Development of a chemogenetic strategy to generate conditionally-active antibodies targeting brain tumors

This is PhD fellowship awarded to Montserrat Escobar thanks to the 2023 Call of F. La Caixa INPhinit.

The aim of this project is to engineer a universal chemogenic strategy to generate activatable antibodies. We aim to apply this new approach to generate activatable antibody derivatives against cancer targets, especially on the resilient glioma stem cells (GSCs) for the treatment of glioblastoma multiforme (GBM), through combining chemistry and biotechnology. GBMs are the most common and uncurable brain tumour Activatable antibodies are a new technology that can target specific cancer cells without affecting healthy tissues. Current therapies struggle with targeting cancer stem cells (CSCs) and crossing the blood-brain barrier (BBB). An objective of this project is to create a versatile method to produce antibodies that activate only in the tumour environment, since one of the main problems of targeting CSC markers is that they are found in healthy tissues also. The focus is on CD133, a CSC marker associated to cancer progenitor cells in GBM able to induce the most aggressive tumour development. Therefore this project aims to apply the novel strategy for antibody masking to obtain a conditionally activated anti-CD133 antibody, by in vitro and in vivo.

This PhD thesis will enable developing the first activable antibody for selective targeting of therapeutics to GSCs, and this approach could be applied to other CSC markers and the new activation strategy may be applied may be rapidly translated to many other antibody-targeted therapies.
Objectives of this PhD thesis:
• To contribute to the generation of therapeutic alternatives for the treatment of cancer.
• To become a specialist in antibody engineering.
• To conduct postdoctoral research to pursue an academic career.
• To train and specify ideas to potentially create a spin-off.