Booe J.M.,The University of Oklahoma Health Sciences Center |
Walker C.S.,University of Auckland |
Barwell J.,Aston University |
Barwell J.,Adaptimmune |
And 11 more authors.
Molecular Cell | Year: 2015
Association of receptor activity-modifying proteins (RAMP1-3) with the G protein-coupled receptor (GPCR) calcitonin receptor-like receptor (CLR) enables selective recognition of the peptides calcitonin gene-related peptide (CGRP) and adrenomedullin (AM) that have diverse functions in the cardiovascular and lymphatic systems. How peptides selectively bind GPCR:RAMP complexes is unknown. We report crystal structures of CGRP analog-bound CLR:RAMP1 and AM-bound CLR:RAMP2 extracellular domain heterodimers at 2.5 and 1.8 Å resolutions, respectively. The peptides similarly occupy a shared binding site on CLR with conformations characterized by a β-turn structure near their C termini rather than the α-helical structure common to peptides that bind related GPCRs. The RAMPs augment the binding site with distinct contacts to the variable C-terminal peptide residues and elicit subtly different CLR conformations. The structures and accompanying pharmacology data reveal how a class of accessory membrane proteins modulate ligand binding of a GPCR and may inform drug development targeting CLR:RAMP complexes. © 2015 The Authors.
British Journal of Clinical Pharmacology | Year: 2013
T cells are a multifaceted family pivotal in the operations of the immune system and many of its associated diseases. The pathway to understanding T cells has been marked by several pharmacological advances including the discoveries of ciclosporin, tacrolimus and the mTOR inhibitors which revolutionized transplant therapy along with providing relief for severe eczema, asthma and other immunological disorders towards the end of the last century. This article will revisit the current understanding and new developments in T cell pharmacology 10 years on from the TeGenero (TGN 1412) debacle and look at more recent successes with ex vivo antigen presenting cell incubation technologies; T cell receptor (TCR) engineering and adoptive T cell therapy both with chimaeric antibodies and also with modified T cell receptors themselves. Features of T cell biology will be explored and processes often highly unique to humans will be used to highlight what many are beginning to see as an exciting new monoclonal (T cell) frontier for drug development. © 2012 The British Pharmacological Society.
Agency: GTR | Branch: Innovate UK | Program: | Phase: Collaborative Research & Development | Award Amount: 2.15M | Year: 2014
Adaptimmune has developed the adoptive transfer of T cells genetically engineered to express optimised affinity T cell Receptors (TCR) that target cancer peptide antigens. This approach generates potent anti-tumour immunity. This disruptive therapy has the potential to treat late stage diseases, such as Triple Negative Breast Cancer, for which there is a great unmet need and is not ammenable to targeted biological therapies. Such targeted T cell therapies represent a significant advance over traditional chemotherapy because they selectively attack the cancer and not the rest of the body offering significant increase in the patient standard of life. This project is for the development of a new TCR gene modified T cell therapy suitable for use in Triple negative Breast cancer and will and evaluate safety and efficacy to assess the potential of this therapy in a disease with a great unmet need.
Adaptimmune | Date: 2016-04-12
Pharmaceutical preparations for the treatment of cancer and autoimmune diseases. Medical treatment services, namely, administration of gene therapy to patients involving harvesting a patients white blood cells, transducing or combining white blood cells with gene encoding T-cell receptor and re-administration of white blood cells to patient; Medical and therapeutic services, namely immunotherapy services comprising harvesting a patients white blood cells, transducing the white blood cells with the gene encoding the engineered T-cell receptor and re-administration of the transduced white blood cells back into the patient.
Adaptimmune and Immunocore | Date: 2014-04-09
A proteinaceous particle, for example a bacteriophage, ribosome or cell, displaying on its surface a T-cell receptor (TCR). The displayed TCR is preferably a heterodimer having a non-native disulfide bond between constant domain residues. Such display particles may be used for the creation of diverse TCR libraries for the identification of high affinity TCRs. Several high affinities are disclosed.