T cell activation; CD80; immonogenicity; Positron Emission Tomography; humanized mouse
Taddio Marco F., Mu Linjing, Castro Jaramillo Claudia A., Bollmann Tanja, Schmid Dominik M., Muskalla Lukas P., Gruene Tim, Chiotellis Aristeidis, Ametamey Simon M., Schibli Roger, Krämer Stefanie D. (2019), Synthesis and Structure-Affinity Relationship of Small Molecules for Imaging Human CD80 by Positron Emission Tomography, in Journal of Medicinal Chemistry
, 62(17), 8090-8100.
Background and rationale: T cell activation and T cell dysfunction are tightly regulated by several co-signalling molecules when an antigen-presenting cell presents an antigen to a T cell. In several diseases, this regulation is overshooting to one or the other side. Cancer cells hide from the immune system by inducing T cell exhaustion while autoimmune diseases are characterized by massive T cell activation. The best described players in T cell activation and dysfunction are the cluster of differentiation 80 (CD80, B7 1) and CD86 (B7-2) on antigen-presenting cells which bind to CD28 on T cells resulting in T cell activation. Both bind with higher affinity to the cytotoxic T lymphocyte antigen 4 (CTLA-4) and this interaction results in T cell dysfunction and removal of CD80 and CD86 from the cell surface.Overall objectives and specific aims: CD80 is frequently used as a marker for activated antigen-presenting cells, e.g., in immunohistochemistry, quantitative PCR (qPCR) and fluorescence activated cell sorting (FACS). Our overall objectives are the development and evaluation of CD80 targeting tracers for the non-invasive imaging and quantification of CD80 by positron emission tomography (PET) in preclinical and clinical research. The specific aims for this funding period (1-year continuation of running project) are the optimization of a small molecule tracer targeting human CD80 (hCD80) and the evaluation of a suited mouse model for the in vivo evaluation of the hCD80-targeting PET tracer(s). Our PET tracer should compete with CD28 but not with CTLA-4 for the binding to CD80 and, therefore, recognize exclusively CD80 involved in T cell activation.Methods: Based on our available high-affinity small molecule CD80 ligands, we will optimize the structure towards improved pharmacokinetic behaviour. We will evaluate the binding affinity by surface plasmon resonance and in vitro autoradiography with hCD80-positive tissues. We will evaluate the huNOG-EXL mouse model, which expresses human IL-3 and human GM-CSF and is engrafted with human CD34-positive hematopoietic stem cells, for hCD80-positive cells under control conditions and after inducing a local inflammation. We will use qPCR and FACS. The model will be scanned with our established large-molecule tracer 64Cu-NODAGA-belatacept. In parallel, we will further optimize a mouse model with a hCD80-positive xenograft. We will evaluate our small molecule hCD80-targeting tracer(s) in these models.Expected results: We expect to develop a small molecule tracer which allows imaging and quantification of hCD80 in vivo by PET, similar as the large-molecule tracers that we already developed. If successful, the tracer can be further developed for first-in-human studies. Furthermore, the results on hCD80 distribution in the huNOG-EXL model will support the research with humanized mice in general.Impact in the field and beyond: Considering the many in vitro studies with CD80 as a marker for the infiltration by antigen presenting cells, we expect that our PET tracer will support the diagnosis and therapy planning and monitoring in diseases with a deregulated immune system. Checkpoint inhibitors may in the future be combined with T cell activating therapies. A CD80-targeting tracer could help finding the optimal balance between checkpoint inhibition and T cell activation. Together with the large-molecule tracers, which recognize both human and mouse CD80 (and CD86), CD80 imaging would become fully translational from preclinical to clinical applications.