McCafferty J.,IONTAS Ltd.
Chemistry and Biology | Year: 2014
In this issue of Chemistry & Biology, Xie and colleagues describe a "phenotype directed" approach to identify antibodies that protect cells from death caused by rhinovirus infection. The cellular antibody library of 108 clones yielded two antibodies that prevented cell death via the same viral target: rhinovirus 3C protease. © 2014 Elsevier Ltd. All rights reserved.
Jones T.D.,Abzena |
Carter P.J.,Genentech |
Pluckthun A.,University of Zurich |
Vasquez M.,Adimab Inc. |
And 31 more authors.
mAbs | Year: 2016
A n important step in drug development is the assignment of an International Nonproprietary Name (INN) by the World Health Organization (WHO) that provides healthcare professionals with a unique and universally available designated name to identify each pharmaceutical substance. Monoclonal antibody INNs comprise a –mab suffix preceded by a substem indicating the antibody type, e.g., chimeric (-xi-), humanized (-zu-), or human (-u-). The WHO publishes INN definitions that specify how new monoclonal antibody therapeutics are categorized and adapts the definitions to new technologies. However, rapid progress in antibody technologies has blurred the boundaries between existing antibody categories and created a burgeoning array of new antibody formats. Thus, revising the INN system for antibodies is akin to aiming for a rapidly moving target. The WHO recently revised INN definitions for antibodies now to be based on amino acid sequence identity. These new definitions, however, are critically flawed as they are ambiguous and go against decades of scientific literature. A key concern is the imposition of an arbitrary threshold for identity against human germline antibody variable region sequences. This leads to inconsistent classification of somatically mutated human antibodies, humanized antibodies as well as antibodies derived from semi-synthetic/synthetic libraries and transgenic animals. Such sequence-based classification implies clear functional distinction between categories (e.g., immunogenicity). However, there is no scientific evidence to support this. Dialog between the WHO INN Expert Group and key stakeholders is needed to develop a new INN system for antibodies and to avoid confusion and miscommunication between researchers and clinicians prescribing antibodies. © 2016, Tim D. Jones….
Targeting the sheddase activity of Adam17 by an Anti-ADAM17 antibody D1(A12) inhibits head and neck squamous cell carcinoma cell proliferation and motility via blockage of bradykinin induced HERs transactivation
Huang Y.,University of Cambridge |
Huang Y.,IONTAS Ltd. |
Benaich N.,University of Cambridge |
Benaich N.,Kings College London |
And 5 more authors.
International Journal of Biological Sciences | Year: 2014
A disintegrin and metalloproteinase 17 (ADAM17) regulates key cellular processes including proliferation and migration through the shedding of a diverse array of substrates such as epidermal growth factor receptor (EGFR) ligands. ADAM17 is implicated in the pathogenesis of many diseases including rheumatoid arthritis and cancers such as head and neck squamous cell carcinoma (HNSCC). As a central mediator of cellular events, overexpressed EGFR is a validated molecular target in HNSCC. However, EGFR inhibition constantly leads to tumour resistance. One possible mechanism of resistance is the activation of alternative EGFR family receptors and downstream pathways via the release of their ligands. Here, we report that treating human HNSCC cells in vitro with a human anti-ADAM17 inhibitory antibody, D1(A12), suppresses proliferation and motility in the absence or presence of the EGFR tyrosine kinase inhibitor (TKI) gefitinib. Treatment with D1(A12) decreases both the endogenous and the bradykinin (BK)-stimulated shedding of HER ligands, accompanied by a reduction in the phosphorylation of HER receptors and downstream signalling pathways including STAT3, AKT and ERK. Knockdown of ADAM17, but not ADAM10, also suppresses HNSCC cell proliferation and migration. Furthermore, we show that heregulin (HRG) and heparin-binding epidermal growth factor like growth factor (HB-EGF) predominantly participate in proliferation and migration, respectively. Taken together, these results demonstrate that D1(A12)-mediated inhibition of cell proliferation, motility, phosphorylation of HER receptors and downstream signalling is achieved via reduced shedding of ADAM17 ligands. These findings underscore the importance of ADAM17 and suggest that D1(A12) might be an effective targeted agent for treating EGFR TKI-resistant HNSCC. © Ivyspring International Publisher.
Dyson M.R.,IONTAS Ltd.
Drugs of the Future | Year: 2015
The discovery and development of therapeutic antibodies to treat cancer or diseases of the immune system were the main subjects of the Biologics Congress 2015. Across the 2-day conference, approximately 150 participants, representing major European biopharmaceutical companies and visitors from the U.S., discussed the growth and development of the biologics market as more and more companies enter it. This report highlights presentations of interest from the 2 days. Copyright © 2015 Prous Science, S.A.U. or its licensors. All rights reserved.
McCafferty J.,IONTAS Ltd. |
Current Opinion in Chemical Biology | Year: 2015
The use of large genetically encoded binder libraries in co-operation with display technologies has matured over the past 25 years, and is now one of the primary methods used for selection of protein binders. Display technology has proven to be a robust and versatile method for generating binders to almost any antigen of interest. The evolution of this technology beyond antibody phage display has opened up new aspects for the concept of designer biologics. The ability to construct large populations of eukaryotic cells, including mammalian cells, where each cell expresses an individual antibody, peptide or engineered protein has added great value in identifying binders with desired properties. Here we review the evolution of display technology and highlight how it is being used today to generate binders with exquisite specificity, selectivity, affinity and developability characteristics. © 2015 .