ProteinConjugates · A training network for the chemical site-selective modification of proteins: Preparation of the next-generation of therapeutic chemically-defined protein conjugates

A training network for the chemical site-selective modification of proteins: Preparation of the next-generation of therapeutic chemically-defined protein conjugates

According to the World Health Organization, Cancer was responsible for an estimated 9.6 million deaths in 2018, being the second leading cause of death globally. Thus, it is necessary to develop efficient treatments against cancer. Recently, the conjugation of monoclonal antibodies directed against tumor marker proteins with highly potent cytotoxic drugs has emerged as a powerful strategy to fight cancer. In addition, chemical protein modification has become a key instrument in Chemical Biology and drug development, hence being of major importance for the development of more efficient ADCs. With this in mind, ProteinConjugates was an inter- and multi-disciplinary network for the education of early young researchers who aimed to learn how to rationally design and construct the next generation of chemically-defined protein drug conjugates. The goal of the ProteinConjugates network was to develop new site-selective bioconjugation methods that explore natural proteinogenic amino acids and their use to build protein conjugates for the treatment of serious conditions such as cancer. Furthermore, the combined expertise of the beneficiaries and industrial partners in synthesis of complex molecules, molecular dynamics, supramolecular self-assembly, site-selective chemical protein modification, protein/antibody engineering, cancer therapeutics and drug development, allowed to develop exciting projects that led to new methods and pre-clinically validated conjugates. Within the course of the 10 ESR projects it was possible to develop several new methods for site-selective modification of proteins (disulfide bonds rebridging with pyridazinediones; disulfide bridging with boronic acids, cysteine modification with carbonylacrylic acid handles), to develop new antibodies (anti-MUC1 and anti-IL7 receptor) and to develop new nanoparticles and functionalized proteins. With these, new protein conjugates were built, leading to a promising anti T-ALL ADC, to an ADC against HER2+ cancer cells, two potential protein conjugates against colon carcinoma, fluorophore protein conjugates as imaging tools and a potent and selective therapy against glioblastoma. The later, resulted in Intellectual Property which led to the formation of a new spin-out company. These newly developed methodologies have and will contribute to the emergence of new potential therapeutic strategies against diseases that are a major burden for society. Moreover, exposure to the highly dynamic and multidisciplinary ProteinConjugates environment will contribute to the education of the next generation of leaders in the emerging field of protein biotherapeutics, a key area of research and drug development for Europe's competitiveness in the field.

Data: CORDIS, © European Union