New study: Binding stability is key to effective T-cell response
With a unique peptide and a new model for analysing the behavior of drug molecules in a subcutaneous environment, Sara Mangsbo and Per Hansson show that T-cell activation can be made more efficient through molecular fine-tuning. The study is published in the International Journal of Biological Macromolecules.
Based on her technology platform ADAC, Sara Mangsbo, Professor at Uppsala University, has developed a system for targeted delivery of tumor antigens to activate T-cells, which can in turn kill the tumor cell. The method uses a specially designed peptide, pTag, which links the antigen to a targeting antibody. In a new study, conducted in collaboration with the university's research group in pharmaceutical physical chemistry, the researchers now present findings of major importance for the project's further development.
Sara Mangsbo, Department of Pharmacy
“We have previously shown in cell and in vivo models that our technology works. In this study, we analyse what happens at the cellular and organismal level when we replace a single amino acid in pTag. Our results show that the binding stability is crucial to achieve the desired T-cell response, providing important information about both the drug candidate and its potential clinical use,” says Sara Mangsbo, Professor of Protein and Antibody Drugs.
A key factor in the study is a new biorelevant, synthetic model that, by mimicking the extracellular environment in human subcutaneous tissue, shows how therapeutic molecules are expected to spread and move in the body. The method, which combines an extracellular matrix with microscopy and FRAP methodology, was recently presented in Julia Parlow's PhD thesis at the Department of Medicinal Chemistry.
Per Hansson, Department of Medicinal Chemistry
“Our model offers a more precise complement to previous tools, and via our involvement in SweDeliver we know that this tool is welcomed by both academia and the industry. In our collaboration with Sara Mangsbo, we confirm that the answers our model provides are consistent with animal models, with the publication putting a stamp of quality on our method and the fact that it delivers robust results,” says Per Hansson, Professor of Pharmaceutical Physical Chemistry.
The work now continues to broaden the use of the ADAC technology by studying the delivery of more drug modalities. With funding from Marie Skłodowska-Curie Actions and ITN, two doctoral students are now being recruited and will join the team at Uppsala Biomedical Center this spring.
“We receive the grant within the framework of ON-TRACT, a new European consortium where academia and industry together pave new ways for the application of oligonucleotides in drug treatments. For us, it means both resources to take our own technology forward and valuable opportunities to develop our international networks,” says Sara Mangsbo.
Facts
- The study was carried out in collaboration between Ida Laurén, David Juriga, Per Hansson, Sara Mangsbo et al.
- Development of the model for studying therapeutic molecules in a subcutaneous environment continues within the framework of Rojita Jadhari's doctoral project: Transport of conjugated drug delivery systems from the subcutaneous injection site to the lymphatic system.
Contact
Per Hansson, Pprofessor
Department of Medicinal Chemistry
Per.Hansson@ilk.uu.se
Sara Mangsbo, Professor
Department of Pharmacy
Sara.Mangsbo@uu.se
text: Magnus Alsne, photo: Mikael Wallerstedt, Pernilla Sjöholm