent with that of extracranial lesions. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. Conclusions: ESG401 monotherapy demonstrates promising antitumor activity in 1L mTNBC pts, characterized by a high response rate and durable response. The ORR numerically exceeded that reported in the BEGONIA Study arm 7 in which pts with the same indication were treated with TROP-2 ADC and PD-L1 combination therapy. Additionally, ESG401 shows clear potential for treating HER2-negative breast cancer with brain metastases, including mTNBC and HR+/HER2- BC. These results support further clinical investigation of ESG401. Clinical trial information: NCT04892342 . [Table: see text]

Pembrolizumab related perforated appendicitis.

Pembrolizumab is a humanized monoclonal antibody IgG4 programmed cell death protein 1 antagonist, and its use in oncology has been increasing in recent years, providing durable and favorable responses and tolerable toxicity profiles in various types of cancer. We describe a case of pembrolizumab related perforated appendicitis in a patient with stage 3C malignant melanoma (MM). A 70-year-old male patient who had no known disease was diagnosed with MM as a result of the excision of the mass on his right shoulder. The disease stage was stage 3C (pT4aN1bM0). Subsequently, adjuvant pembrolizumab treatment was started. A few days after the fourth maintenance course, he presented to the emergency department complaining of abdominal pain, nausea and vomiting. Emergency abdominal tomography showed a significant increase in the diameter of the appendix vermiformis, peritoneal thickening and appendiceal wall defects that could be significant in terms of perforation. The mentioned finding and given the clinical presentation, was attributed to a perporating of the appendix, so the patient was hospitalized in the Department of Surgery and the patient underwent emergency appendectomy. Histological findings were consistent with appendicitis. After a day in the hospital, the abdominal pain subsided, C-reactive protein tended to decrease and the patient was discharged. In patients who develop acute abdominal pain with or without diarrhea during immunotherapy, urgent imaging, endoscopic and clinical evaluation should be performed, and bowel perforation, although rare, should be considered as a potential complication of any immunotherapy.

Analysis of the diverse antigenic landscape of the malaria protein RH5 identifies a potent vaccine-induced human public antibody clonotype

The highly conserved and essential Plasmodium falciparum reticulocyte-binding protein homolog 5 (PfRH5) has emerged as the leading target for vaccines against the disease-causing blood stage of malaria. However, the features of the human vaccine-induced antibody response that confer highly potent inhibition of malaria parasite invasion into red blood cells are not well defined. Here, we characterize 236 human IgG monoclonal antibodies, derived from 15 donors, induced by the most advanced PfRH5 vaccine. We define the antigenic landscape of this molecule and establish that epitope specificity, antibody association rate, and intra-PfRH5 antibody interactions are key determinants of functional anti-parasitic potency. In addition, we identify a germline IgG gene combination that results in an exceptionally potent class of antibody and demonstrate its prophylactic potential to protect against P.falciparum parasite challenge invivo. This comprehensive dataset provides a framework to guide rational design of next-generation vaccines and prophylactic antibodies to protect against blood-stage malaria.

Adopting adalimumab combined surgery in the management of moderate to severe hidradenitis suppurativa: Experience from a single medical center in southern Taiwan.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder primarily affecting the intertriginous and anogenital regions. Guidelines recommend various treatments for HS, including biologic agents like adalimumab for moderate to severe cases. Adalimumab is a type of human monoclonal IgG1 antibody designed to target tumor necrosis factor α. Recent studies have shown the effectiveness of adalimumab, either alone or combined with surgery, in managing HS. We retrospectively analyzed the medical chart of HS patients in a southern Taiwan medical center from 2019 to 2022 and investigated clinical features and treatment response. The institutional review board at Chang Gung Medical Foundation granted approval for the study. We primarily focused on moderate to severely affected patients. One hundred and two clinically diagnosed HS patients participated, with a male-to-female ratio of 2:1 and an average age of 31.8 at diagnosis. Among them, 41.2% were in Hurley stage III and 32.4% in stage II. Nineteen patients received excision with pre-surgical adalimumab; their average age at diagnosis was 31.1, with a gender ratio of 5.3:1. Surgery was most common on the buttocks (68%), axillae (21%), and groin (10%). Excision patients were primarily in advanced stages (Hurley III 94.7%, II 5.3%) with high body mass index. Adalimumab and surgery combined yielded a 68.4% improvement rate, while 15.8% remained stable and 15.8% did not respond as expected. In addition, smoking and obesity were prevalent among patients. Adalimumab showed promising results in moderate to severe HS, with significant improvement observed in our cases. The combination of adalimumab and surgery appeared effective in advanced HS patients with larger involved areas and more tunnels. No severe adverse events were reported. However, our study was limited by its retrospective nature and the lack of a control group. Despite these limitations, our study revealed the benefits of integrating adalimumab with suitable surgical procedures in managing patients experiencing moderate to severe HS in real-world scenarios.

Pharmacokinetics of Briquilimab as a Conditioning Agent for Hematopoietic Stem Cell Transplantation in Patients With Severe Combined Immunodeficiency, Myelodysplastic Syndrome, or Acute Myeloid Leukemia

For successful engraftment of donor hematopoietic stem cells (HSC), conditioning with chemotherapy and/or radiation prior to hematopoietic cell transplantation (HCT) has been required to open marrow niche space and minimize the risk of immune rejection. Briquilimab, a humanized IgG1 monoclonal antibody that blocks the interaction between the c-Kit receptor and stem cell factor on various C-Kit expressing tissues including HSC, is a potential nonmyeloablative conditioning agent in clinical development for patients with severe combined immunodeficiency (SCID), myelodysplastic syndromes (MDS), and acute myeloid leukemia (AML). This study aimed to characterize pharmacokinetics (PK) and develop a population PK model of briquilimab after single intravenous infusions of 4 different doses in patients with SCID, MDS, or AML receiving HCT. The PK data was collected from 2 different studies: JAS-BMT-CP-001 and JSP-CP-003. JAS-BMT-CP-001 is a phase 1/2 open-label study of briquilimab as a conditioning agent prior to allogenic HCT in SCID patients. The participants received single intravenous infusions of 0.1, 0.3, 0.6, or 1.0 mg/kg. JSP-CP-003 was a phase 1a/b open-label study of briquilimab in combination with a standard conditioning regimen of low dose total body irradiation and fludarabine in MDS or AML subjects undergoing HCT. The participants received a single intravenous dose of 0.6 mg/kg briquilimab. In both studies, briquilimab PK samples were obtained at pre-treatment, 5 minutes post-end of infusion, 4- and 24-hours post-start of infusion, any time between 2 days and 30 days postinfusion, and on the day of HCT prior to donor cell infusion.The population PK model was developed using the PK data from these 2 clinical studies, and the effect of participants’ baseline characteristics on the briquilimab PK was evaluated. PK simulations were performed using the developed PK model to calculate the time to reach target concentrations for HCT. A total of 49 participants (21 SCID adult and pediatric participants with a median age of 12 yr and 28 MDS/AML adult participants with a median age of 70 yr) were included in the PK analysis. A 2-compartment model with combined linear and non-linear elimination best described the PK of briquilimab. Body weight was determined as the sole covariate of the PK parameters among the explored covariates. For a typical subject with a body weight 70 kg, the estimated parameters for clearance, maximum metabolic rate of Michaelis Menten elimination, Michaelis Menten constant, central volume, peripheral volume, and intercompartmental clearance were 17.6 mL/h, 51,434.8 ng/h, 71.5 ng/mL, 3444.0 mL, 1613.3 mL, and 21.2 mL/h, respectively. The median time to reach target concentrations of 500, 1000, and 2000 ng/mL after a single dose of 0.6 mg/kg was calculated as 12.3, 10.4, and 7.7 days, respectively. The PK of intravenous briquilimab was characterized in subjects with SCID, MDS, or AML receiving HCT, and a population PK model was developed to estimate briquilimab clearance to use as a guide to the timing of donor cell infusion post-briquilimab. Body weight was identified as a significant covariate on elimination and volume of distribution of briquilimab.

A rapid and novel quantitative determination of Lecanemab monoclonal antibody for Alzheimer’s disease using reverse phase ultra performance liquid chromatography

A novel humanized IgG1 monoclonal antibody known as Lecanemab is used to treat Alzheimer’s disease. Utilizing the RP-UPLC technique, the current investigation aims to develop a robust, stable and rapid method for determining Lecanemab. By applying this method, the ultimate chromatographic conditions were obtained using a BEH C8 (1.7 μm, 2.1 x 100 mm) and a mobile phase prepared with acetonitrile and formic acid buffer in a 7: 3 ratio, respectively (1.0 mL of formic acid diluted in 1 liter of HPLC-grade water), by means of adopting isocratic elution. Detection limit (LOD) and quantitation limit (LOQ) were 0.30 and 1.00 μg/mL, respectively, and linearity (R2 = 0.999) was demonstrated in the range of 25-150 μg/mL of working concentration with PDA detection at 219 nm. The results of the forced degradation investigation also make it evidently visible; the drug’s degradation products could be separated from the main peak, assuring the effectiveness of the stability-indicating method. Thus, routine analysis and stability studies favor of enormously from the use of this method of analysis.

Safety and efficacy of burosumab in improving phosphate metabolism, bone health, and quality of life in adolescents with X-linked hypophosphatemic rickets

Background and objectiveX-linked hypophosphatemic rickets (XLH) is due to loss-of-function mutations in the phosphate-regulating endopeptidase homologue on the X chromosome (PHEX) that lead to increased fibroblast growth factor 23 (FGF23) production. FGF23 excess causes renal phosphate wasting and insufficient 1,25-dihydroxyvitamin D (1,25(OH)2D) synthesis with reduced intestinal phosphate absorption, ultimately resulting in chronic hypophosphatemia.Children with XLH show typical skeletal lesions of rickets, deformities of the lower limbs, stunted growth with disproportionate short stature, bone pain, and physical dysfunctions.Burosumab, a fully human IgG1 monoclonal antibody that binds to FGF23 to inhibit its activity, is more effective to improve the biochemical and clinical signs of XLH than conventional treatment with phosphate supplements and vitamin D active metabolites. Data on adolescents with XLH during the transition period to young adulthood are few.In this prospective case series, we aimed to assess safety and efficacy of burosumab in adolescents with XLH who discontinued long-term conventional therapy. MethodsFive Caucasian adolescents (4 males, 1 female; mean age 15.4 ± 1.5 years) with XLH were recruited and switched from conventional treatment to burosumab (0.8–1.2 mg/kg, s. c. QW2). Burosumab was continued for 12–48 months and, once discontinued, patients were followed-up for 6–12 months. In all patients, serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and 1,25(OH)2D levels, and renal tubular reabsorption of phosphate (TmP/GFR) values were assessed at entry and during burosumab. Intact FGF23 plasma levels were measured at entry. Patient-reported outcomes (PROs) were assessed at entry and every 3–6 months to evaluate the impact of low extremity pain, stiffness, and difficulties performing daily activities. ResultsAt entry, all patients showed hypophosphatemia, increased intact FGF23 levels, reduced TmP/GFR, insufficient 1,25(OH)2D levels, and in four out of five increased ALP levels. Two patients had radiological signs of rickets. During burosumab, all patients showed a significant increase in serum phosphate and 1,25(OH)2D levels, and in TmP/GFR values (P < 0.05 - P < 0.0001). Serum ALP levels significantly declined (P < 0.05) to normal values. No changes of serum calcium and PTH levels (PNS) were found during burosumab. PROs significantly improved (P < 0.02 - P < 0.0001) in all patients. Four patients discontinued burosumab when they turned 18 or 19, whereas one continued the treatment since he was still younger than 18 during the study period. Four patients who suspended burosumab showed a rapid decline in serum phosphate and 1,25(OH)2D levels and in TmP/GFR values; serum ALP levels increased, and PROs progressively worsened with a significant reduction in quality of life. These consequences were not observed in the patient who continued burosumab treatment. DiscussionOur data showed that conventional treatment improved only in part the signs and symptoms of XLH. Burosumab was well tolerated and was effective in improving phosphate metabolism, bone health, and PROs. All the benefits of burosumab were lost after its discontinuation. These results suggested that continuing burosumab is required to achieve and maintain the clinical benefits of the treatment during the transition to young adulthood in patients with XLH.

Construction of [89Zr]Zr-Labeled HuL13 for ImmunoPET Imaging of LAG-3 Checkpoint Expression on Tumor-Infiltrating T Cells.

Lymphocyte activation gene 3 (LAG-3) has attracted much attention as a potentially valuable immune checkpoint. Individual identification of LAG-3 expression at screening and during treatment could improve the successful implementation of anti-LAG-3 therapies. HuL13 is a human IgG1 monoclonal antibody that binds to the LAG-3 receptor in T cells. Here, we used [89Zr]Zr-labeled HuL13 to delineate LAG-3+ T-cell infiltration into tumors via positron emission tomography (PET) imaging. A549/LAG-3 cells, which stably express LAG-3, were generated by infection with lentivirus. The uptake of [89Zr]Zr-DFO-HuL13 in A549/LAG-3 cells was greater than that in the negative control (A549/NC) cells at each time point. The equilibrium dissociation constant (Kd) of [89Zr]Zr-DFO-HuL13 for the LAG-3 receptor was 8.22 nM. PET imaging revealed significant uptake in the tumor areas of A549/LAG-3 tumor-bearing mice from 24 h after injection (SUVmax = 2.43 ± 0.06 at 24 h). As a proof of concept, PET imaging of the [89Zr]Zr-DFO-HuL13 tracer was further investigated in an MC38 tumor-bearing humanized LAG-3 mouse model. PET imaging revealed that the [89Zr]Zr-DFO-HuL13 tracer specifically targets human LAG-3 expressed on tumor-infiltrating lymphocytes (TILs). In addition to the tumors, the spleen was also noticeably visible. Tumor uptake of the [89Zr]Zr-DFO-HuL13 tracer was lower than its uptake in the spleen, but high uptake in the spleen could be reduced by coinjection of unlabeled antibodies. Coinjection of unlabeled antibodies increases tracer activity in the blood pool, thereby improving tumor uptake. Dosimetry evaluation of the healthy mouse models revealed that the highest absorbed radiation dose was in the spleen, followed by the liver and heart wall. In summary, these studies demonstrate the feasibility of using the [89Zr]Zr-DFO-HuL13 tracer for the detection of LAG-3 expression on TILs. Further clinical evaluation of the [89Zr]Zr-DFO-HuL13 tracer may be of significant help in the stratification and management of patients suitable for anti-LAG-3 therapy.

A phase 2 study of spartalizumab (PDR001) among patients with recurrent or metastatic esophageal squamous cell carcinoma (KCSG HN18-17, K-MASTER project 12)

ABSTRACT Spartalizumab (PDR001) is a humanized IgG4 monoclonal antibody targeting programmed cell death protein 1 (PD-1). We conducted a single-arm, phase 2 trial to investigate the efficacy and safety of spartalizumab in patients with refractory esophageal squamous cell carcinoma (ESCC). Patients with histologically confirmed ESCC who experienced disease progression after platinum-based chemotherapy received 300 mg of intravenous spartalizumab every three weeks until disease progression or occurrence of unacceptable toxicity. The primary endpoint was centrally assessed objective response according to the Response Evaluation Criteria in Solid Tumors, version 1.1. Adverse events were closely monitored throughout the study. From March 2020 through April 2021, 44 patients with ESCC were enrolled. Of the 44 patients, the objective response rate was 20.5% (95% confidence interval: 8.5–32.4). With a median follow-up of 10.9 months, median progression-free survival and overall survival were 3.2 months and 11.2 months, respectively. In addition, the median duration of response was 24.7 months. The most common grade 3 or 4 adverse event was grade 3 dysphagia (eight [18%] patients). Biomarker analyses explored programmed cell death ligand 1 and CD20 as potential predictive markers for PD-1 blockade. Spartalizumab showed promising activity with a manageable safety profile, indicating its potential as a new treatment option for patients with refractory ESCC. Trial registration The trial was registered at ClinicalTrials.gov under the identifier NCT03785496.

Implications of therapy interruption on monthly migraine days and modified migraine disability assessment in patients treated with erenumab for chronic and episodic migraine: SQUARE study interim results

BackgroundThere are limited real-world data in Switzerland examining the impact of erenumab, a fully human IgG2 monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) receptor, on migraine-related quality of life.ObjectiveThis 18-month interim analysis of 172 patients with episodic or chronic migraine from the SQUARE study provides first prospective insights on the impact of mandatory erenumab treatment interruption, following Swiss-reimbursement requirements, in a real-world clinical setting in Switzerland.FindingsRecruited patients receiving 70 or 140 mg erenumab underwent treatment interruption on average 11.2 months after therapy onset with a mean duration of 4 months. There were sustained improvements in mean monthly migraine days (MMD) and migraine disability (mMIDAS) during initial treatment with erenumab. Treatment interruption was associated with a temporary worsening of condition. Symptoms ameliorated upon therapy reuptake reaching improvements similar to pre-break within 3 months.ConclusionsTreatment interruption was associated with a temporary worsening of condition, which improved again after therapy restart.