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 anchoring through the antibody's Fc domain and does not involve the engagement of FcγR signaling. The aim of this study was to elicit agonistic activity from αCD40 and αCD95 antibodies in a myeloma cell anchoring-controlled FcγR-independent manner. For this purpose, various antibody variants (IgG1, IgG1N297A, Fab2) against the TNFRSF members CD40 and CD95 were genetically fused to a single-chain-encoded B-cell activating factor (scBaff) trimer as a C-terminal myeloma-specific anchoring domain substituting for Fc domain-mediated FcγR binding. The antibody-scBaff fusion proteins were evaluated in binding studies and functional assays using tumor cell lines expressing one or more of the three receptors of Baff: BaffR, transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA). Cellular binding studies showed that the binding properties of the different domains within the fusion proteins remained fully intact in the antibody-scBaff fusion proteins. In co-culture assays of CD40- and CD95-responsive cells with BaffR, BCMA or TACI expressing anchoring cells, the antibody fusion proteins displayed strong agonism while only minor receptor stimulation was observed in co-cultures with cells without expression of Baff-interacting receptors. Thus, our CD40 and CD95 antibody fusion proteins display myeloma cell-dependent activity and promise reduced systemic side effects compared to conventional CD40 and CD95 agonists.
journal_name
MAbsjournal_title
mAbsauthors
Nelke J,Medler J,Weisenberger D,Beilhack A,Wajant Hdoi
10.1080/19420862.2020.1807721subject
Has Abstractpub_date
2020-01-01 00:00:00pages
1807721issue
1eissn
1942-0862issn
1942-0870journal_volume
12pub_type
杂志文章相关文献
mAbs文献大全abstract::Post-translational modifications can have a signification effect on antibody stability. A comprehensive approach is often required to best understand the underlying reasons the modification affects the antibody's potency or aggregation state. Monoclonal antibody 001 displayed significant variation in terms of potency,...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1160179
更新日期:2016-05-01 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::High titer (>10 g/L) monoclonal antibody (mAb) cell culture processes are typically achieved by maintaining high viable cell densities over longer culture durations. A corresponding increase in the solids and sub-micron cellular debris particle levels are also observed. This higher burden of solids (≥15%) and sub-micr...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2015.1007824
更新日期:2015-01-01 00:00:00
abstract::Antibodies provide immune protection by recognizing antigens of diverse chemical properties, but elucidating the amino acid sequence-function relationships underlying the specificity and affinity of antibody-antigen interactions remains challenging. We designed and constructed phage-displayed synthetic antibody librar...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1550320
更新日期:2019-02-01 00:00:00
abstract::Ricin is a toxin that could potentially be used as a bioweapon. We identified anti-ricin A chain antibodies by sequencing the antibody repertoire from immunized mice and by selecting high affinity antibodies using yeast surface display. These methods led to the isolation of multiple antibodies with high (sub-nanomolar...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1190059
更新日期:2016-08-01 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::Bispecific antibodies can uniquely influence cellular responses, but selecting target combinations for optimal functional activity remains challenging. Here we describe a high-throughput, combinatorial, phenotypic screening approach using a new bispecific antibody target discovery format, allowing screening of hundred...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1859049
更新日期:2021-01-01 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::Multispecific antibody formats provide a promising platform for the development of novel therapeutic concepts that could facilitate the generation of safer, more effective pharmaceuticals. However, the production and use of such antibody-based multispecifics is often made complicated by: 1) the instability of the anti...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1248012
更新日期:2017-01-01 00:00:00
abstract::Fusion to an IgG Fc region is an established strategy to extend the half-life of therapeutic proteins. Most Fc fusion proteins, however, do not achieve the long half-life of IgGs. Based on findings that scFv-Fc fusion proteins exhibit a shorter half-life than the corresponding IgG molecules, we performed a comparative...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2015.1113360
更新日期:2016-01-01 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::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::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::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::Biosimilars are designed to be highly similar to approved or licensed (reference) biologics and are evaluated based on the totality of evidence from extensive analytical, nonclinical and clinical studies. As part of the stepwise approach recommended by regulatory agencies, the first step in the clinical evaluation of ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1171431
更新日期:2016-07-01 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::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::The neonatal Fc receptor (FcRn) is a key membrane protein that plays an integral role in serum immunoglobulin (IgG) recycling, which extends the half-life of antibody. In addition, FcRn is known to traffic antigen-bound immunoglobulins (Ag-IgGs), and to interact with immune complexes to facilitate the antigen cross-pr...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1802135
更新日期:2020-01-01 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::Complex cellular targets such as G protein-coupled receptors (GPCRs), ion channels, and other multi-transmembrane proteins represent a significant challenge for therapeutic antibody discovery, primarily because of poor stability of the target protein upon extraction from cell membranes. To assess whether a limited set...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1755069
更新日期:2020-01-01 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::A dual-specific, tetravalent immunoglobulin G-like molecule, termed dual variable domain immunoglobulin (DVD-Ig™), is engineered to block two targets. Flexibility modulates Fc receptor and complement binding, but could result in undesirable cross-linking of surface antigens and downstream signaling. Understanding the ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.24258
更新日期:2013-05-01 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::Therapeutic monoclonal antibodies (mAbs) are highly complex proteins that must be exhaustively characterized according to the regulatory authorities' recommendations. MAbs display micro-heterogeneity mainly due to their post-translational modifications, but also to their susceptibility to chemical and physical degrada...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1781743
更新日期:2020-01-01 00:00:00
abstract::Immunotherapy approaches for Alzheimer disease currently are among the leading therapeutic directions for the disease. Active and passive immunotherapy against the beta-amyloid peptides that aggregate and accumulate in the brain of those afflicted by the disease have been shown by numerous groups to reduce plaque path...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.1.2.7829
更新日期:2009-03-01 00:00:00
abstract::The American Association of Pharmaceutical Scientists (AAPS) National Biotechnology Conference Short Course "Translational Challenges in Developing Antibody-Drug Conjugates (ADCs)," held May 24, 2012 in San Diego, CA, was organized by members of the Pharmacokinetics, Pharmacodynamics and Drug Metabolism section of AAP...
journal_title:mAbs
pub_type:
doi:10.4161/mabs.22909
更新日期:2013-01-01 00:00:00
abstract::Monoclonal antibodies (mAbs) are a burgeoning class of therapeutics, with more than 25 approved in countries worldwide. Novel molecules are entering clinical study at a rate of nearly 40 per year, and the commercial pipeline includes approximately 240 mAb therapeutics in clinical studies that have not yet progressed t...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.2.1.10677
更新日期:2010-01-01 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::Glycosylation is a critical attribute for development and manufacturing of therapeutic monoclonal antibodies (mAbs) in the pharmaceutical industry. Conventional antibody glycan analysis is usually achieved by the 2-aminobenzamide (2-AB) hydrophilic interaction liquid chromatography (HILIC) method following the release...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2016.1156828
更新日期:2016-05-01 00:00:00
abstract::During the past two decades we have seen a phenomenal evolution of bispecific antibodies for therapeutic applications. The 'zoo' of bispecific antibodies is populated by many different species, comprising around 100 different formats, including small molecules composed solely of the antigen-binding sites of two antibo...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.1080/19420862.2016.1268307
更新日期:2017-02-01 00:00:00