Periodic Reporting for period 1 - ISOBIOTICS (Isotopic Labeling of Biotherapeutics)
Periodo di rendicontazione: 2023-02-01 al 2025-01-31
Biological therapeutics based on biomolecules have been skyrocketed on the drug market due to their very high specificity, excellent selectivity and resulting high efficiency with resulting reduced side-effects, lower drug attrition and lower development costs. However, there is an urgent need for isotopically-labeled biodrugs utilized for in vitro assays and in vivo (preclinical and clinical) tests.
In contrast with chemical drugs, there is only a very limited number of strategies devised for the specific and selective isotopic labeling of biological molecules because of the size, fragility and complexity of biologicals and also because most of biologics are exclusively soluble in water, a medium which notably disfavors classical chemical reactions.
To date, in most cases, biotherapeutics have been labeled using chemical methods that are only poorly selective and usually give a polydisperse mixture of modified biologics, a situation which makes further analysis of results more complex and prone to biases (figure 1). Therefore, there is a pressing demand from the Pharmaceutical Industry for straightforward, simple, reproducible and chemically benign strategies that enable the isotopically labeling biological molecules in particular with hydrogen and carbon stable isotopes (respectively deuterium and carbon-13), hydrogen and carbon radio-isotopes (respectively tritium and carbon-14) and fluorine-18 (radioisotope for medical imaging).
There is also a lack of specialized chemists capable of devising and implementing such strategies that require an in-depth knowledge of synthetic chemistry and isotopic chemistry but also an intensive experience of biomolecules handling, engineering and analysis. In the same way, there are extremely few mixed Academic/Industrial structures that propose such a training encompassing strategic, scientific and technical aspects of the chemically-benign labeling of biologics.
In contrast with chemical drugs, there is only a very limited number of strategies devised for the specific and selective isotopic labeling of biological molecules because of the size, fragility and complexity of biologicals and also because most of biologics are exclusively soluble in water, a medium which notably disfavors classical chemical reactions.
To date, in most cases, biotherapeutics have been labeled using chemical methods that are only poorly selective and usually give a polydisperse mixture of modified biologics, a situation which makes further analysis of results more complex and prone to biases (figure 1). Therefore, there is a pressing demand from the Pharmaceutical Industry for straightforward, simple, reproducible and chemically benign strategies that enable the isotopically labeling biological molecules in particular with hydrogen and carbon stable isotopes (respectively deuterium and carbon-13), hydrogen and carbon radio-isotopes (respectively tritium and carbon-14) and fluorine-18 (radioisotope for medical imaging).
There is also a lack of specialized chemists capable of devising and implementing such strategies that require an in-depth knowledge of synthetic chemistry and isotopic chemistry but also an intensive experience of biomolecules handling, engineering and analysis. In the same way, there are extremely few mixed Academic/Industrial structures that propose such a training encompassing strategic, scientific and technical aspects of the chemically-benign labeling of biologics.
The ISOBIOTICS project has been developing:
1) New strategies for the straightforward labeling of biotherapeutics utilizing end-use molecules through direct hydrogen- or carbon-exchange but also using a deconstruction/reconstruction process which do not affect the final molecule integrity;
2) Novel paradigms for the precision engineering of biomolecules using biochemical/chemical translational methods in view of their versatile isotopic labeling using a single biomolecule intermediate;
3) Improved grafting of tiny chemical motifs onto the end-use biomolecules that are expected not affecting neither their structure nor their biological properties.
To date first results have been published Open-Access in Peer-Review journals in order permit a wide dissemination of knowledge and project’s outputs.
ISOBIOTICS also implements:
1) The training of Doctoral Candidates (DCs) in order to provide the academic and industrial labs with young first-class chemists that will be trained through a mixed-system of research in lab, international and intersectorial secondments as well as a specialized and adapted training system;
2) The building a European intersectorial research consortium that will be consolidated by long-term academic-industry collaborations, a strategy known for boosting both the academic and industrial research;
3) Communication actions about ISOBIOTICS aims, results, impacts and practical applications using adapted channels and adopting a popularized in didactic style in order to inform and attract the European Citizens, to implicate patients associations, to inform regulation and policy makers.
ISOBIOTICS expected outputs are:
1) Expanding the toolbox for the chemically-benign isotopic labeling of biodrugs candidates (short-term);
2) Training the new generation of 1st-Class young Chemists for meeting the needs of both industrial and academic Research (short-term);
3) Increasing the portfolio of new biodrugs in development for curing serious diseases more efficiently with minimized side effects (medium-term);
4) Inciting the Pharmaceutical Industries to explore new therapeutic fields, especially when there are still no treatments to date (medium-term);
5) Helping the growth of European pharmaceutical companies and initiating the creation of start-ups and blooming of SMEs specialized in the isotopic labeling of biomolecules for subcontracting with Big Pharmas (long-term).
1) New strategies for the straightforward labeling of biotherapeutics utilizing end-use molecules through direct hydrogen- or carbon-exchange but also using a deconstruction/reconstruction process which do not affect the final molecule integrity;
2) Novel paradigms for the precision engineering of biomolecules using biochemical/chemical translational methods in view of their versatile isotopic labeling using a single biomolecule intermediate;
3) Improved grafting of tiny chemical motifs onto the end-use biomolecules that are expected not affecting neither their structure nor their biological properties.
To date first results have been published Open-Access in Peer-Review journals in order permit a wide dissemination of knowledge and project’s outputs.
ISOBIOTICS also implements:
1) The training of Doctoral Candidates (DCs) in order to provide the academic and industrial labs with young first-class chemists that will be trained through a mixed-system of research in lab, international and intersectorial secondments as well as a specialized and adapted training system;
2) The building a European intersectorial research consortium that will be consolidated by long-term academic-industry collaborations, a strategy known for boosting both the academic and industrial research;
3) Communication actions about ISOBIOTICS aims, results, impacts and practical applications using adapted channels and adopting a popularized in didactic style in order to inform and attract the European Citizens, to implicate patients associations, to inform regulation and policy makers.
ISOBIOTICS expected outputs are:
1) Expanding the toolbox for the chemically-benign isotopic labeling of biodrugs candidates (short-term);
2) Training the new generation of 1st-Class young Chemists for meeting the needs of both industrial and academic Research (short-term);
3) Increasing the portfolio of new biodrugs in development for curing serious diseases more efficiently with minimized side effects (medium-term);
4) Inciting the Pharmaceutical Industries to explore new therapeutic fields, especially when there are still no treatments to date (medium-term);
5) Helping the growth of European pharmaceutical companies and initiating the creation of start-ups and blooming of SMEs specialized in the isotopic labeling of biomolecules for subcontracting with Big Pharmas (long-term).
Herein is listed a selection of 3 results from EU-granted Beneficiaries athat have been validated by applications, demonstrating that the strategy devised can produce results that are clearly beyond the State-of-the-Art. Key Exploitation Results are mentioned when necessary.
1) New water-soluble iridium catalysts have demonstrated their efficiency for the specific and selective deuteration and tritiation of biologically important peptides through direct hydrogen exchange with a high potential for preparing isotopically (radio)labeled peptides and peptide analogs from the end-use biological material (KER1 - SANOFI-DC9);
2) The rhodium-catalyzed dynamic carbon isotopic exchange on carbonyl compounds applied to the carbon-13 and carbon-14 labeling of complex biologically active molecules (KER2 - CEA-DC2)
3) The hydroformylation allyglycine for the late-stage installation of deuterium/tritium- and carbon-13/carbon-14-labeled lysines in peptides enables the versatile isotopic labeling of small to medium-size peptides (KER3 - AZ-DC8).
Other innovations are also ongoing.
1) New water-soluble iridium catalysts have demonstrated their efficiency for the specific and selective deuteration and tritiation of biologically important peptides through direct hydrogen exchange with a high potential for preparing isotopically (radio)labeled peptides and peptide analogs from the end-use biological material (KER1 - SANOFI-DC9);
2) The rhodium-catalyzed dynamic carbon isotopic exchange on carbonyl compounds applied to the carbon-13 and carbon-14 labeling of complex biologically active molecules (KER2 - CEA-DC2)
3) The hydroformylation allyglycine for the late-stage installation of deuterium/tritium- and carbon-13/carbon-14-labeled lysines in peptides enables the versatile isotopic labeling of small to medium-size peptides (KER3 - AZ-DC8).
Other innovations are also ongoing.