Project Reference: TRG27-BIO-MD1
Project title: Design of therapeutic CXCR4 antibodies targeting a three-dimensional epitope
Project outline
The project will validate and characterise antibodies, derived through conventional immunisation and in silico design, against clinically relevant targets.
Therapeutic antibodies typically bind to linear peptides of approximately 10 amino acids rather than three-dimensional structures. This reflects how host animals process antigens during antibody generation and the technical ease of validating linear epitopes during development.
However, linear epitopes are often unsuitable for receptor modulatory antibodies. Linear motifs can be masked by the receptor’s protein fold, and antibody binding can trigger spurious receptor activation.
To overcome these limitations, we have combined conventional antibody generation with in silico design. Recent advances in AI and structural prediction algorithms have proven increasingly accurate in generating antibodies targeting three-dimensional epitopes.
Our first target protein CXCR4, a G-protein coupled receptor activated by the CXCL12 ligand. CXCR4 resides on the plasma membrane and is expressed by different cell types including T cells where HIV engages it to enable viral entry. CXCR4 is also upregulated in certain cancer cells where ligand activation promotes proliferation and metastasis. Our goal is to generate antibodies that block the CXCR4-CXCL12 interaction to disrupt pathways contributing to various pathologies.
We have generated antibodies to CXCR4 against a linear peptide within the extracellular domain. Through collaboration, have also designed two antibodies targeting the three-dimensional CXCL12 binding site.
The project will now focus on developing these antibodies as blocking agents and evaluating their performance through using a series of bioassays.
Follow-on work will test in vivo efficacy of the CXCR4 antibodies and extend this approach to develop new antibodies towards clinically relevant targets in inflammatory diseases.
Principal Supervisor
Dr Marc de la Roche
Email address: mad58@cam.ac.uk
Department / Partner Institute: Biochemistry
Website: https://delarochelab.co.uk/
BBSRC strategic theme
Bioscience for an integrated understanding of health