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 hundreds of target combinations. Simple in vitro mixing of Fab-fusion proteins from a diverse library enables the generation of thousands of screen-ready bispecific antibodies for high-throughput, biologically relevant assays. We identified an obligate bispecific co-targeting CD79a/b and CD22 as a potent inhibitor of human B cell activation from a short-term flow cytometry signaling assay. A long-term, high-content imaging assay identified anti-integrin bispecific inhibitors of human cell matrix accumulation targeting integrins β1 and β6 or αV and β1. In all cases, functional activity was conserved from the bispecific screening format to a therapeutically relevant format. We also introduce a broader type of mechanistic screen whereby functional modulation of different cell subsets in peripheral blood mononuclear cells was evaluated simultaneously. We identified bispecific antibodies capable of activating different T cell subsets of potential interest for applications in oncology or infectious disease, as well as bispecifics abrogating T cell activity of potential interest to autoimmune or inflammatory disease. The bispecific target pair discovery technology described herein offers access to new target biology and unique bispecific therapeutic opportunities in diverse disease indications.
journal_name
MAbsjournal_title
mAbsauthors
Bhatta P,Whale KD,Sawtell AK,Thompson CL,Rapecki SE,Cook DA,Twomey BM,Mennecozzi M,Starkie LE,Barry EMC,Peters SJ,Kamal AM,Finney HMdoi
10.1080/19420862.2020.1859049subject
Has Abstractpub_date
2021-01-01 00:00:00pages
1859049issue
1eissn
1942-0862issn
1942-0870journal_volume
13pub_type
杂志文章相关文献
mAbs文献大全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::Antibody-drug conjugates (ADCs) represent a new class of cancer therapeutics. Their design involves a tumor-specific antibody, a linker and a cytotoxic payload. They were designed to allow specific targeting of highly potent cytotoxic agents to tumor cells whilst sparing normal cells. Frequent toxicities that may be d...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.1080/19420862.2016.1156829
更新日期:2016-05-01 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::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 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::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::Immunoglobulins and T cell receptors (TCRs) share common sequences and structures. With the goal of creating novel bispecific antibodies (BsAbs), we generated chimeric molecules, denoted IgG_TCRs, where the Fv regions of several antibodies were fused to the constant domains of the α/β TCR. Replacing CH1 with Cα and CL...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2015.1007826
更新日期:2015-01-01 00:00:00
abstract::Antibody-drug conjugates (ADCs) that exploit the active metabolite SN-38, which is derived from the popular anticancer drug, irinotecan (a camptothecin that inhibits the nuclear topoisomerase I enzyme, inducing double-stranded DNA breaks during the mitotic S-phase of affected cells), represent a substantial advance in...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.1080/19420862.2019.1632115
更新日期:2019-08-01 00:00:00
abstract::Colorectal cancer represents the second most common cause of cancer-related death. The human A33 transmembrane glycoprotein is a validated tumor-associated antigen, expressed in 95% of primary and metastatic colorectal cancers. Using phage display technology, we generated a human monoclonal antibody (termed A2) specif...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1714371
更新日期:2020-01-01 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::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::The epidermal growth factor receptor (EGFR) is frequently dysregulated in human malignancies and a validated target for cancer therapy. Two monoclonal anti-EGFR antibodies (cetuximab and panitumumab) are approved for clinical use. However, the percentage of patients responding to treatment is low and many patients exp...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.3.6.17955
更新日期:2011-11-01 00:00:00
abstract::The Annual bioProcessUK Conference has acted as the key networking event for bioprocess scientists and engineers in the UK for the past 10 years. The following article is a report from the sessions that focused on continuous bioprocessing during the 10(th) Annual bioProcessUK Conference (London, December 2013). These ...
journal_title:mAbs
pub_type:
doi:10.4161/mabs.36151
更新日期:2014-01-01 00:00:00
abstract::Process intensification has shown great potential to increase productivity and reduce costs in biomanufacturing. This case study describes the evolution of a manufacturing process from a conventional processing scheme at 1000-L scale (Process A, n = 5) to intensified processing schemes at both 1000-L (Process B, n = 8...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1770669
更新日期:2020-01-01 00:00:00
abstract::Interactions between the cytoplasmic domains of viral transmembrane proteins and host machinery often determine the outcome of viral infection. The M2 protein of influenza A has been identified as a key player in autophagy-mediated viral replication. Here, we describe the engineering and validation of an antibody spec...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1843754
更新日期:2020-01-01 00:00:00
abstract::Monoclonal antibodies (mAb) have become a mainstay in tumor therapy. Clinical responses to mAb therapy, however, are far from optimal, with many patients presenting native or acquired resistance or suboptimal responses to a mAb therapy. MAbs exert antitumor activity through different mechanisms of action and we propos...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.22775
更新日期:2013-01-01 00:00:00
abstract::Severe forms of dengue virus (DENV) infection frequently cause high case fatality rate. Currently, there is no effective vaccine against the infection. Clinical cases are given only palliative treatment as specific anti-DENV immunotherapy is not available and it is urgently required. In this study, human single-chain ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.27874
更新日期:2014-03-01 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::Certolizumab pegol (Cimzia(®)) is currently the only PEGylated anti-TNFα biologic approved for the treatment of rheumatoid arthritis and Crohn disease. The product, developed by UCB, is a humanized antigen-binding fragment (Fab') of a monoclonal antibody that has been conjugated to polyethylene glycol. Certolizumab pe...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.4161/mabs.2.2.11271
更新日期:2010-03-01 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::Despite availability of biologic therapies, limited patient access to many of the most-effective cancer treatments affects overall health outcomes. To address this issue, many governments have enacted legislation for the approval of biosimilars. The term "biosimilar" refers to a biologic product that is developed to b...
journal_title:mAbs
pub_type: 杂志文章,评审
doi:10.1080/19420862.2015.1008346
更新日期:2015-01-01 00:00:00
abstract::Antibodies are routinely used to study the activity of transcription factors, using various in vitro and in vivo approaches such as electrophoretic mobility shift assay, enzyme-linked immunosorbent assay, genome-wide method analysis coupled with next generation sequencing, or mass spectrometry. More recently, a new ap...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2018.1451288
更新日期:2018-05-01 00:00:00
abstract::MPDL3280A is a human monoclonal antibody that targets programmed cell death-1 ligand 1 (PD-L1), and exerts anti-tumor activity mainly by blocking PD-L1 interaction with programmed cell death-1 (PD-1) and B7.1. It is being investigated as a potential therapy for locally advanced or metastatic malignancies. The purpose ...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2015.1136043
更新日期:2016-01-01 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::The plasticity of natural immunoglobulin repertoires can be exploited for the generation of phage display libraries. Secondary lymphoid organs, such as the spleen and the lymph nodes, constitute interesting sources of diversity because they are rich in B cells, part of which can be affinity matured. These organs, howe...
journal_title:mAbs
pub_type: 杂志文章
doi:10.4161/mabs.25592
更新日期:2013-09-01 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::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::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::Tandem single-chain variable fragment (scFv) bispecific antibodies (bsAb) are one of the most promising bsAb formats reported thus far. Yet, because of their increased aggregation propensity, high impurity content due to low expression level, smaller size and lack of the Fc region, it is challenging to isolate these p...
journal_title:mAbs
pub_type: 杂志文章
doi:10.1080/19420862.2020.1718440
更新日期:2020-01-01 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