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Enabling Techniques for the Development of a Novel Class of Protein Antibiotics

Final Report Summary - ET-PA (Enabling Techniques for the Development of a Novel Class of Protein Antibiotics)

The quality of medical care has widely benefited from the introduction of antibiotic agents, both anti-infective and anti-neoplastic, which have been central to the increase in life expectancy and our quality of life. A serious and growing problem with their extensive use, however, is the growing rate of drug resistance phenomena; a problem compounded by the fact that the development of new drugs is lagging. We risk losing the benefits gained from these drugs and any new class of antibiotic agent that can contribute to novel therapeutic options is a valid pursuit.

Resistance of pathogens to antibiotics is a major threat to public health and safety, increasing the risk of mortality, especially in hospital settings. The increased aging of the population in the developed world means that an ever greater proportion develops infections and neoplasias of different types. Currently the market for antibiotic agents is dominated by small molecule classes, which are all facing increased drug resistance and requiring product differentiation. While this remains a primary focus in anti-infectives and anti-tumour development, new concepts for entirely new classes of substances opening novel therapeutic options are essential.

The ET-PA project focused on the implementation of a generic platform to enable the development of a new class of protein-antibiotics; rationally modified, single-chain class II restriction enzymes (RE) fused to cell penetration peptide sequences (PP). These REPP compounds allow selective target cell penetration and inactivation. The power of the REPP principle is that it lends itself equally to the development of potential antimicrobial agents and powerful anti-neoplastic leads; the selective factor is the specific PP. The key technology behind this platform is based on inventions proprietary to the participating SMEs that enabled maximal freedom to operate during the entire ET-PA program:
(i) REPP principles and their application by Adriacell;
(ii) isolation and purification via the novel CIM chromatographic techniques provided by Biasep.

The ET-PA project brought together three SMEs (Adriac, Biasep and HECUS) and two RTD performers (UTS-BC and Ubimmi) from four different European countries, which are leaders in their field. An outcome of the project was the creation and testing of a solid R&D network that will continue to collaborate in the future. The primary scientific and technological outcome was the successful development of a technology platform that allows for the construction and screening of large REPP protein libraries. This platform will be applied for further lead development, not only with respect to antibacterial REPPs, but also with respect to the third generation of analogous REPP compounds under an ongoing tumour-therapeutic developments program in one of the SMEs, Adriac. In constructing the REPP platform that was the central ET-PA objective, all SME partners gained profitable value added to their businesses. REPP platform development also brought about consolidated prototypes for CIM monolytic purification device applications in high throughput (HT) genomics and proteomics, benefiting the producer Biaseparations, as well as Adriacell. The interdisciplinary nature of the project also created the critical mass for entry into the medical applications market for the third SME in designing thermo-elements and software for the existing small angle X-ray scattering device pallet of the company and allows them now to leverage their share in the growing proteomics and genomics R&D market. The RTD partners contributed design features, helped characterise and validate REPP constructs and CIM devices and conducted assay development and screening.

REPP technology is now strongly supported by the successful A venture round of the coordinating SME, Adriac, whose success depended in significant measure on the activities of the ET-PA project. The successful application of CIM technology during the project allows Biasep to access the biotech market, and along these lines the potential HT applications can also be considered a successful outcome of ET-PA. The third SME, Hecus, has grown by acquisition of a complementary company during the ET-PA period and has now the critical mass and in house expertise to further integrate instrumentation developed during ET-PA outcome into their product portfolio. RTD partners have instead been able to develop methods and find exploitable outcomes for their ongoing studies, contributing also to dissemination of some results via publications in international journals and technical handbooks.

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