A New Approach to the Chemical Modification of Antibodies via Maleimide Bridging of Disulfides
Lead Research Organisation:
University College London
Department Name: Chemistry
Abstract
We are entering extremely exciting times in the development of the next generation of therapeutics, as scientists have turned their attention to the manipulation of part of nature's own defense mechanism; antibodies. Antibodies can now be designed in the lab to target a variety of diseases, including cancer and infectious diseases. They represent the fastest growing class of therapeutics, with a market value estimated to be around $50 billion. Currently however, a limiting factor in the area is the lack of reliable chemical methods that will allow the modification and optimisation of the properties of antibodies. We are proposing here to exemplify a new class of chemical reagents that will allow the highly effective modification of antibodies for the first time. This exemplification will enable us to establish partnerships with pharmaceutical and biotechnology companies to facilitate the optimisation of future antibody-based therapeutics.
Publications
Nathani RI
(2013)
Reversible protein affinity-labelling using bromomaleimide-based reagents.
in Organic & biomolecular chemistry
Schumacher F
(2014)
Next generation maleimides enable the controlled assembly of antibody-drug conjugates via native disulfide bond bridging
in Org. Biomol. Chem.
Hull EA
(2014)
Homogeneous bispecifics by disulfide bridging.
in Bioconjugate chemistry
Schumacher FF
(2013)
Homogeneous antibody fragment conjugation by disulfide bridging introduces 'spinostics'.
in Scientific reports
Castañeda L
(2013)
Acid-cleavable thiomaleamic acid linker for homogeneous antibody-drug conjugation
in Chemical Communications
Castañeda L
(2013)
A mild synthesis of N-functionalised bromomaleimides, thiomaleimides and bromopyridazinediones.
in Tetrahedron letters
| Description | Using antibodies as therapeutics and diagnostics is one of the most promising areas of research into new healthcare products. Antibodies represent the fastest growing class of therapeutics, with over 30 approved for clinical use to date and over 150 in clinical development. It is estimated that the global market for antibody therapeutics is currently around $50 billion. Aparticularly promising class of antibody based therapeutics are antibody-drug-conjugates (ADCs), commonly referred to as 'magic-bullet' therapies due to their ability to seek and destroy just diseased cells within the body (e.g. cancer cells). However, a major hindrance to the area is the lack of suitable chemical methods for the construction of homogeneous, well defined, antibody conjugates. In this project we developed a new platform for homogeneous antibody conjugation, which we expect to offer major advantages in the construction of next geneation antibody conjugates as therapetics. This was achieved by the design, synthesis and successful application. of a range of new reagents which target specific amino-acid residues present in antibodies. |
| Exploitation Route | The development of defined antibody conjugates by this research provides an improved method for generating antibody conjugates as therapeutics and also diagnostics. This should lead to improved healthcare products e.g. better tolerated therapies, improved therapeutic index, more sensitive diagnostic methods and more reproducible/economical products. |
| Sectors | Chemicals,Healthcare,Pharmaceuticals and Medical Biotechnology |
| Description | In this project we demonstrated new methods for the generation of homogeneous anibody fragment and full antibody conjugates. These methods are extremely promising for the generation of superior antibody conjugates for therapeutic applications. This possibility is currently being explored by us (and others) for use in the area of antibody-drug conjugates, as highly targetted 'magic-bullet' therapeutics. |
| First Year Of Impact | 2013 |
| Sector | Chemicals,Healthcare |
| Description | EPSRC |
| Amount | £514,721 (GBP) |
| Funding ID | EP/R034621/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2018 |
| End | 04/2021 |
| Description | EPSRC CASE Award with Albumedix |
| Amount | £100,567 (GBP) |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2016 |
| End | 09/2020 |
| Description | EPSRC CASE Award with MRCT |
| Amount | £95,000 (GBP) |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2016 |
| End | 09/2020 |
| Description | EPSRC grant |
| Amount | £564,009 (GBP) |
| Funding ID | EP/M01732X/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2015 |
| End | 06/2018 |
| Description | UCL Technology Fund |
| Amount | £100,000 (GBP) |
| Organisation | University College London |
| Sector | Academic/University |
| Country | United Kingdom |
| Start | 07/2017 |
| End | 01/2018 |
| Title | New reagents for antibody conjugation |
| Description | In this project we developed a range of new reagents for application in antibody conjugation. These included reagents of the type; dibromomaleimide-linker-fluorophore, dibromomaleimide-linker-PEG and dibromomaleimide-linker-fluorophore, and thiophenolmaleimide versions of these reagents. The methodology we developed involved employing these reagents to react with reduced disulfide bonds in antibody fragments and antibodies, affording antibody conjugates which retained the interchain covalent bridges. In this way we were able to generate superior antibody conjugates to those accessible by the current state-of-the-art methods (targeting lysine residues, or reduced disulfide bonds without re-bridging). This methodology has highly significant potential for widespread use in the generation of the next generation of antibody conjugates. |
| Type Of Material | Technology assay or reagent |
| Year Produced | 2013 |
| Provided To Others? | Yes |
| Impact | Not applicable yet |
| URL | http://dx.doi.org/10.1038/srep01525 |
| Description | Collaboration with Novozymes |
| Organisation | Novozymes Biopharma UK ltd |
| Country | United Kingdom |
| Sector | Private |
| PI Contribution | Option and evaluation agreement signed between Novozymes and UCL Business to exploit our protein conjugation technology for the development of albumin conjugates for therapy. Our role is to provide the expertise on the use of next generation maleimides for protein conjugation. |
| Collaborator Contribution | Novozymes are providing funds (contractually confidential) and are also carrying out proof of concept experiments as part of the collaboration. |
| Impact | N/A |
| Start Year | 2013 |
| Title | CHEMICAL MODIFICATION OF ANTIBODIES |
| Description | The present invention relates to antibodies and antibody fragments, one or more of whose native inter-chain disulfide bridges have been replaced with a specific bridging moiety. The bridging moiety can be selectively targeted to inter-chain disulfide bonds within the antibody or antibody fragment, enabling the construction of more homogeneously modified products such as antibody-drug conjugates. |
| IP Reference | WO2013132268 |
| Protection | Patent application published |
| Year Protection Granted | 2013 |
| Licensed | No |
| Impact | None yet. |
| Title | REVERSIBLE COVALENT LINKAGE OF FUNCTIONAL MOLECULES |
| Description | The present invention relates to the use of a compound containing a moiety of formula (I) as a reagent for linking a compound of formula R1-H which comprises a first functional moiety of formula F1 to a second functional moiety of formula F2 wherein X, X', Y, R1, F1 and F2 are as defined herein. The present invention also provides related processes and products. The present invention is useful for creating functional conjugate compounds, and specifically conjugates in which at least one of the constituent molecules carries a thiol group. |
| IP Reference | WO2011018611 |
| Protection | Patent granted |
| Year Protection Granted | 2011 |
| Licensed | Yes |
| Impact | Ongoing evaluations with other companies in biopharmaceutical area. |
| Company Name | Thiologics |
| Description | In 2011 Dr James Baker co-founded Thiologics (www.thiologics.com), to provide a vehicle to translate the Next Generation Maleimide platform for homogeneous protein conjugation towards clinical product development. ThioLogics is a company formed by UCL Business (UCLB) and is in an early pre-seed phase of development supported solely by UCLB funds. The formation of ThioLogics has created a market presence and facilitated early engagement through our existing networks. |
| Year Established | 2011 |
| Impact | N/A |
| Website | http://www.thiologics.com/ |