Biology subjects

Burden, S. J.

Publications and source records attributed to Burden, S. J..

4 recordsLinked to original sources

bioRxiv2024

ARGX-119, a therapeutic agonist antibody targeting MuSK

ARGX-119 is a novel, humanized, agonist monoclonal SIMPLE Antibody specific for muscle-specific kinase (MuSK) that is being developed for treatment of patients with neuromuscular diseases. ARGX-119 is the first monoclonal antibody (mAb) that binds with high affinity to the Frizzled-like domain of human, non-human primate, rat and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc-region, ARGX-119 harbors L234A, L235A mutations to diminish potential immune-activating effector functions. Its mode-of-action is to activate MuSK without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors (AChRs) in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model for DOK7 congenital myasthenia (CM), ARGX-119 prevented early postnatal lethality and reversed disease relapse by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic (PK) studies in non-human primates, rats and mice revealed non-linear PK behavior of ARGX-119, indicative of target-mediated-drug disposition (TMDD) and in vivo target engagement. Instability of neuromuscular synapses contributes to symptoms in many neuromuscular diseases for example congenital myasthenia (CM), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). ARGX-119 is a novel, first-in-class MuSK agonist mAb in clinical development. Based on this proof-of-concept study, it has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function. One sentence summaryARGX-119 is a novel first-in-class MuSK agonist monoclonal antibody in clinical development for treatment of neuromuscular diseases.

neuroscience↗

bioRxiv2020

Self-antigen driven affinity maturation is required for pathogenic monovalent IgG4 autoantibody development

Pathogenic IgG4 autoantibodies in autoimmune myasthenia gravis (MG) are functionally monovalent as a result of Fab-arm exchange. The origin and development of these unique autoantibodies are not well understood. We examined MG patient-derived monoclonal autoantibodies (mAbs), their corresponding germline-encoded unmutated common ancestors (UCA) and monovalent antigen-binding fragments (Fabs) to investigate how antigen-driven affinity maturation contributes to both binding and immunopathology. Mature mAbs, their UCA counterparts and mature monovalent Fabs bound to the autoantigen and retained their pathogenic capacity. However, monovalent UCA Fabs still bound the autoantigen but lost their pathogenic capacity. The mature Fabs were characterized by very high affinity (sub-nanomolar) driven by a rapid on-rate and slow off-rate. However, the UCA affinity was approximately 100-fold less than that of the mature Fabs, which was driven by a rapid off-rate. Crystal structures of two Fabs shed light on how mutations acquired during affinity maturation may contribute to increased MuSK binding affinity. These collective findings indicate that the autoantigen initiates the autoimmune response in MuSK MG and drives autoimmunity through the accumulation of somatic hypermutation such that monovalent IgG4 Fab-arm exchanged MG autoantibodies reach a high affinity threshold required for pathogenic capacity. SummaryIgG4 autoantibodies in autoimmune myasthenia gravis are functionally monovalent, requiring a high affinity threshold featuring fast on/slow off rates, to reach pathogenic capacity. This capacity is dependent on self-antigen initiated and driven maturation, which includes the accumulation of indispensable somatic hypermutations that may alter electrostatic interactions with the antigen.

immunology↗

bioRxiv2019

Universal assay for measuring vertebrate telomeres by real-time quantitative PCR

Telomere length dynamics are an established biomarker of health and aging in animals. The study of telomeres in numerous species has been facilitated by methods to measure telomere length by real-time quantitative PCR (qPCR). In this method, telomere length is determined by quantifying the amount of telomeric DNA repeats in a sample and normalizing this to the total amount of genomic DNA. This normalization requires the development of genomic reference primers suitable for qPCR, which remains challenging in non-model organism with genomes that have not been sequenced. Here we report reference primers that can be used in qPCR to measure telomere lengths in any vertebrate species. We designed primer pairs to amplify genetic elements that are highly conserved between evolutionarily distant taxa and tested them in species that span the vertebrate tree of life. We report five primer pairs that meet the specificity and reproducibility standards of qPCR. In addition, we demonstrate how to choose the best primers for a given species by testing the primers on multiple individuals within a species and applying an established computational tool. These reference primers can facilitate the application of qPCR-based telomere length measurements in any vertebrate species of ecological or economic interest.

molecular biology↗

bioRxiv2017

Abelson tyrosine-protein kinase 2 Regulates Myoblast Proliferation and Controls Muscle Fiber Length

Muscle fiber length is nearly uniform within a muscle but widely different among muscles. Here, we show that Abelson tyrosine-protein kinase 2 (Abl2) has a key role in regulating myofiber length, as a loss of Abl2 leads to excessively long myofibers in the diaphragm and other muscles. Increased myofiber length is caused by enhanced myoblast proliferation, expanding the pool of available myoblasts and leading to increased myoblast fusion. Abl2 acts in myoblasts, but expansion of the diaphragm muscle causes a reduction in size of the diaphragm central tendon. Replacement of tendon for muscle is likely responsible for the reduced stamina of abl2 mutant mice. Further, ectopic muscle islands, each composed of myofibers of uniform length and orientation, form within the central tendon in abl2+/- mice. Induction of scleraxis in tendon cells at the ends of these muscle islands suggests that myofibers stimulate tendon differentiation, which in turn regulates myofiber length.

developmental biology↗