Abstract:
:An immunotoxin (IT) constructed with RFB4, a murine anti-CD22 monoclonal antibody, and the "deglycosylated" A chain of ricin has shown activity at safe doses in patients with non-Hodgkin lymphoma and in children with acute lymphoblastic leukemia. The dose limiting toxicity is vascular leak syndrome (VLS), which appears to be due to a unique amino acid motif in the ricin toxin A (RTA) chain that damages vascular endothelial cells. We mutated recombinant (r) RTA to disable this site, but await testing of the IT prepared with this mutant RTA in humans. Another possible approach to reducing IT-induced VLS is to shorten the half-life of the IT in vivo. We previously constructed a mouse-human chimeric RFB4 by grafting the variable genes of RFB4 onto the human IgG1k constant regions. Here, we report the expansion of our panel of mutant chimeric RFB4s (mcRFB4s) that lack the ability to bind to the neonatal Fc receptor (FcRn). In comparison with cRFB4, which had a T1/2 of 263 h, the mcRFB4s had T1/2s ranging from 39 to 106 h. ITs were constructed with these mcRFB4s and rRTA. The mcRFB4-RTA ITs retained their cytotoxicity in vitro and had shorter half lives than the parental cRFB4-RTA IT. In addition, the mcRFB4 IT with the shortest T1/2 induced less pulmonary vascular leak in mice, which we have postulated is a surrogate marker for VLS in humans.
journal_name
MAbsjournal_title
mAbsauthors
Liu XY,Pop LM,Schindler J,Vitetta ESdoi
10.4161/mabs.4.1.18348subject
Has Abstractpub_date
2012-01-01 00:00:00pages
57-68issue
1eissn
1942-0862issn
1942-0870pii
18348journal_volume
4pub_type
杂志文章相关文献
mAbs文献大全abstract::Monoclonal antibodies (mAbs) against human proteins are the primary protein capture reagents for basic research, diagnosis, and molecular therapeutics. The 2 most important attributes of mAbs used in all of these applications are their specificity and avidity. While specificity of a mAb raised against a human protein ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/19420862.2014.985919
更新日期:2015-01-01 00:00:00
abstract::Ch-mAb7F9, a human-mouse chimeric monoclonal antibody (mAb) designed to bind (+)-methamphetamine (METH) with high affinity and specificity, was produced as a treatment medication for METH abuse. In these studies, we present the preclinical characterization that provided predictive evidence that ch-mAb7F9 may be safe a...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.27620
更新日期:2014-03-01 00:00:00
abstract::Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) or TRAIL-receptor agonistic monoclonal antibodies promote apoptosis in most cancer cells, and the differential expression of TRAIL-R2 between tumor and normal tissues allows its exploitation as a tumor-associated antigen. The use of thes...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1494105
更新日期:2018-10-01 00:00:00
abstract::Monoclonal antibodies play an increasingly important role for the development of new drugs across multiple therapy areas. The term 'developability' encompasses the feasibility of molecules to successfully progress from discovery to development via evaluation of their physicochemical properties. These properties includ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1743053
更新日期:2020-01-01 00:00:00
abstract::Site-specific antibody-drug conjugates (ADCs) are designed to overcome the heterogeneity observed with first-generation ADCs that use random conjugation to surface-exposed lysine residues or conjugation to interchain disulfide bonds. Despite significantly enhanced homogeneity, however, the production of site-specific ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2019.1624127
更新日期:2019-08-01 00:00:00
abstract::Vedolizumab (VDZ) is a humanized monoclonal antibody in development for the treatment of inflammatory bowel disease. VDZ binds to the α4β7 integrin complex and inhibits its binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus preventing lymphocyte extravasation to gut mucosal tissues. To understand w...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.26392
更新日期:2013-11-01 00:00:00
abstract::Pharmacokinetic (PK) testing of a humanized (κI, VH3 framework) and affinity matured anti-hepatitis C virus E2-glycoprotein (HCV-E2) antibody (hu5B3.κ1VH3.v3) in rats revealed unexpected fast clearance (34.9 mL/day/kg). This antibody binds to the rat recycling receptor FcRn as expected for a human IgG1 antibody and do...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.29809
更新日期:2014-01-01 00:00:00
abstract::Antibodies that target a clinically relevant group of receptors within the tumor necrosis factor receptor superfamily (TNFRSF), including CD40 and CD95 (Fas/Apo-1), also require binding to Fc gamma receptors (FcγRs) to elicit a strong agonistic activity. This FcγR dependency largely relies on the mere cellular anchori...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1807721
更新日期:2020-01-01 00:00:00
abstract::Although extensively studied, protein-protein interactions remain highly elusive and are of increasing interest in drug development. We show the assembly of a monoclonal antibody, using multivalent carboxylate ions, into highly-ordered structures. While the presence and function of similar structures in vivo are not k...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.23183
更新日期:2013-03-01 00:00:00
abstract::In recent years, capillary electrophoresis-sodium dodecyl sulfate (cSDS) has been widely used for high resolution separation and quantification of the fragments and aggregates of monoclonal antibodies (mAbs) to ensure the quality of mAb therapeutics. However, identification of the low-molecular-weight (LMW) and high-m...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2019.1646554
更新日期:2019-10-01 00:00:00
abstract::Respiratory syncytial virus (RSV) is a common cause of acute lower respiratory disease in infants and young children worldwide. Currently, treatment is supportive and no vaccines are available. The use of newborn lambs to model hRSV infection in human infants may provide a valuable tool to assess safety and efficacy o...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1470727
更新日期:2018-07-01 00:00:00
abstract::The neonatal Fc receptor (FcRn) is important for the metabolic fate of IgG antibodies in vivo. Analysis of the interaction between FcRn and IgG in vitro might provide insight into the structural and functional integrity of therapeutic IgG that may affect pharmacokinetics (PK) in vivo. We developed a standardized pH gr...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.24981
更新日期:2013-07-01 00:00:00
abstract::Ang1 is a soluble ligand to receptor Tie2, and increasing the circulating Ang1 level may improve vascular stabilization under certain disease conditions. Here, we found that the circulating Ang1 level was significantly increased in cynomolgus monkeys treated with non-neutralizing anti-Ang1 antibodies. Improving the an...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1521130
更新日期:2018-11-01 00:00:00
abstract::While many antibody therapeutics are formulated at low concentration (~10-20 mg/mL) for intravenous administration, high concentration (> 100 mg/mL) formulations may be required for subcutaneous delivery in certain clinical indications. For such high concentration formulations, product color is more apparent due to th...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.28257
更新日期:2014-05-01 00:00:00
abstract::High physical stability is required for the development of monoclonal antibodies (mAbs) into successful therapeutic products. Developability assays are used to predict physical stability issues such as high viscosity and poor conformational stability, but protein aggregation remains a challenging property to predict. ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1815995
更新日期:2020-01-01 00:00:00
abstract::Genomic studies have been revolutionized by the use of next generation sequencing (NGS) that delivers huge amounts of sequence information in a short span of time. The number of applications for NGS is rapidly expanding and significantly transforming many areas of life sciences. The field of antibody research and disc...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.3.1.14169
更新日期:2011-01-01 00:00:00
abstract::We describe here the identification of a stop codon TAA (Stop) → GAA (Glu) = Stop221E mutation on the light chain of a recombinant IgG1 antibody expressed in a Chinese hamster ovary (CHO) cell line. The extended light chain variants, which were caused by translation beyond the mutated stop codon to the next alternativ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.22232
更新日期:2012-11-01 00:00:00
abstract::Optimization of biophysical properties is a critical success factor for the developability of monoclonal antibodies with potential therapeutic applications. The inter-domain disulfide bond between light chain (Lc) and heavy chain (Hc) in human IgG1 lends structural support for antibody scaffold stability, optimal anti...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.24291
更新日期:2013-05-01 00:00:00
abstract::The neonatal Fc receptor (FcRn) plays an important and well-known role in antibody recycling in endothelial and hematopoietic cells and thus it influences the systemic pharmacokinetics (PK) of immunoglobulin G (IgG). However, considerably less is known about FcRn's role in the metabolism of IgG within individual tissu...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.28254
更新日期:2014-05-01 00:00:00
abstract::Multivalent mono- or bispecific antibodies are of increasing interest for therapeutic applications, such as efficient receptor clustering and activation, or dual targeting approaches. Here, we present a novel platform for the generation of Ig-like molecules, designated diabody-Ig (Db-Ig). The antigen-binding site of D...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2019.1603024
更新日期:2019-07-01 00:00:00
abstract::Tremendous knowledge has been gained in the understanding of various modifications of IgG antibodies, driven mainly by the fact that antibodies are one of the most important groups of therapeutic molecules and because of the development of advanced analytical techniques. Recombinant monoclonal antibody (mAb) therapeut...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.29883
更新日期:2014-01-01 00:00:00
abstract::The aim of this study was to investigate neonatal Fc receptor (FcRn) concentration developmental pharmacology in adult and pediatric subjects using minimal physiologically-based pharmacokinetic (mPBPK) modelling. Three types of pharmacokinetic (PK) data for three agents (endogenous/exogenous native IgG, bevacizumab an...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1494479
更新日期:2018-10-01 00:00:00
abstract::Given the increasing use of combination therapy with multiple monoclonal antibodies (mAbs), there is a clinical need for multiplexing assays. For the frequently co-administered anti-human epidermal growth factor receptor 2 (HER2) mAbs trastuzumab and pertuzumab, we developed a high-throughput and robust hybrid ligand-...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1795492
更新日期:2020-01-01 00:00:00
abstract::Monoclonal antibodies are used with great success in many different therapeutic domains. In order to satisfy the growing demand and to lower the production cost of these molecules, many alternative systems have been explored. Among them, the baculovirus/insect cells system is a good candidate. This system is very safe...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.19942
更新日期:2012-05-01 00:00:00
abstract::Monoclonal antibodies are widely used for the treatment of cancer, inflammatory and infectious diseases and other disorders. Most of the marketed antibodies are monospecific and therefore capable of interacting and interfering with a single target. However, complex diseases are often multifactorial in nature, and invo...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.4.2.19000
更新日期:2012-03-01 00:00:00
abstract::The critical role played by IgE in allergic asthma is well-documented and clinically precedented, but some patients in whom IgE neutralization may still offer clinical benefit are excluded from treatment with the existing anti-IgE therapy, omalizumab, due to high total IgE levels or body mass. In this study, we sought...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.28394
更新日期:2014-05-01 00:00:00
abstract::Plasmacytoid dendritic cells (pDCs) play a central role for both innate and adaptive antiviral responses, as they direct immune responses through their unique ability to produce substantial concentrations of type I interferon (IFNs) upon viral encounter while also activating multiple immune cells, including macrophage...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1451283
更新日期:2018-05-01 00:00:00
abstract::Neutralizing antibody responses to the surface glycoproteins of enveloped viruses play an important role in immunity. Many of these glycoproteins, including the severe acute respiratory syndrome-coronavirus (SARS-CoV) spike (S) protein form trimeric units in the membrane of the native virion. There is substantial expe...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.2.1.10788
更新日期:2010-01-01 00:00:00
abstract::The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharm...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1462429
更新日期:2018-07-01 00:00:00
abstract::One aspiration for the formulation of human monoclonal antibodies (mAb) is to reach high solution concentrations without compromising stability. Protein surface activity leading to instability is well known, but our understanding of mAb adsorption to the solid-liquid interface in relevant pH and surfactant conditions ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.22522
更新日期:2013-01-01 00:00:00