Abstract:
:Pathogenic immunoglobulin G (IgG) autoantibodies characterize some human autoimmune diseases; their high concentration and long half-life are dependent on recycling by the neonatal Fc receptor (FcRn). Inhibition of FcRn is an attractive new treatment concept for IgG-mediated autoimmune diseases. Rozanolixizumab (UCB7665; CA170_01519.g57 IgG4P) is an anti-human FcRn monoclonal antibody. In cynomolgus monkeys, rozanolixizumab reduced IgG (maximum 75 to 90% by about day 10), was well tolerated, and did not increase risk of infection. We also report a first-in-human, randomized, double-blind, placebo-controlled, dose-escalating study of intravenous (IV) or subcutaneous (SC) rozanolixizumab in healthy subjects (NCT02220153). The primary objective was to evaluate safety and tolerability. Secondary objectives were assessment of rozanolixizumab pharmacokinetics and pharmacodynamics, including effects on circulating IgG concentrations. Forty-nine subjects were randomized to receive rozanolixizumab (n = 36) or placebo (n = 13) across six cohorts. The first three cohorts received IV doses, and the subsequent three cohorts received SC doses, of rozanolixizumab 1, 4, or 7 mg/kg (n = 6 for each cohort; plus n = 7 or 6 for placebo, respectively). The most frequent treatment-emergent adverse event [TEAE; headache, 14 of 36 (38.9%) subjects] was dose-dependent and more prominent after IV administration. Severe TEAEs occurred in four subjects, all in the highest-dose IV group [headache (n = 3) and back pain (n = 1)]. Rozanolixizumab pharmacokinetics demonstrated nonlinear increases with dose. There were sustained dose-dependent reductions in serum IgG concentrations (IV and SC rozanolixizumab). These data provide clinical evidence for the therapeutic potential of rozanolixizumab.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Kiessling P,Lledo-Garcia R,Watanabe S,Langdon G,Tran D,Bari M,Christodoulou L,Jones E,Price G,Smith B,Brennan F,White I,Jolles Sdoi
10.1126/scitranslmed.aan1208subject
Has Abstractpub_date
2017-11-01 00:00:00issue
414eissn
1946-6234issn
1946-6242pii
9/414/eaan1208journal_volume
9pub_type
杂志文章,随机对照试验abstract::A rare neurodevelopmental disorder in the Old Order Mennonite population called PMSE (polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome; also called Pretzel syndrome) is characterized by infantile-onset epilepsy, neurocognitive delay, craniofacial dysmorphism, and histopathological evidence of heteroto...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005271
更新日期:2013-04-24 00:00:00
abstract::The invasive nature of glioblastoma (GBM) represents a major clinical challenge contributing to poor outcomes. Invasion of GBM into healthy tissue restricts chemotherapeutic access and complicates surgical resection. Here, we test the hypothesis that an effective anti-invasive agent can "contain" GBM and increase the ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003016
更新日期:2012-03-28 00:00:00
abstract::Protein replacement therapies for rare monogenic diseases have a higher probability of regulatory approval compared with biologics, small molecules, and grant-funded orphan drugs. ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005007
更新日期:2013-03-27 00:00:00
abstract::Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. The most common CF-associated mutation is ΔF508, which deletes a phenylalanine in position 508. In vitro studies indicate that the resultant prot...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001868
更新日期:2011-03-16 00:00:00
abstract::Obesity increases the risk of adverse outcomes during acute critical illnesses such as burns, severe trauma, and acute pancreatitis. Although individuals with more body fat and higher serum cytokines and lipase are more likely to experience problems, the roles that these characteristics play are not clear. We used sev...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3002573
更新日期:2011-11-02 00:00:00
abstract::The epidermal growth factor receptor (EGFR) plays an important role in tissue homeostasis and tumor progression. However, cancer patients treated with EGFR inhibitors (EGFRIs) frequently develop acneiform skin toxicities, which are a strong predictor of a patient's treatment response. We show that the early inflammato...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005886
更新日期:2013-08-21 00:00:00
abstract::Essential hypertension is a complex, multifactorial disease associated with a high cardiovascular risk and whose genetic-molecular basis is heterogeneous and largely unknown. Although multiple antihypertensive therapies are available, the large individual variability in drug response results in only a modest reduction...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001815
更新日期:2010-11-24 00:00:00
abstract::Next-generation sequencing technologies have greatly expanded our understanding of cancer genetics. Antisense technology is an attractive platform with the potential to translate these advances into improved cancer therapeutics, because antisense oligonucleotide (ASO) inhibitors can be designed on the basis of gene se...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aac5272
更新日期:2015-11-18 00:00:00
abstract::Research standards deviate in genetic versus nongenetic epidemiology. Besides some immutable differences, such as the correlation pattern between variables, these divergent research standards can converge considerably. Current research designs that dissociate genetic and nongenetic measurements are reaching their limi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3000247
更新日期:2009-11-18 00:00:00
abstract::Children who survive preterm birth exhibit persistent unexplained disturbances in cerebral cortical growth with associated cognitive and learning disabilities. The mechanisms underlying these deficits remain elusive. We used ex vivo diffusion magnetic resonance imaging to demonstrate in a preterm large-animal model th...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3004669
更新日期:2013-01-16 00:00:00
abstract::Physiological data are routinely recorded in intensive care, but their use for rapid assessment of illness severity or long-term morbidity prediction has been limited. We developed a physiological assessment score for preterm newborns, akin to an electronic Apgar score, based on standard signals recorded noninvasively...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001304
更新日期:2010-09-08 00:00:00
abstract::In acute and chronic inflammation, neutrophils and platelets, both of which promote monocyte recruitment, are often activated simultaneously. We investigated how secretory products of neutrophils and platelets synergize to enhance the recruitment of monocytes. We found that neutrophil-borne human neutrophil peptide 1 ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aad5330
更新日期:2015-12-09 00:00:00
abstract::Parenteral and oral routes have been the traditional methods of administering cytotoxic agents to cancer patients. Unfortunately, the maximum potential effect of these cytotoxic agents has been limited because of systemic toxicity and poor tumor perfusion. In an attempt to improve the efficacy of cytotoxic agents whil...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3009951
更新日期:2015-02-04 00:00:00
abstract::Recessive dystrophic epidermolysis bullosa (RDEB) is a rare inherited skin and mucous membrane fragility disorder complicated by early-onset, highly malignant cutaneous squamous cell carcinomas (SCCs). The molecular etiology of RDEB SCC, which arises at sites of sustained tissue damage, is unknown. We performed detail...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aas9668
更新日期:2018-08-22 00:00:00
abstract::Metabolic reprogramming is linked to cancer cell growth and proliferation, metastasis, and therapeutic resistance in a multitude of cancers. Targeting dysregulated metabolic pathways to overcome resistance, an urgent clinical need in all relapsed/refractory cancers, remains difficult. Through genomic analyses of clini...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aau1167
更新日期:2019-05-08 00:00:00
abstract::Osteoarthritis (OA) is a common degenerative condition that afflicts more than 70% of the population between 55 and 77 years of age. Although its prevalence is rising globally with aging of the population, current therapy is limited to symptomatic relief and, in severe cases, joint replacement surgery. We report that ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3005409
更新日期:2013-03-13 00:00:00
abstract::Obesity promotes breast cancer by enhancing the stiffness of breast adipose tissue through changes in the extracellular matrix (Seo et al., this issue). ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aac9446
更新日期:2015-08-19 00:00:00
abstract::The clinical application of cytokine therapies for cancer treatment remains limited due to severe adverse reactions and insufficient therapeutic effects. Although cytokine localization by intratumoral administration could address both issues, the rapid escape of soluble cytokines from the tumor invariably subverts thi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aaw2614
更新日期:2019-06-26 00:00:00
abstract::Some funding agencies now require consideration of sex and gender in preclinical research, a policy that heralds opportunities and challenges for researchers. ...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3009859
更新日期:2014-10-15 00:00:00
abstract::Glycogen synthase kinase 3 (GSK3), a key regulatory kinase in the wingless-type MMTV integration site family (WNT) pathway, is a therapeutic target of interest in many diseases. Although dual GSK3α/β inhibitors have entered clinical trials, none has successfully translated to clinical application. Mechanism-based toxi...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aam8460
更新日期:2018-03-07 00:00:00
abstract::Magnetic resonance imaging (MRI) is a powerful diagnostic tool, but its use is restricted to the scanner suite. Here, we demonstrate that a bedside nuclear magnetic resonance (NMR) sensor can assess fluid status changes in individuals at a fraction of the time and cost compared to MRI. Our study recruited patients wit...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.aau1749
更新日期:2019-07-24 00:00:00
abstract::Metastasis is the major cause of cancer mortality. A more thorough understanding of the mechanisms driving this complex multistep process will aid in the identification and characterization of therapeutically targetable genetic drivers of disease progression. We demonstrate that KLF6-SV1, an oncogenic splice variant o...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3004688
更新日期:2013-01-23 00:00:00
abstract::A new type of biological clock regulates the unfolded protein response. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aan6728
更新日期:2017-06-28 00:00:00
abstract::Touch perception on the fingers and hand is essential for fine motor control, contributes to our sense of self, allows for effective communication, and aids in our fundamental perception of the world. Despite increasingly sophisticated mechatronics, prosthetic devices still do not directly convey sensation back to the...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3008669
更新日期:2014-10-08 00:00:00
abstract::Heparin-based anticoagulant drugs have been widely used for the prevention of blood clotting during surgical procedures and for the treatment of thromboembolic events. However, bleeding risks associated with these anticoagulants demand continuous monitoring and neutralization with suitable antidotes. Protamine, the on...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3009427
更新日期:2014-10-29 00:00:00
abstract::Low-grade polymicrobial infection induced by cecal ligation and puncture is lethal in heme oxygenase-1-deficient mice (Hmox1(-/-)), but not in wild-type (Hmox1(+/+)) mice. Here we demonstrate that the protective effect of this heme-catabolizing enzyme relies on its ability to prevent tissue damage caused by the circul...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3001118
更新日期:2010-09-29 00:00:00
abstract::The importance of a broad CD8 T lymphocyte (CD8-TL) immune response to HIV is unknown. Ex vivo measurements of immunological activity directed at a limited number of defined epitopes provide an incomplete portrait of the actual immune response. We examined viral loads in simian immunodeficiency virus (SIV)-infected ma...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3000524
更新日期:2010-03-10 00:00:00
abstract::Amine-containing polymers immobilized on mesh and placed at trauma sites scavenge biomolecules that initiate a damaging immune response. ...
journal_title:Science translational medicine
pub_type: 评论,杂志文章
doi:10.1126/scitranslmed.aam6068
更新日期:2017-02-22 00:00:00
abstract::In recent years, there has been a growing focus on the unreliability of published biomedical and clinical research. To introduce effective new scientific contributors to the culture of health care, we propose a "datathon" or "hackathon" model in which participants with disparate, but potentially synergistic and comple...
journal_title:Science translational medicine
pub_type: 杂志文章,评审
doi:10.1126/scitranslmed.aad9072
更新日期:2016-04-06 00:00:00
abstract::Elucidating the factors that impinge on the stability of bacterial communities in the vagina may help in predicting the risk of diseases that affect women's health. Here, we describe the temporal dynamics of the composition of vaginal bacterial communities in 32 reproductive-age women over a 16-week period. The analys...
journal_title:Science translational medicine
pub_type: 杂志文章
doi:10.1126/scitranslmed.3003605
更新日期:2012-05-02 00:00:00