Evolution and protein engineering

Lead Research Organisation: MRC Laboratory of Molecular Biology

Abstract

The origins of proteins are buried in the mists of time but comparisons of their gene sequences and/or 3 D protein structures can help us understand how they have evolved. As proteins close in evolution often have similar functions, this can help to make sense of the large amounts of DNA sequence information emerging from the Genome projects (for example to identify target proteins for therapeutic drugs). We propose to add a further dimension to existing approaches; to harness the power of evolution itself and to evolve proteins in the test-tube. We anticipate that this will help to understand how proteins evolved, to identify hidden relationships between modern proteins, and to endow modern proteins with novel functions, for example as antibodies or vaccines.

Technical Summary

We will harness the power of phage selection technologies to provide insights into the evolution of proteins and their biophysical properties, and to the creation of novel proteins. More specifically, we will combine repertoires of gene fragments and use methods of selection to identify those with folded surfaces that retain features of the parent domains. We will use these combinatorial proteins as immunogens to focus the antibody response against a single epitope of the parent protein; this may have application in the development of vaccines targeted against self-antigens or the neutralizing epitopes of viruses. We will also develop the use of selection methods as a genomic tool to identify folded domains in sequences of the E. coli genome. Not only should this greatly facilitate the systematic assignment of sequences from whole genomes to families of known structures, but also pinpoint those encoding unknown architectures for structural determination. A key element of all the studies above will be the use of X-ray crystallography to determine the structures of domains, combinatorial proteins or antibody fragments.

Publications

10 25 50
 
Description Jeantet Fellowship - Daniel Christ
Amount £2,500 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 10/2006 
End 11/2006
 
Description Jeantet Fellowship - Heinis
Amount £2,500 (GBP)
Organisation Medical Research Council (MRC) 
Department Medical Research Foundation
Sector Charity/Non Profit
Country United Kingdom
Start 01/2008 
End 01/2008
 
Description Novartis Foundation Fellowship
Amount £17,400 (GBP)
Organisation Novartis 
Sector Private
Country Global
Start 01/2007 
End 12/2007
 
Description SNSF Fellowship
Amount £18,700 (GBP)
Organisation Swiss National Science Foundation 
Sector Public
Country Switzerland
Start 01/2006 
End 12/2006
 
Description Garvan Collaboration 
Organisation The Garvan Institute for Medical Research
Country Australia 
Sector Hospitals 
PI Contribution Provision of advice; secondment of Peter Jones for 3 months in 2008 to set up fractionation protocols for investigation of role of gamma globulin in diseases including rhumatoid arthritis
Collaborator Contribution Hosting Pete Jones during secondment; testing of fractionation in various animal models
Impact Advanced understanding of role of gamma globulin in treatment of rhumatoid arthritis
Start Year 2008
 
Title Method for Amplication of Ligation Reactions 
Description The invention provides a method for preparing a library of transformed host cells said method comprising the steps of taking a library of closed circular DNA molecules; amplifying said library of closed circular DNA molecules through a rolling circle mechanism in the presence of a strand displacement polymerase to generate a library of linear concatamers; cleaving said linear concatamers to generate a library of linear DNA molecules; re-circularising said library of linear DNA molecules to generate a library of circular DNA molecules; and transforming said library of circular DNA molecules into host cells. 
IP Reference WO2008012529 
Protection Patent granted
Year Protection Granted 2008
Licensed Commercial In Confidence
Impact NA
 
Title ABT-874 
Description Antibody therapeutic against IL-12/23 developed by Abbott and Cambridge Antibody Technology (licensees of MRC/Cambridge Antibody Technology inventions of combinatorial antibody libraries/phage display) 
Type Therapeutic Intervention - Drug
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact Treatment for psoriasis 
 
Title Abthrax 
Description Antibody therapeutic against Anthrax developed by Human Genome Sciences and Cambridge Antibody Technology (licensees of MRC/Cambridge Antibody Technology inventions of combinatorial antibody libraries/phage display) 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2009
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Stockpiled by US Government for treatment of anthrax infections 
URL https://clinicaltrials.gov/show/NCT00639678
 
Title Actemra 
Description Antibody therapeutic against IL6 receptor developed by Chugai/Roche licensees of MRC invention of humanised antibodies, approved in Japan 
Type Therapeutic Intervention - Drug
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Treatment of rheumatoid arthritis 
 
Title Actemra 
Description Antibody therapeutic against IL6 receptor developed by Chugai/Roche licensees of MRC invention of humanised antibodies. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Treatment of systemic onset juvenile idiopathic arthritis 
 
Title Benlysta 
Description Antibody therapeutic against the target Blys developed by Human Genome Sciences and Cambridge Antibody Technology (licensees of MRC/Cambridge Antibody Technology inventions of combinatorial antibody libraries/phage display) 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2009
Development Status Under active development/distribution
Clinical Trial? Yes
Impact First new treatment of systemic lupus erythematosis (SLE) for fifty years. 
URL https://clinicaltrials.gov/show/NCT01532310
 
Title CAT-354 
Description Antibody therapeutic against IL-13 developed by Medimmune (licensees of MRC/Cambridge Antibody Technology inventions of combinatorial antibody libraries/phage display) 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Safety data for treatment of asthma 
 
Title Cimzia 
Description Antibody therapeutic against TNF alpha developed by Celltech/UBS licensees of MRC invention of humanised antibodies, approved by US FDA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact Treatment of Crohn's disease 
 
Title Humira 
Description Antibody therapeutic against TNF alpha developed by Abbott and Cambridge Antibody Technology (licensees of MRC/Cambridge Antibody Technology inventions of combinatorial antibody libraries/phage display) approved by FDA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2010
Development Status Under active development/distribution
Impact Treatment of Crohn's disease 
 
Title Humira 
Description Antibody therapeutic against TNF alpha developed by Abbott and Cambridge Antibody Technology (licensees of MRC/Cambridge Antibody Technology inventions of combinatorial antibody libraries/phage display) approved by US FDA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2006
Development Status Under active development/distribution
Impact Treatment for ankylosing spondylitis 
 
Title Humira 
Description Antibody therapeutic against TNF alpha developed by Abbott and Cambridge Antibody Technology (licensees of MRC/Cambridge Antibody Technology inventions of combinatorial antibody libraries/phage display) approved by US FDA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Market authorisation
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact Treatment of psoriasis 
 
Title Lucentis 
Description Antibody therapeutic against VEGF developed by Genentech/Roche, licensees of MRC invention of humanised antibodies, approved in Japan 
Type Therapeutic Intervention - Drug
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2008
Development Status Under active development/distribution
Impact Treatment of wet age-related macular degeneration 
 
Title Soliris 
Description Antibody therapeutic against complement system C5 developed by Alexion Pharmaceuticals, licensees of MRC invention of humanised antibodies, approved by US FDA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2009
Development Status Under active development/distribution
Impact Treatment of paroxysmal nocturnal hemoglobinuria 
 
Title Tysabri 
Description Antibody therapeutic against cellular adhesion molecule alpha 4 integrin, developed by Biogen Idec and Elan, licensees of MRC invention of humanised antibodies, approved by US FDA 
Type Therapeutic Intervention - Drug
Current Stage Of Development Small-scale adoption
Year Development Stage Completed 2007
Development Status Under active development/distribution
Impact Treatment of multiple sclerosis 
 
Description Australian media 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Media (as a channel to the public)
Results and Impact Interviewed by ABC Radio and TV for programs on my work on antibody therapeutics

Not known
Year(s) Of Engagement Activity 2008
 
Description Japanese industrialists-Tokyo 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Described antibody technologies to Japanese industrialists at British Embassy Tokyo

None yet
Year(s) Of Engagement Activity 2007,2008,2009
 
Description Nobel Lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact As part of the Nobel Prize I gave a lecture on 08/12/2018 to the Nobel committee, previous laureates and other invited dignatories. My lecture title was Harnessing Evolution to Make Medicines. As a result of the award I have had many invitations to give lectures and media interviews.
Year(s) Of Engagement Activity 2018
URL https://www.youtube.com/watch?v=kV8BXi3aRsI
 
Description Radio Interview - The Life Scientific 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact I was interviewed by Professor Jim Al-Khalili on Radio's 4's The Life Scientific about my work with the MRC which led to the Nobel Prize award.
Year(s) Of Engagement Activity 2019