Unlocking the complement-suppressing potential of factor H with a bacterial polypeptide
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Chemistry
Abstract
A challenge in medicine is that contact between blood and manmade devices (such as intra-vascular stents used in cardiac surgery or dialysis equipment for kidney-failure patients) can trigger part of the human immune system called the complement cascade, with dire clinical consequences. We discovered that PspCN, a polypeptide of microbial origin, "turbocharges" a human protein (CFH) that inhibits the complement cascade. Guided by the results of a market assessment, we now propose to design, manufacture and test PspCN-decorated surface coatings for medical implants. We aim to demonstrate that the PspCN displayed on these potentially protective coatings will grab hold of CFH, which is abundant in blood, and induce the captured CFH to switch from a latent to an activated form. Thus, in an improvement on the efforts of competitors to utilize CFH in its latent form, our approach will afford coated surfaces that are protected from the complement cascade by the patient's own, activated, CFH.
People |
ORCID iD |
Paul Barlow (Principal Investigator) |
Publications
Chen ZA
(2016)
Structure of Complement C3(H2O) Revealed By Quantitative Cross-Linking/Mass Spectrometry And Modeling.
in Molecular & cellular proteomics : MCP
Harder MJ
(2016)
Comparative Analysis of Novel Complement-Targeted Inhibitors, MiniFH, and the Natural Regulators Factor H and Factor H-like Protein 1 Reveal Functional Determinants of Complement Regulation.
in Journal of immunology (Baltimore, Md. : 1950)
Herbert AP
(2015)
Complement Evasion Mediated by Enhancement of Captured Factor H: Implications for Protection of Self-Surfaces from Complement.
in Journal of immunology (Baltimore, Md. : 1950)
Kerr H
(2017)
Disease-linked mutations in factor H reveal pivotal role of cofactor activity in self-surface-selective regulation of complement activation.
in The Journal of biological chemistry
Makou E
(2015)
Creating functional sophistication from simple protein building blocks, exemplified by factor H and the regulators of complement activation
in Biochemical Society Transactions
Description | Our goal was to explore the utility of a bacterial peptide as an anchor for the human suppressor of complement, factor H (FH), which is abundant in blood. We were hoping to emulate the bacterial complement-evasion strategy whereby FH is both irreversibly bound on the bacterial surface and held in a functionally enhanced form that ensures it acts as a potent blocker of C3b amplification and deposition. The ultimate aim was to attach the bacterial peptide onto the manmade surfaces lining medical devices as a means to protect them against damage from the two linked pathways of complement and clotting. As planned we were able to immobilise the N-terminal domain of the D39 Streptococcus pneumoniae protein PspC (i.e. PspCN) to surfaces. We engineered N-terminal and C-terminal Cys (-SH) labelled versions and found the N-terminally labelled version performed better. We initially used maleimide-coated polystyrene multi-well plates to show that we could covalently attach SH-PspCN and use this to anchor factor H (detected by an anti-FH antibody). We were able to show convincing decreases in C3b deposition (monitored with an anti-C3b antibody) on the PspCN/FH-decorated surfaces compared to controls. We were subsequently able to immobilise PspCN on a range of other materials including polymers developed (by Mark Bradley's laboratory) for stent coatings that favour re-endothelialilasion of stent-damaged arterial segments. We were also able to illustrate the potential utility of PspCN on bare-metal stents by coating metal strips with PspCN. In suppression of complement activation assays (C3-deposition, C5b-9 formation) the coated strips easily outperformed uncoated ones. Also in line with our objectives we looked at PspCN from other strains of S. pneumoniae. We found that certain truncations of TigR4 PspCN has very similar functions to D39 PspCN (including the anchoring and activating of FH), despite having only low sequence similarity. Indeed _none_ of the residues of TigR4 that were critical to its complex with FH (according to a crystal structure of the complex) were conserved in D39 PspCN. This was consistent with out hypothesis that FH can oscillate between different conformations, one of which is readily stabilised by binding of a protein to its modules 8-10, with the actual details of the binding being of only secondary importance. With potential therapeutic uses in mind, we also prepared PEGylated SH-PspCN, in line with our aims, and showed that it retained the biological properties of the non-PEGylated material. Our collaborators in the USA showed that our PEGylatd PspCN was less immunogenic than the nonPEGylatd version in mice. Our results were used to obtain further funding from Scottish Enterprise for development of "H-guard", a PspCN-based coating for medical devices with novel anti-complement properties. |
Exploitation Route | Our attempts to spin-out a company making medical device coatings are well advanced and we have successfully obtained Phase II of Scottish Enterprise High-Growth Spinout funding. The therapeutic use of PspC as an enhancer of Fh in age-related macular degeneration is an exciting possibility. We have a commercial partner who has funded PK studies in mice and NHPs (conducted by a CRO in the US). |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | Andrew Herbert who was a PDRA on the grant is the founder and CTO of Invizius, a spinout that launched January 2018. Invizius has now fully spun out from the University and is located in Glasgow BioCity with a team of six. |
First Year Of Impact | 2017 |
Sector | Healthcare,Pharmaceuticals and Medical Biotechnology |
Impact Types | Economic |
Description | Industrial collaboration funding (one off) |
Amount | £150,000 (GBP) |
Funding ID | Fellowship Eliza Makou |
Organisation | Gemini Therapeutics, Inc. |
Sector | Private |
Country | United States |
Start | 02/2018 |
End | 02/2019 |
Description | Medical Device Coatings (H-Guard) Phase 2 |
Amount | £420,365 (GBP) |
Funding ID | PS7305CA45 |
Organisation | Scottish Enterprise |
Sector | Public |
Country | United Kingdom |
Start | 08/2016 |
End | 04/2018 |
Description | Research Project Grant |
Amount | £218,000 (GBP) |
Funding ID | RPG-2015-109 |
Organisation | The Leverhulme Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2015 |
End | 03/2017 |
Description | Structural and functional studies of complement regulation |
Amount | £150,000 (GBP) |
Organisation | Gemini Therapeutics, Inc. |
Sector | Private |
Country | United States |
Start | 01/2019 |
End | 01/2020 |
Description | Ocular therapeutics |
Organisation | Pathfinder Bio |
Country | United States |
Sector | Private |
PI Contribution | I will be a Scientific Founder of new ocular therapeutics company, Gemini Therapeutics. Focus is on complement and factor H. I have helped to raise seed funding from VCs. Our research team is contributing expertise in experimental design and data analysis and interpretation, preparation and testing of complement proteins for PK studies, advice and consultancies. |
Collaborator Contribution | James McLaughlin has led in company formation and raising seed funding. |
Impact | None yet - research activities commencing in March 2016 |
Start Year | 2015 |
Description | Partnership with Scottish Enterprise |
Organisation | Scottish Enterprise |
Country | United Kingdom |
Sector | Public |
PI Contribution | Andrew Herbert in my research team is spinning out a company |
Collaborator Contribution | Exoertise, advice, the funding of salaries |
Impact | None yet |
Start Year | 2015 |
Title | PROTEINS WITH DIAGNOSTIC AND THERAPEUTIC USES |
Description | The present invention provides a recombinant protein capable of binding to complement factor H (CFH), and thereby inducing increased binding of C3d and C3b by bound CFH compared to unbound CFH. Methods and medical devices for using utilising the same are also described. |
IP Reference | WO2015055991 |
Protection | Patent application published |
Year Protection Granted | 2015 |
Licensed | Yes |
Impact | None |
Company Name | Gemini Therapeutics |
Description | Gemini Therapeutics is a Boston-based precision medicine company focused on genetically-defined dry age-related macular degeneration (AMD) and associated rare genetic diseases. Gemini's therapeutic candidates are matched to molecular abnormalities found in patients with high clinical need and Gemini's broad multimodal pipeline includes monoclonal antibodies, recombinant proteins (including factor H) and gene therapies. Launched with funding from leading life science investors and powered by academic partnerships around the world, Gemini is developing a series of potentially first-in-class therapeutics. Paul Barlow (PI) and Andrew Herbert (PDRA on grant) are scientific co-founders of Gemini Therapeutics. |
Year Established | 2017 |
Impact | Gemini raised > $43M in seed and Series-A funding from Atlas Ventures, Lightstone and Orbimed. Gemini have recently commenced enrolment in a Phase I study of intravitreal administration of FH to treat dry AMD. |
Website | https://www.geminitherapeutics.com |
Company Name | Invizius |
Description | Invizius develops medical technology, called The H-Guard Priming Solution, that aims to eradicate side effects when conducting hemodialysis. |
Year Established | 2018 |
Impact | Invizius has recently secured seed funding totalling nearly £3 from a consortium including Mercia Asset Management. Invizius, is now fully spun out and located in BioCity Glasgow with a team of 6. It is developing biocompatible medical devices such as dialysers coated with a functionally augmented form of FH (anchored by PspCN). It was named in 2018 as one of the 15 "Fierce Med Tech" companies, predicted to become one of the most important new companies in the industry. |
Website | https://www.invizius.com/ |