The group studies the structure and function of antibodies and T-cell receptors, the specific detection molecules of the adaptive immune system. The purpose of the work is to engineer soluble T-cell receptors and antibodies for use in therapy and as research reagents.
About the group
We study the structure and function of antibodies and Tcell receptors (TCRs), which is the specific detecting-molecules of the adaptive immune system.
The purpose of the work is to engineer soluble TCRs, antibodies and antibody-derived molecules to be used in therapy and as research reagents. The main areas of interest are stability and affinity engineering of binding molecules.
Most projects involve close collaboration with other research groups within CIR. Some projects also bridge protein engineering with clinical applications. TCRs recognise antigen in the form of peptide-MHC molecule complexes (pMHC) on antigen-presenting cells. The affinity and specificity of each of the three components contribute to Tcell activation and shaping of the activated Tcell repertoire. We explore E. coli expression and phage display of soluble TCRs, and have found that they are correctly folded in the periplasm of E.coli and displayed provided coexpression with high levels of a chaperone which offers folding assistance. This is a major finding with wide implications. For one, it allows engineering of soluble TCRs for increased stability and affinity.
So far, we have selected murine and human TCR variants with improved thermostability that could be purified directly from the periplasmic fraction as monomers. This is a great improvement over inclusion body production, denaturation and refolding procedure. Importantly, purification from the periplasm allows high throughout projects, such as testing of multiple mutant variants to dissect the contribution of individual amino acids for binding to a given pMHC, which is a major breakthrough.
Proteins in the blood stream are short lived and normally degraded in lysosomes within a few hours or days. But the two most abundant proteins, IgG and albumin, are rescued from intracellular degradation and have half-lives of three weeks. The rescue mechanism depends on their interaction with the neonatal Fc receptor, FcRn. For us, it is crucial to understand how FcRn rescues the ligands, and to study how long half life may be transferred to other protein therapeutics. To this end, we have engineered receptor and ligand variants, mapped interaction sites and found how classes of natural ligands compete for binding to the receptor.