Understanding and manipulating Antibody Dependent Cell Cytotoxicity (ADCC) by human Natural Killer (NK) cells

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Biologists have given names to nearly all the different protein molecules that mediate communication between human cells. Now, the audacious goal of contemporary cell biology is to understand how the billion proteins in a live cell allow them to move, multiply, contribute to a brain or defend us against viruses and bacteria. Imaging where and when proteins interact with each other has a major role to play at this frontier. Recent imaging of just a few types of proteins has already led to important new concepts in how immune cells communicate with each other and how they recognize signs of disease. High-resolution microscope images of immune cells contacting other cells have revealed temporary membrane structures, often called immune synapses, similar to the synapses that nerve cells make with one another for communication. Proteins commonly segregate into specific regions at the contacts between cells, and exploring how such changing arrangements of proteins occur and how they control immune cell communication is the new science opened up by the immune synapse concept. Over the last decade the use of antibodies has revolutionised the treatment of severe human diseases, such as non hodgkins lymphoma (NHL) and rheumatoid arthritis (RA). One way that these antibodies work is by triggering Natural Killer cells to directly kill diseased target cells. Crucially, nobody has yet determined what happens at immune synapses when antibodies trigger killing of diseased cells. Here, we plan to use state-of-the-art technologies to image immune synapses during antibody-medaited killing with a view to learning how to best optimise antibodies for this function. We will apply the understanding gained from these basic studies to the rational design of modified antibodies for optimal efficiency in a range of disease treatments.

Technical Summary

We aim to characterise the NK cell immune synapse (IS) during antibody dependent cellular cytotoxicity (ADCC) with a view to determining the key properties and regions on the target antigens or effector cells that promote optimal cell killing. Using antibodies and model systems developed at MedImmune, the effects of antibody affinity, receptor density and effector function will be used to determine the effects of antibody engineering on ADCC. Using state-of-the-art confocal microscopy within Prof D. Davis group (Imperial College), the spatial relationship and segregation of proteins at the submicrometer scale within the activating IS will be determined during ADCC and compared for the different antibodies and model systems developed by MedImmune. Specifically, we propose to:

1. Determine, for the first time, the supramolecular organisation of the NK cell IS during ADCC.
2. Determine how antibody affinity and ligand density relates to NK cell effector functions, including cytotoxicity and cytokine release, and how these correlate with changes within the supramolecular organisation of the IS.
3. Determine how the location of epitope and size of antibody relates to effector functions and the supramolecular organisation of the IS.

The overarching aim will then be to apply the understanding gained from these basic studies to the rational design of modified antibodies for optimal efficiency in ADCC.
 
Description European Reintegration Grant, from Marie Curie FP7-Reintegration-Grants
Amount £32,052 (GBP)
Organisation Marie Sklodowska-Curie Actions 
Sector Charity/Non Profit
Country Global
Start 01/2010 
End 12/2010
 
Description Wellcome Trust Investigator award
Amount £1,800,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Charity/Non Profit
Country United Kingdom
Start 10/2016 
End 10/2021
 
Description Collaboration with MedImmune 
Organisation MedImmune
Department Infection
Country United States 
Sector Private 
PI Contribution The project is entirely collaborative with this company
Collaborator Contribution Many reagents are being made in this company for our research
Impact We hope to determine the best approach for antibody-based drugs that work through ADCC
Start Year 2010
 
Description Understanding and manipulating Antibody Dependent Cell Cytotoxicity (ADCC) by human Natural Killer (NK) cells 
Organisation MedImmune
Country United States 
Sector Private 
PI Contribution This is a new grant funded by the MRC in collaboration with the company MedImmune
Collaborator Contribution Reagents and expertise is provided.
Impact This is a new funded grant, work is just now beginning. In addition, a postdoc from my lab will take up a new permanent post at this company
Start Year 2009
 
Description Popular Science Book 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact The Compatibility Gene was longlisted for the 2014 Royal Society Winton Science Book Prize, short-listed for the Society of Biology book prize and received a series of outstanding reviews in The Times, New York Times, Guardian, New Scientist, New Statesman, BBC Focus, Nature and so on. It was picked by Bill Bryson for the Guardian's Books of the Year feature 2013 and was included in Nature's features on Summer Books 2014 and Autumn Books 2014. A humorous piece by the popular journalist Tim Dowling, highlighted The Compatibility Gene on the front cover of The Guardian (8th Sept 2013) and featured in Dowling's own book How to be a Husband (2014).

Public awareness of immunology. This lead to extensive interantional coverage including TV appearences in the UK and USA, tens of radio interviews and my book received superb reviews in The New York Times, The Times, The Guardian, New Scientist and many many other places.
Year(s) Of Engagement Activity 2012
URL http://www.amazon.co.uk/The-Compatibility-Gene-Daniel-Davis/dp/1846145147/
 
Description Summary of media activities 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Davis keenly engages in making immunology accessible to non-specialist audiences. In August 2013, his popular-level book about the immune system entitled The Compatibility Gene was published by Penguin. The book received praise from Steven Pinker (Harvard), Steve Jones (UCL), Armand Leroi (Imperial) and Peter Doherty (Nobel Laureate), and had fantastic reviews, including in The Times, New York Times, Guardian, New Scientist, New Statesman, BBC Focus and Nature. It was picked by Bill Bryson in the Guardian's Books of the Year feature. An article about the book was also written by the popular journalist Tim Dowling, highlighted on the front cover of the Guardian (8th Sept 2013), and was discussed by comedian Russell Brand. The book and these articles also brought awareness to Anthony Nolan, the bone marrow transplantation charity.
In 2013, Davis discussed the immune system and genetics with Bill Turnbull and Susannah Reid on BBC Breakfast TV, watched by over 1 million, and also on live US TV on The Circle, MSNBC. In 2013, Davis did over 15 radio interviews including several BBC radio stations, NPR California and Radio New Zealand. The Smithsonian Institute (USA) published a profile of Davis in 2013 and Nature magazine also profiled Davis in its feature on scientists who write books (Get the word out, Nature, 504, 177-179, 2013).
In 2006, Davis published a major article - Secrets of the Immune Synapse - in Scientific American magazine, which has a worldwide readership of 1 million. In 2014, he published an article on the frontiers of immunology in BBC Focus magazine. He has been interviewed for features in New Scientist, The Guardian, The BMJ and various TV programs have solicited his advice. The BBC filmed an experiment performed in his laboratory for broadcast in 'The History of Transplantation', first shown on BBC FOUR, Sept 3rd 2008. He has given many interviews for international science magazines including in Spain, France and Portugal, on US Public Radio, and Australian radio. With Prof. Paul French (Physics, Imperial College), he presented his research at the Royal Society Summer Exhibition in 2003. In 2000, he won the Oxford University Press Science Writing Prize.
Davis has given numerous public lectures in immunology, including four at The Royal Institution. In 2008, Baroness Susan Greenfield commented in a letter that Davis's Friday Evening Discourse was 'really one of the most enjoyable in years'. Davis has presented his research at the Edinburgh, Manchester and Cheltenham Science Festivals, at Science Show Off events, on the Guardian science podcast, at a TED youth conference for ~500 6th formers, York's Festival of Ideas and at Latitude music festival (where he will return in 2017). Davis enjoys a close relationship with the Hay Festival where he has presented his own work as well as chaired and helping arrange many other science speakers (8 events in 2016), including Steve Jones, Jeremey Farrar and Martin Rees. Davis has written a second popular-level book about the immune system which will be published by Penguin Random House late 2017/early 2018.
Year(s) Of Engagement Activity 2013,2014,2015,2016,2017
 
Description TV/Radio interviews 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I gave multiple TV and radio interviews regarding my book The Compatibility Gene, including on BBC Breakfast TV, NBC in the USA, and many radio stations in the UK, Europe, Australia, New Zealand, Canada and so on.

A huge number of people got to hear about immune system genes as a result of this activity - 1 million people watched the BBC Breakfast discussion alone.
Year(s) Of Engagement Activity 2012,2013,2014
URL http://www.davislab.ls.manchester.ac.uk/book/bookreviews/