A New Approach to the Chemical Modification of Antibodies via Maleimide Bridging of Disulfides

Lead Research Organisation: University College London
Department Name: Chemistry


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.


10 25 50
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 04/2018 
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 08/2016 
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 08/2016 
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 05/2015 
End 06/2018
Description UCL Technology Fund
Amount £100,000 (GBP)
Organisation University College London 
Sector Academic/University
Country United Kingdom
Start 06/2017 
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
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.
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/