Gustavsson, T. | bioRxiv Science

bioRxiv2024

Brain Pretargeted PET - New Horizons to Image CNS Targets with Monoclonal Antibodies

Antibodies are excellent targeting vectors for molecular imaging. Slow pharmacokinetics and low blood-brain barrier penetration hinder their widespread application for molecular imaging within CNS. Improved brain uptake can be achieved via transferrin-mediated transcytosis. Pretargeted imaging can increase imaging contrast and reduce radiation exposure to the patient. Here, we report for the first time that pretargeted imaging of CNS targets using intravenously administered target vectors is feasible. Specific binding to A{beta}-bound antibody was achieved. We believe that this proof-of-concept study will facilitate molecular imaging of currently undruggable targets with antibodies where small molecule PET tracer discovery has been challenging.

neuroscience↗

bioRxiv2024

Conditional CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors

Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype-binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of conditional chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be armed with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While un-armed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell types in vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity. In vivo, armed CAR T cells rapidly targeted bladder tumors and increased survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans can be exploited as potential targets for CAR T cell therapy.

cancer biology↗