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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - ProteinConjugates (A training network for the chemical site-selective modification of proteins: Preparation of the next-generation of therapeutic chemically-defined protein conjugates)

Teaser

Summary

ProteinConjugates is an inter- and multi-disciplinary network for the education of early young researchers who are learning how to rationally design and construct the next generation of chemically-defined protein drug conjugates for the targeted treatment of several diseases. The aim of the ProteinConjugates network is 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 or reumathoid arthritis. Furthermore, due to the collaboration with the pharmaceutical industry, the ITN benefits from the combined expertise of academia and industry on the synthesis of complex molecules, molecular dynamics, supramolecular self-assembly, site-selective chemical protein modification, protein/antibody engineering, drug development and cancer therapeutics. The development of these new methodologies will contribute to the emergence 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.

Work performed

During the first two years of the ProteinConjugates ITN several of the main goals where already achieved. As predicted, several methods for new site selective modifications and new protein functionalization approaches were developed, namely:
- Three new methods of disulfide re-bridging using pyradizinediones (UCL);
- Site-selective installation of salicylhydroxamate handles on disulfide bonds (MPIP);
- Development of a boronic acid-based protein modification technique (FFUL);
- A new method that uses the cysteine residues resulting from reduction of the interchain disulfides of the full-length IgG antibody, to create stable antibody-drug conjugates (IMM)
- A new method that uses iminoboronates as a multifunctional platform for the construction of functional homogeneous multivalent targeting drug conjugates (FFUL):
- Development of a new anti-MUC1-antibody with high affinity and selectivity for modified MUC1 glycopeptides (UniRioja);
- Microfluidic setup for the generation of monodisperse protein nanoparticles that are susceptible to surface modification (UCAM);
- A new approach for functionalization of lectins (Institute Curie)
- A new strategy for functionalization of silaffins with polyamides at lysine residues (UniVie).

Final results

The work of the students of the ITN ProteinConjugates has already produced significant results both in terms of new methods for protein site-selective chemistry as well as their use to develop new drug-delivery strategies. The methods developed are robust and may be used by any laboratory to produce chemically-defined conjugates. This has potential economical impact since the routine construction of therapeutic proteins and antibodies with cargo chemically conjugated at precise sites remains a challenge. The methods our students have developed are highly selective and produce constructs that are stable in circulation, only releasing their cargo at the site of disease. Thus, there is an enormous potential to translate these technologies to the production of current antibody-drug conjugates which is a major area of development within the pharmaceutical industry. Taking into account the need to have safer and more efficient cancer treatment, the development of precision medicines can impact the life of patients