Regeneron Pharmaceuticals, Inc. is an American biotechnology company headquartered in Tarrytown, New York. The company was founded in 1988. Originally focused on neurotrophic factors and their regenerative capabilities (thus the name), it branched out into the study of both cytokine and tyrosine kinase receptors.
Camptothecin (CPT)-based antibody-drug conjugates (ADCs) have become popular oncology biotherapeutics that integrate the targeted specificity of monoclonal antibodies (mAbs) with camptothecin and its derivatives. Because mAbs are vulnerable to photodegradation and the light-absorbing characteristics of camptothecin, understanding the effects of light exposure on CPT-based ADCs is critical to ensure product quality, efficacy, and safety. Herein, we harnessed the capabilities of advanced liquid chromatography-mass spectrometry (LC-MS) to perform in-depth molecular-level characterization of photo-stressed antibodies conjugated with a camptothecin derivative payload, deruxtecan (DXd). Peptide mapping via LC-MS/MS revealed significant oxidative modifications in methionine, tryptophan, and histidine residues, and degradation of the linker payload in the photo-stressed ADC molecules. Native SEC-MS with post-column denaturation was conducted to further characterize the covalent nature of high molecular weight species formed under photo stress and provide insights into aggregation mechanisms. Additionally, coupling LC to high-resolution MS enabled the identification and quantitation of degradants from excipients and the linker payload, thus providing a comprehensive understanding of light exposure effects on DXd ADCs. Application of these LC-MS based assays to evaluate the effects of various formulations on photostability revealed that histidine and methionine act as oxidative scavengers that protect ADC molecules against light-induced degradation. This study highlights the utility of LC-MS methods in the comprehensive characterization of photo-stressed CPT-based ADCs, and provides valuable insights for process optimization, formulation development, and storage condition recommendations.
Oligonucleotide therapeutics (ONTs) have emerged as a transformative treatment modality with numerous products approved globally for addressing a variety of diseases. Within this class, siRNAs therapeutics have achieved remarkable success, with eight approvals to date. siRNA therapeutics are short double-stranded RNAs designed to hybridize with complementary mRNA sequences and regulate disease-related protein expression through endogenous RNA interference (RNAi) mechanism. This manuscript outlines a framework of immunogenicity risk assessment for siRNA therapeutics, discusses the challenges associated with anti-drug antibody (ADA) assay development, and reviews available immunogenicity data from both approved and investigational GalNAc-siRNA therapeutics. Across clinical development programs, GalNAc- conjugated siRNA therapeutics have demonstrated a low immunogenicity risk profile, supported by comprehensive immunogenicity risk assessment and accumulated clinical data. Reported treatment-emergent ADA response has been generally low (≤ 6
Coexisting type 2 inflammatory diseases such as allergic rhinitis (AR), atopic dermatitis (AD), chronic rhinosinusitis (CRS) and/or nasal polyposis (NP), eosinophilic esophagitis (EoE), and urticaria are common in asthma. RAPID (NCT04287621), a global prospective registry, aimed to characterize patients with asthma initiating dupilumab in a real-world clinical setting. This analysis investigated the prevalence of coexisting type 2 inflammatory diseases in these patients. Patients aged ≥ 12 years initiating dupilumab for asthma (primary indication) according to country-specific prescribing information were enrolled in RAPID. Patients had regular assessments at 1 month and thereafter every 3 months for up to 3 years, per standard of care across study sites. At the time of analysis, 205 patients were enrolled. Mean age of patients (stratified by type 2 coexisting disease) ranged from 42.3 to 57.3 years and mean body mass index from 29.9 to 31.8 kg/m2. Most patients were female (67.3
In pooled LIBERTY-PN PRIME/PRIME2 trials on prurigo nodularis (PN), at week 24, the stringent composite endpoint of a ≥ 4-point reduction from baseline in Worst Itch Numeric Rating Scale (WI-NRS) score combined with an Investigator’s Global Assessment for PN-Stage (IGA PN-S) score of 0/1 (clear/almost clear skin) was achieved by 35.3
Crohn’s disease is an inflammatory bowel disease (IBD) commonly treated through anti-TNF blockade. However, most patients still relapse and inevitably progress. Comprehensive single-cell RNA-sequencing (scRNA-seq) atlases have largely sampled patients with established treatment-refractory IBD, limiting our understanding of which cell types, subsets, and states at diagnosis anticipate disease severity and response to treatment. Here, through combining clinical, flow cytometry, histology, and scRNA-seq methods, we profile diagnostic human biopsies from the terminal ileum of treatment-naïve pediatric patients with Crohn’s disease (pediCD; n=14), matched repeat biopsies (pediCD-treated; n=8) and from non-inflamed pediatric controls with functional gastrointestinal disorders (FGID; n=13). To resolve and annotate epithelial, stromal, and immune cell states among the 201,883 baseline single-cell transcriptomes, we develop a principled and unbiased tiered clustering approach, ARBOL. Through flow cytometry and scRNA-seq, we observe that treatment-naïve pediCD and FGID have similar broad cell type composition. However, through high-resolution scRNA-seq analysis and microscopy, we identify significant differences in cell subsets and states that arise during pediCD relative to FGID. By closely linking our scRNA-seq analysis with clinical meta-data, we resolve a vector of T cell, innate lymphocyte, myeloid, and epithelial cell states in treatment-naïve pediCD (pediCD-TIME) samples which can distinguish patients along the trajectory of disease severity and anti-TNF response. By using ARBOL with integration, we position repeat on-treatment biopsies from our patients between treatment-naïve pediCD and on-treatment adult CD. We identify that anti-TNF treatment pushes the pediatric cellular ecosystem towards an adult, more treatment-refractory state. Our study jointly leverages a treatment-naïve cohort, high-resolution principled scRNA-seq data analysis, and clinical outcomes to understand which baseline cell states may predict Crohn’s disease trajectory.
