Drug Delivery at the Immunological Synapse

Lead Research Organisation: University of Manchester
Department Name: Life Sciences

Abstract

We 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 an average cell allow them to move, multiply, create 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. 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. It has been postulated that one function for such an immune synapse is to assemble a 'gasket' that to some extent isolates the synaptic cleft from the bulk extracellular environment. However, the precise extent as to which the synapse acts as a gasket has not been studied. This fundamental knowledge can have a major importance for the design of novel drugs, because understanding to what extent and how the immune synapse is shielded from the bulk extracellular environment could, in the longer term, facilitate the rational design of drugs that penetrate the immune synapse to work more effectively, e.g. for blocking proteins secreted across the synapse. It may also be useful to note that to realize the proposed experiments we will exploit new imaging technologies which will be of broad interest across several biological research fields. Patents may be sought upon development of specific applications. In addition to the specific hypotheses to be studied here, the application of high-resolution microscopy to study immune cell interactions is also to some extent explorative and hypothesis-forming; this is still a very young field and more surprises are surely in store.

Technical Summary

Directed secretion of soluble proteins, such as cytokines, across intercellular contacts plays a central role in establishing immune responses. A large structured interface is formed at such intercellular contacts where molecules required for adhesion and signalling accumulate to establish the immune synapse. It has been postulated that one function for such an immune synapse is to assemble a 'gasket' that to some extent isolates the synaptic cleft from the bulk extracellular environment. However, to the best of my knowledge, antibodies or other potential therapeutic agents have not been designed with a view to being able to readily penetrate and act within the context of such a gasket. Thus, I propose here to study fundamental properties of immune synapses that may impede drug/antibody delivery and apply this knowledge to the design of drugs/antibodies to act within immune synapses. I first aim to clarify the extent to which the immune synapse functions as 'gasket' and determine the underlying molecular and cellular mechanisms by which such a gasket is established. This will give important insights into the nature of the immune synapses and its importance for intercellular communication in the immune system. I then propose to assess different approaches in drug design to facilitate penetration into immune synapses, including lipid conjugation, varying drug size, and using bispecific antibodies. I propose to specifically compare the efficacy of different strategies for blocking synaptic cytokine secretion. Establishing the best approach for antibodies or other drugs to act within the context of an immune synapse can be an important consideration for the design of effective drugs for many diseases.

Planned Impact

Cancer, viral infections and auto-immune diseases can all be associated with cytokine secretion for which blocking antibodies or other drugs could target. Moreover, many pathological conditions, e.g. sepsis, are a direct result of immune cell activation including high levels of cytokine secretion. Intravenous injection of antibodies against cytokines or cytokine receptors has been attempted across several clinical trials for numerous diseases. There has been some limited success with this approach so far but many antibody-based therapies have not worked well and one possible reason could be because cytokines are, in some circumstances, secreted specifically across intercellular immune synapses. To the best of my knowledge, antibody-based drugs or other drugs have not been specifically designed with a view to being able to readily penetrate the immune synapse. Chemokines can also be secreted into the synaptic cleft by antigen-presenting cells to co-activate T cells in an antigen-specific manner. Thus, drugs that block chemokine activities may also benefit from being able to specifically penetrate immune synapses. Thus although a specific disease will not be studied here, the fundamental research outlined here can establish an important new consideration for drug design that can have a wide range of specific applications. That is, the best approach for antibodies or other drugs to act within the context of an immune synapse may prove to be an important consideration for the design of effective drugs for many diseases and hence there could be considerable impact for the pharmaceutical industry. To realize the proposed experiments, we will also exploit novel imaging technologies, developed by us in collaboration with Laser Physics group at Imperial College, which will be of broad interest across several biological fields. Patents may be sought upon development of specific imaging applications and/or in the development of practical applications. For the researcher employed, the proposed research provides a useful and rare opportunity to provide training in protein and cellular biochemistry, bioimaging, and state-of-the-art fluorescence spectroscopic techniques. Such a combination of technical skills is highly desirable in interdisciplinary environments within both commercial and academic settings. In addition, I am involved a wide range of teaching activity at Imperial College, including teaching segments of first and second year undergraduate degrees. The proposed research activity does directly impact my teaching style and allows me to enthuse young undergraduates by discussing cutting edge research in my lectures. I also keenly engage in making my research accessible to non-specialist audiences. For example, I published a major article in this research area in Scientific American magazine (Oct 2006) which has a worldwide readership of over one million. In addition, I was interviewed for a feature article published in New Scientist magazine in Nov 2008, and was interviewed for The Guardian newspaper regarding the award of the Nobel Prize for GFP (Oct 10th, 2008). The BBC filmed an experiment performed in my laboratory for broadcast in 'The History of Transplantation', first shown on BBC FOUR, Sept 3rd 2008. In addition, I gave public lectures at the Royal Institution in 2000, 2005 and 2008. I also gave interviews for many other magazines including several in Europe. Together with Prof. P. French (Physics, Imperial College London), I presented my research at the Royal Society Summer Exhibition in 2003. In 2000, I won the Oxford University Press/Times Higher Education Supplement Science Writing Prize, and my article was published in The Times Higher Education Supplement. Finally, members of my laboratory have presented their research twice at the House of Commons and also across several secondary schools in London. Similar activities will continue throughout the duration of the current proposal.

Related Projects

Project Reference Relationship Related To Start End Award Value
BB/I013407/1 16/04/2012 31/03/2013 £363,095
BB/I013407/2 Transfer BB/I013407/1 01/04/2013 30/04/2015 £255,832
 
Title Book: The Compatibility Gene 
Description The Compatibility Gene is a scientific adventure story set in a new field of genetic discovery - that of the crucial genes that define our relationships, our health and our individuality. Here, Daniel M Davis, one of the leading scientists in the field, tells us the story of its grounbreaking developments that have the potential to change us all We each possess a similar set of around 25,000 human genes. Yet a tiny, distinctive cluster of these genes plays a disproportionately large part in how our bodies work. These few genes, argues Daniel M. Davis, hold the key to who we are as individuals and our relationship to the world: how we combat disease, how our brains are wired, how attractive we are, even how likely we are to reproduce. In The Compatibility Gene, one of our foremost immunologists tells the remarkable history of these genes' discovery and the unlocking of their secrets. From the British scientific pioneers who, during the Second World War, struggled to understand the mysteries of transplants and grafts, to the Swiss zoologist who devised an entirely new method of assessing potential couples' compatibility based on the smell of worn T-shirts, Davis traces what is nothing less than a scientific revolution in our understanding of the human body: a global adventure spanning some sixty years. Davis shows how the compatibility gene is radically transforming our knowledge of the way our bodies work - and is having profound consequences for medical research and ethics. Looking to the future, he considers the startling possibilities of what these wondrous discoveries might mean for you and me. 
Type Of Art Creative Writing 
Year Produced 2014 
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). Davis discussed The Compatibility Gene on BBC Breakfast TV, as well as on US TV (The Circle, MS-NBC), the Guardian science podcast and several radio stations. Nature profiled Davis twice in 2013; in a feature on scientists who write books (Get the word out) and for his research discoveries. He has published articles in Scientific American, BBC Focus magazine, Physics World and previously won the Oxford University Press Science Writing Prize. In 2014, Davis presented The Compatibility Gene at the Hay Festival (Wales stage; 700 attendees), The Royal Institution in London (400 attendees), Edinburgh Science Festival, Manchester Science Festival, York's Festival of Ideas, Latitude music festival and many other events. 
URL http://www.amazon.co.uk/The-Compatibility-Gene-Daniel-Davis/dp/1846145147/ref=tmm_hrd_title_0
 
Description Mind the Gap - How new insight into cells could lead to better drugs

A new insight into immune cells by scientists at The University of Manchester could lead to more effective drug treatments.

Professor Dan Davis and his team at the Manchester Collaborative Centre for Inflammation Research, working in partnership with GlaxoSmithKline, investigated how different types of immune cells communicate with each other - and how they kill cancerous or infected cells. Their research has been published in Nature Communications.

Professor Davis says: "We study the immune system and then stumbled across something that may explain why some drugs don't work as well as hoped. We found that immune cells secrete molecules to other cells across a very small gap. This happens when immune cells talk to each other and also, when they kill diseased cells. But crucially, some types of drugs aren't able to penetrate the gap between the cells. So they can't easily reach targets within the gap, to work effectively."

The researchers took molecules of different sizes and colours and used microscopic imaging to see which size of molecule could get into the gap between an immune cell and another cell. They found that only the smaller molecules could penetrate the gap.

They even found that when an immune cell attaches to another cell it clears out all but the smallest molecules between them.

Professor Davis explains the significance of their findings: "Our research demonstrates that any drugs targeting immune cells need to be very small. Antibody proteins, for example, are too big and aren't able to get into the gap between the cells - they're even cleared away when cells meet. To make them more effective they must be smaller - something that GlaxoSmithKline is working on."

This research leads to new ideas for making drugs that, for example switch off immune activity in auto-immune diseases like diabetes or increasing immune reactivity to cancer. "A lot of important things that drugs could target are in the very small gap between cells. This research demonstrates why we need drug molecules to be especially small to work effectively. " said.at GSK quote?

PhD student Adam Cartwright played a key role in the research, spending time at GlaxoSmithKline as well as in Davis's lab at the University of Manchester.

He says: "Being able to test out our theory with drugs that GSK has designed was fantastic. The idea that something I had found out can be used to develop treatments to help patients is incredibly exciting."

Professor Davis, author of the popular Penguin paperback The Compatibility Gene, concludes: "The practical application of this basic research comes from bouncing around our ideas with scientists working on drug design. The interaction between academia and pharma is hugely beneficial and we hope it will lead to more effective drug treatments."
Exploitation Route GSK use our research in drug design
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

URL http://www.davislab.ls.manchester.ac.uk/
 
Description GSK use our findings in drug design
First Year Of Impact 2012
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Economic

 
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 Manchester Collaborative Centre
Amount £2,000,000 (GBP)
Organisation University of Manchester 
Department Manchester Collaborative Centre for Inflammation Research (MCCIR)
Sector Academic/University
Country United Kingdom
Start 11/2012 
End 10/2017
 
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 Communicating complex network information by intercellular transfer of macrophage proteins and RNA 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution Communicating complex network information by intercellular transfer of macrophage proteins and RNA
Collaborator Contribution Communicating complex network information by intercellular transfer of macrophage proteins and RNA
Impact Communicating complex network information by intercellular transfer of macrophage proteins and RNA
Start Year 2008
 
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 Public Lectures / Interviews 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? Yes
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Davis discussed The Compatibility Gene on BBC Breakfast TV, as well as on US TV (The Circle, MS-NBC), the Guardian science podcast and several radio stations. Nature profiled Davis twice in 2013; in a feature on scientists who write books (Get the word out) and for his research discoveries. He has published articles in Scientific American, BBC Focus magazine, Physics World and previously won the Oxford University Press Science Writing Prize. In 2014, Davis presented The Compatibility Gene at the Hay Festival (Wales stage; 700 attendees), The Royal Institution in London (400 attendees), Edinburgh Science Festival, Manchester Science Festival, York's Festival of Ideas, Latitude music festival and many other events.

Public lectures were extremely well attended
Year(s) Of Engagement Activity 2006,2007,2008,2009,2010,2011,2012,2013,2014,2015,2016
URL http://www.davislab.ls.manchester.ac.uk/book/articlesandvideos/
 
Description Science Museum talks 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact As one example of my public talks, I gave two talks at The Science Museum, London, on the immune system as part of their Lates event on Feb 24th 2016.
Year(s) Of Engagement Activity 2016
 
Description Scientific American article 
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 I published a major article in this research area in Scientific American magazine which has a worldwide subscription of over one million.

This was the most downloaded article at the time of publication
Year(s) Of Engagement Activity 2006
 
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/
 
Description Various media engagements 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact I have interacted with many media outlets in relation to my research and been quoted widely as a spokesperson for discoveries in immunology. For example, I was quote on the front page of The Times newspaper on Feb 16th 2016 and featured in almost every UK paper (including The Telegraph, The Mirror and The Sun). I have also advised several TV programs.
Year(s) Of Engagement Activity 2012,2013,2014,2015,2016
URL http://www.telegraph.co.uk/news/science/science-news/12157788/Cancer-vaccine-that-remembers-disease-...