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 tissues after intravenous administration. To elucidate the organ distribution and gain insight into the metabolism of humanized IgG1 antibodies with different binding affinities FcRn, comparative biodistribution studies in normal CD-1 mice were conducted. Here, we generated variants of herpes simplex virus glycoprotein D-specific antibody (humanized anti-gD) with increased and decreased FcRn binding affinity by genetic engineering without affecting antigen specificity. These antibodies were expressed in Chinese hamster ovary cell lines, purified and paired radiolabeled with iodine-125 and indium-111. Equal amounts of I-125-labeled and In-111-labeled antibodies were mixed and intravenously administered into mice at 5 mg/kg. This approach allowed us to measure both the real-time IgG uptake (I-125) and cumulative uptake of IgG and catabolites (In-111) in individual tissues up to 1 week post-injection. The PK and distribution of the wild-type IgG and the variant with enhanced binding for FcRn were largely similar to each other, but vastly different for the rapidly cleared low-FcRn-binding variant. Uptake in individual tissues varied across time, FcRn binding affinity, and radiolabeling method. The liver and spleen emerged as the most concentrated sites of IgG catabolism in the absence of FcRn protection. These data provide an increased understanding of FcRn's role in antibody PK and catabolism at the tissue level.
journal_name
MAbsjournal_title
mAbsauthors
Yip V,Palma E,Tesar DB,Mundo EE,Bumbaca D,Torres EK,Reyes NA,Shen BQ,Fielder PJ,Prabhu S,Khawli LA,Boswell CAdoi
10.4161/mabs.28254subject
Has Abstractpub_date
2014-05-01 00:00:00pages
689-96issue
3eissn
1942-0862issn
1942-0870pii
28254journal_volume
6pub_type
杂志文章相关文献
mAbs文献大全abstract::During cell line development for an IgG1 antibody candidate (mAb1), a C-terminal extension was identified in 2 product candidate clones expressed in CHO-K1 cell line. The extension was initially observed as the presence of anomalous new peaks in these clones after analysis by cation exchange chromatography (CEX-HPLC) ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.36222
更新日期:2014-01-01 00:00:00
abstract::The importance of antibodies in activating immune responses against tumors is now better appreciated with the emergence of checkpoint blockade antibodies and with engineered antibody Fc domains featuring enhanced capacity to focus potent effector cells against cancer cells. Antibodies designed with Fc regions of the I...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.27029
更新日期:2014-01-01 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::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::In the present study, we conducted a Phase 1 study of a recombinant anti-EGFR monoclonal antibody (CMAB009) that has the same amino acid sequence as cetuximab. The purpose of this study was to evaluate the safety, pharmacokinetics, and potential benefit of CMAB009 in Chinese patients with advanced chemotherapy-resista...
journal_title:mAbs
pub_type: 杂志文章,随机对照试验
doi:10.4161/mabs.3.1.14021
更新日期:2011-01-01 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::Monoclonal antibodies constitute a robust class of therapeutic proteins. Their stability, resistance to stress conditions and high solubility have allowed the successful development and commercialization of over 40 antibody-based drugs. Although mAbs enjoy a relatively high probability of success compared with other t...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.25269
更新日期:2013-09-01 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::Genetically encoded fluorescent antibodies are desirable for many applications in biotechnology, proteomics, microscopy, cell biology and molecular diagnostics, although efficient production of fluorescent IgGs in mammalian cells has been hampered by different and mutually incompatible secretion- and folding-requireme...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.2.6.13179
更新日期:2010-11-01 00:00:00
abstract::A mono-specific antibody may recruit a second antigen binding specificity, thus converting to a dual-specific Two-in-One antibody through mutation at the light chain complementarity-determining regions (CDRs). It is, however, unknown whether mutation at the heavy chain CDRs may evolve such dual specificity. Herein, we...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.28483
更新日期:2014-05-01 00:00:00
abstract::Fusion proteins combining oligomeric assemblies of a genetically obtained single-chain (sc) variant of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with antibodies directed against tumor-associated antigens represent a promising strategy to overcome the limited therapeutic activity of conventional s...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1172163
更新日期:2016-07-01 00:00:00
abstract::Surface and interfacial adsorption of antibody molecules could cause structural unfolding and desorbed molecules could trigger solution aggregation, resulting in the compromise of physical stability. Although antibody adsorption is important and its relevance to many mechanistic processes has been proposed, few techni...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1276141
更新日期:2017-04-01 00:00:00
abstract::A costimulatory signal is required for the full activation of T cells, in addition to the antigen-specific signal via the T cell receptor. The inducible costimulator, ICOS is one of the costimulatory molecules that play an essential role in this process, particularly in the expansion or the development of effector T c...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.1.5.9633
更新日期:2009-09-01 00:00:00
abstract::The development and production of recombinant monoclonal antibodies is well established. Although most of these are IgGs, there is also great interest in producing recombinant IgAs since this isotype plays a critical role in providing immunologic protection at mucosal surfaces. The choice of expression system for prod...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.2.3.11802
更新日期:2010-05-01 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::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::Non-enzymatic glycation is a challenging post-translational modification to characterize due to the structural heterogeneity it generates in proteins. Glycation has become increasingly recognized as an important product quality attribute to monitor, particularly for the biotechnology sector, which produces recombinant...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2015.1046663
更新日期:2015-01-01 00:00:00
abstract::The development of antibody therapeutics relies on animal models that accurately recapitulate disease biology. Syngeneic mouse models are increasingly used with new molecules to capture the biology of complex cancers and disease states, and to provide insight into the role of the immune system. The establishment of sy...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2019.1685350
更新日期:2020-01-01 00:00:00
abstract::Efficient production of large quantities of therapeutic antibodies is becoming a major goal of the pharmaceutical industry. We developed a proprietary expression system using a polyprotein precursor-based approach to antibody expression in mammalian cells. In this approach, the coding regions for heavy and light chain...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.25161
更新日期:2013-07-01 00:00:00
abstract::Antibody engineering must be accompanied by mapping strategies focused on identifying the epitope recognized by each antibody to define its unique functional identity. High throughput fine specificity determination remains technically challenging. We review recent experiences aimed at revisiting the oldest and most ex...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.36144
更新日期:2014-01-01 00:00:00
abstract::Bispecific antibody therapeutics can expand the functionality of a conventional monoclonal antibody drug because they can bind multiple antigens. However, their great potential is counterbalanced by the challenges faced in their production. The classic asymmetric bispecific containing an Fc requires the expression of ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1519631
更新日期:2018-11-01 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::The B cell antigen receptor repertoire is highly diverse and constantly modified by clonal selection. High-throughput DNA sequencing (HTS) of the lymphocyte repertoire (Rep-Seq) represents a promising technology to explore such diversity ex-vivo and assist in the identification of antigen-specific antibodies based on ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2015.1026502
更新日期:2015-01-01 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::Animal cell culture technology has advanced significantly over the last few decades and is now generally considered a reliable, robust and relatively mature technology. A range of biotherapeutics are currently synthesized using cell culture methods in large scale manufacturing facilities that produce products for both...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.2.5.12720
更新日期:2010-09-01 00:00:00
abstract::Due to their excellent specificity for a single epitope, monoclonal antibodies (mAbs) present a means of influencing the function of cells at the molecular level. In particular they show great promise in the treatment of cancer because they can inhibit cancer cell proliferation, tumor angiogenesis, invasiveness and ma...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.3.5.16089
更新日期:2011-09-01 00:00:00
abstract::Manipulation of binding affinity between monoclonal antibodies (mAbs) and the neonatal Fc receptor (FcRn) has been leveraged to extend mAb half-life; however, the steps required for success remain ambiguous and experimental observations are inconsistent. Recent models have considered the time course of endosomal trans...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1506648
更新日期:2018-11-01 00:00:00
abstract::The current standard treatment for acute myeloid leukemia (AML) is chemotherapy based on cytarabine and daunorubicine (7 + 3), but it discriminates poorly between malignant and benign cells. Dose-limiting off‑target effects and intrinsic drug resistance result in the inefficient eradication of leukemic blast cells and...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2015.1007818
更新日期:2015-01-01 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::The importance of the neonatal Fc receptor (FcRn) in extending the serum half-life of monoclonal antibodies (mAbs) is well demonstrated, and has led to the development of multiple engineering approaches designed to alter Fc interactions with FcRn. Recent reports have additionally highlighted the effect of nonspecific ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1208330
更新日期:2016-10-01 00:00:00