Novel theranostic agent for PET imaging and targeted radiopharmaceutical therapy of tumour-infiltrating immune cells in glioma
Alexandra Foster,
Shubhanchi Nigam,
David S Tatum,
Itay Raphael,
Jide Xu,
Rajeev Kumar,
Elizabeth Plakseychuk,
Joseph D Latoche,
Sarah Vincze,
Bo Li,
Rajan Giri,
Lauren H McCarl,
Robert Edinger,
Murat Ak,
Vishal Peddagangireddy,
Lesley M Foley,
T Kevin Hitchens,
Rivka R Colen,
Ian F Pollack,
Ashok Panigrahy,
Darren Magda,
Carolyn J Anderson,
W Barry Edwards,
Gary Kohanbash
Affiliations
Alexandra Foster
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Shubhanchi Nigam
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
David S Tatum
Lumiphore, Inc., 600 Bancroft Way Berkeley, CA 94710, USA
Itay Raphael
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Jide Xu
Lumiphore, Inc., 600 Bancroft Way Berkeley, CA 94710, USA
Rajeev Kumar
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Elizabeth Plakseychuk
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Joseph D Latoche
Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA
Sarah Vincze
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Bo Li
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Rajan Giri
Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA
Lauren H McCarl
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Robert Edinger
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Murat Ak
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Vishal Peddagangireddy
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Lesley M Foley
Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA 15213, USA
T Kevin Hitchens
Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Rivka R Colen
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Ian F Pollack
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
Ashok Panigrahy
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA
Darren Magda
Lumiphore, Inc., 600 Bancroft Way Berkeley, CA 94710, USA; Co-corresponding author.
Carolyn J Anderson
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Bioengineering, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh 15213, USA; Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Chemistry, University of Missouri, Columbia, MO, 65211 USA; Co-corresponding author.
W Barry Edwards
Department of Radiology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Biochemistry, University of Missouri, Columbia, MO, 65211, USA; Co-corresponding author.
Gary Kohanbash
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Co-corresponding author.
Background: Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment. Methods: Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT. Findings: 89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy. Interpretation: 89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
