Periodic Reporting for period 1 - ALISE (Anti-Cancer Light-Controllable Antibody-Peptide Conjugates)
Okres sprawozdawczy: 2021-03-01 do 2024-02-29
Project ALISE (Antibody Light-Induced Selectivity Enhancement) integrates the expertise, resources and knowledge of participating Institutions focusing on design, synthesis and preclinical study of conjugates of monoclonal antibodies with peptides whose anti-cancer activity can be enhanced in tumours by irradiation with light (LC-APCs). The idea behind the project consists in combining the primary advantages of both, antibody drug conjugates (ADCs) and light-controllable cytotoxic peptides. LC-APCs will deliver the peptides to the sites of action – the tumor cells – with high level of safety, specifically interacting with tumor-associated antigens, to release the peptide molecules there and then. The control of the peptide cytotoxicity by light will provide a second level of safety to sharply enhance the peptide activity on-site. Switching the cytotoxicity “on” with non-thermal red light irradiation in tumors will allow avoiding side-effects in the healthy tissues. Irradiation will be used to reach places where ADCs underperform, narrowing the cell-killing activity only to solid tumors. In other words, while ADCs may be considered as the “magic bullets”, a concept introduced by Paul Ehrlich, the ability to control the bullet’s action by light can be regarded as the “laser sight” of the weapon. The possibility to boost the anti-cancer activity only in tumours, multiplied by targeting cancer cells by antibodies will be a basis for innovative and safer therapeutic strategies. Given an immense unmet medical needs, especially in pancreatic cancer, the positive outcome of this Project will therefore add to the research and innovation potential in Europe and will contribute to the healthcare in Europe and worldwide.
The participating Institutions are complementary in their expertise and know-how: the University of Cambridge contributes with its know-how in design and preparation of antibodies. Light controllable peptides are designed at Latvian Institute of Organic Synthesis and Karlsruhe Institute of Technology, synthesized, then loaded onto the antibodies in Cambridge. Company Enamine performs initial screening of the conjugates in vitro and assess their safety. National Cancer Institute of Ukraine contributes with its expertise in immunology, Cancer Center Amsterdam – with its expertise and knowledge in preclinical and clinical oncology. Lumobiotics GmbH complements the consortium with its expertise in drug development. Integration of this potential is achieved through research staff exchange and other activities organized in five work packages: 1) design and synthesis of novel light-controllable peptides as anti-cancer antibody payloads; 2) preparation and characterization of peptide conjugates with a model antibody; 3) biological screening of model LC-APCs; 4) preclinical evaluation of the LC-APCs aiming at treatment of human PDAC; 5) management, training, communication, dissemination.
The participating Institutions are complementary in their expertise and know-how: the University of Cambridge contributes with its know-how in design and preparation of antibodies. Light controllable peptides are designed at Latvian Institute of Organic Synthesis and Karlsruhe Institute of Technology, synthesized, then loaded onto the antibodies in Cambridge. Company Enamine performs initial screening of the conjugates in vitro and assess their safety. National Cancer Institute of Ukraine contributes with its expertise in immunology, Cancer Center Amsterdam – with its expertise and knowledge in preclinical and clinical oncology. Lumobiotics GmbH complements the consortium with its expertise in drug development. Integration of this potential is achieved through research staff exchange and other activities organized in five work packages: 1) design and synthesis of novel light-controllable peptides as anti-cancer antibody payloads; 2) preparation and characterization of peptide conjugates with a model antibody; 3) biological screening of model LC-APCs; 4) preclinical evaluation of the LC-APCs aiming at treatment of human PDAC; 5) management, training, communication, dissemination.
Eleven diarylethene light-controllable analogues of natural cytotoxic peptides, Gymnopeptide A and Tubulysin, and one azobenzene-derived p53-MDM2-inhibiting peptide were successfully designed and synthesized and their biological activity is tested. The tests of the activity demonstrated that they are highly cytotoxic and have prospects to be used as antibody-drug conjugate payloads. Artificial intelligence approach to assess the biological activity of the light-controllable peptides in silico (two neuronal network models) were developed and successfully applied to the objects of studies. Two linkers for the known (gramicidin S analogues) and newly synthesized light-controllable peptides to be conjugated to antibodies and construct Light-controllable antibody-peptide conjugates (LC-APCs) were designed and synthesized. In vitro results proving high anti-cancer immunogenic potential of the gramicidin S and its analogues are obtained.
The Project has practically oriented goals: it aims at ultimate development of an innovative products, anti-cancer LC-APCs. Given an immense unmet medical needs, especially in pancreatic cancer, the positive outcome of this Project will therefore add to the research and innovation potential in Europe and will contribute to the healthcare in Europe and worldwide.