A strategy for rapid directed modification of protein binding properties
Lead Research Organisation:
University of Leicester
Department Name: Cardiovascular Sciences
Abstract
Development of new protein-based drugs would be greatly helped if there was a straightforward and rapid method by which proteins could be changed so they would bind more specifically and strongly to their targets within the body. This would allow drugs with fewer side effects and higher potency to be made. In addition, changing proteins so they can bind to new disease targets would allow new types of drugs to be developed. This project aims to establish and test a novel method for changing protein binding very much more easily and rapidly than ever before.
Technical Summary
This project seeks to establish and test a new method for straightforward, rapid modification of recognition and binding characteristics of proteins. The method will find applications in a number of areas including development of biological therapeutics and biosensors. The proposed strategy will utilize mutagenesis together with surface display. This will be combined with selection of protein variants with specific binding characteristics based on their interaction with fluorescently-labelled partners. The approach aims to generate novel proteins with specified binding properties more rapidly and easily than previously possible.
People |
ORCID iD |
| Nicholas Brindle (Principal Investigator) |
Publications
Brindle NP
(2013)
Directed evolution of an angiopoietin-2 ligand trap by somatic hypermutation and cell surface display.
in The Journal of biological chemistry
| Description | The project has now provided proof of concept for a new method to generate proteins with specific binding characteristics. This will be useful for application to generation of therapeutics as well as biotechnological uses. In addition the project has shown that this method can be used to help define what parts of a protein contribute to specific aspects of its function. |
| Exploitation Route | The work provides a method that can be used to create new proteins for use in medical and biotechnology applications. The project has produced a new protein with therapeutic potential that could have use as a novel drug. |
| Sectors | Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology |
| Description | The findings have two potential impacts - a new biological therapeutic and a method for creating further protein-based therapeutics and biotechnology products. We have patented the potential therapeutic and are developing this to a stage when it can be tested in vivo. This is likley to be the stage at which impact is most likely to occur - if the protein is taken up by pharma for further development. If so impact would be societal and economic. UPDATE 2018 - we have been approached by a pharma company, Inotrem, and are currently in discussion with them for potential development of the protein as a biotherapeutic. |
| First Year Of Impact | 2013 |
| Sector | Pharmaceuticals and Medical Biotechnology |
| Description | Project Grant |
| Amount | £196,423 (GBP) |
| Organisation | British Heart Foundation (BHF) |
| Sector | Charity/Non Profit |
| Country | United Kingdom |
| Start | 04/2016 |
| End | 03/2019 |
| Title | Ang2 Ligand Trap |
| Description | New protein variant with therapeutic potential |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2013 |
| Provided To Others? | Yes |
| Impact | Publication of the method and evolved molecule, patent, conference presentations |
| Description | Ang2 ligand trap |
| Organisation | Medical Research Council (MRC) |
| Department | MRC Laboratory of Molecular Biology (LMB) |
| Country | United Kingdom |
| Sector | Academic/University |
| PI Contribution | I used the expertise built up during the grant period to set up the evolution system at LMB and evolve the protein |
| Collaborator Contribution | Expertise in using the DT40 cell line and access to facilities and other expertise |
| Impact | Publication in JBC and patent. The collaboration was covered by an agreement during my secondment to LMB, I have a less formal continuing collaboration with the LMB PI ongoing |
| Start Year | 2011 |
| Description | Inotrem |
| Organisation | Inotrem SA |
| Country | France |
| Sector | Private |
| PI Contribution | Expertise and intellectual input to targeting Ang2 in vascular inflammation and other conditions, potentially access to data |
| Collaborator Contribution | Access to expertise, potentially access to disease models |
| Impact | Collaboration is newly initiated |
| Start Year | 2018 |
| Title | ANGIOPOIETIN-2 SPECIFIC TIE2 RECEPTOR |
| Description | In one aspect, provided herein is a polypeptide comprising a modified angiopoietin receptor or fragment thereof, wherein the polypeptide binds preferentially to angiopoietin-2 compared to angiopoeitin-1. Nucleic acid sequences encoding the polypeptide, as well as pharmaceutical uses of the polypeptide in treating diseases such as cancer and inflammation are also provided. |
| IP Reference | WO2014096855 |
| Protection | Patent application published |
| Year Protection Granted | 2014 |
| Licensed | No |
| Impact | This PCT filing followed on from an initial UK patent application in December 2012. The discovery is currently being made available for licenesing via MRCT. This is the original ligand trap that we are now developing further with BHF funding. |
| Title | Ang2 ligand trap |
| Description | New variant of Tie2 ectodomain that acts as a ligand trap to block pathological actions of Ang2. We have developed the initial variant with funding from the original BBSRC Tools and Resources Development grant and subsequently in collaboration with MRC LMB. |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Refinement. Non-clinical |
| Year Development Stage Completed | 2014 |
| Development Status | Actively seeking support |
| Impact | None as yet |
| Title | Ang2 ligand trap 2018 developments |
| Description | The Ang2 ligand trap is a fusion protein with potential as a biothrapeutic. With BHF funding we have substantially improved affinity and specificity and the project as attracted interest from a pharmaceutical company. We are currently in negotiation with this company for the development of the ligand trap as a possible biotherapeutic. |
| Type | Therapeutic Intervention - Drug |
| Current Stage Of Development | Refinement. Non-clinical |
| Year Development Stage Completed | 2017 |
| Development Status | Under active development/distribution |
| Impact | The ligand-trap has already revealed a significant novel cellular mechanism controlling blood vessel integrity. This data has not yet been published. |
| Description | Project result communications |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Professional Practitioners |
| Results and Impact | The method we developed during this project and resulting biological insight and potential therapeutic have been presented at a number of seminars and meetings, for example 2014 Harden Conference on Receptor tyrosine kinases. In addition, a summary of the method was published in BBSRC Business magazine (December 2013) and the publicity regarding the paper carried on a number of websites including MRC LMB, BBSRC and Science Daily. Several enquiries from scientists about using the technique as well as the molecule created |
| Year(s) Of Engagement Activity | 2013 |