Towards conditionally active pH-dependent therapeutic antibodies: Increasing specificity and activity of therapeutic antibodies with pH-switchable binding
pH variations in various physiological or physiopathological conditions can modulate antibody/antigen binding affinity. This is likely to impact the pharmacological properties of antibodies and their expected therapeutic effect. Most antibodies from synthetic or immune libraries are selected to bind their antigen at physiological pH (7,0 -7,4); however, whether their function is modulated in acidic environment is not always carefully assessed. For instance, antibodies interacting with internalizing receptors in endosomes or antibodies targeting solid tumours encounter acidic microenvironment. The acidic nature of the pH in endosomes or at the cell surface is likely to dissociate antibodies from, or modify their affinity with their antigen. On one hand, this apparent limitation can be exploited to selectively bind the antigen in specific pH conditions. On the other hand, antibodies able to bind in various pH conditions can be selected to preserve binding and pharmacological properties. Overall, strategies in antibody design, selection and engineering should allow to promote or improve pharmacological effect, drug delivery in the case of antibody drug conjugates or to better target solid tumours. The objective of the KQ1-CDI1 flagship is to directly select or evolve promising lead antibodies for improved activity and specificity by modulating their binding affinity according to the pH in various pathologies.
The project is organised in 3 workpackages aimed at:
- Achieving a pH-directed evolution/maturation of available lead antibodies
- Characterising the antibody, its target, and their intracellular trafficking in a functional perspective
- Evaluating the impact of the antibody pH-sensitivity in vitro and in vivo.
Teams involved in the project and their tasks:
| BIOS – UMR INRA 0085 – Nouzilly | Docking Ag/Ab interactions Antibody Library design Mapping of Intellectual Property for pH-switchable Ab Selection/maturation of pH-dependant VHH |
| Functional screening and targeting in cancer – IRCM – Montpellier | Antibody Library design Maturation of pH-dependent Ab Validation of pH-dependent Ab |
| Tumor Microenvironment and Resistance to Treatment – IRCM – Montpellier | Yeast display Selection/maturation of pH-dependent Ab |
| IMGT® – IGH – Montpellier | Histidine distribution in Ig repertoire, healthy and diseased |
| Platform of Proteomic Identification and Interactions – IRCM – Montpellier | SPR characterisation of Ab |
| Breast cancer, Microenvironment and Immunotargeting – IRCM – Montpellier | Validation of pH-dependent Ab in selected diseases |
| Neurogenomics and neuronal physiopathology – U1253 – Tours | Validation of pH-dependent Ab in selected diseases |
Objectives of the project:
- Publication of a review summarising the influence of pH on physiological and pathophysiological processes
- Validation of robust methods for the selection of pH-switchable antibodies in phage/yeast display libraries
- Construction of a new library favoring pH-modulated Ab
- Selection of antibodies with improved activity and specificity due to pH-dependent binding