Development of MDSC - CD11b tracer for immune PET imaging in glioblastoma model

Introduction: Malignant gliomas are the most common primary central nervous system tumor with over 12,000 newly diagnosed cases each year in the United States. As up to 30% of a glioma cellular mass may be attributed to immunosuppressive myeloid cells, including myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), these cells represent a highly attractive therapeutic target.^1-3Multiple preclinical and clinical trials have attempted to target these cells, however monitoring of biologic responses to therapy remains a challenge. Quantifying TAMs and MDSCs at the tumor site using non-invasive immunoPET could improve therapeutic response and allow for better patient stratification and monitoring of targeted treatment responses. The cell surface marker, CD11b (Mac-1, αMβ2) which is theα subunit of the predominant β subunit CD18, is highly expressed on MDSCs and TAMs and may be a highly effective imaging target for immunoPET strategies.

Methods: The human/mouse cross-reactive anti-CD11b antibody (clone M1/70) was conjugated with p-NCS-Bz-DFO chelator and radiolabeled with ⁸⁹Zr for PET imaging with specific activity of 2 µCi/µg. PET/CT imaging, with or without a blocking dose of anti-CD11b Ab, was performed in mice bearing established orthotopic syngeneic GL261 gliomas. Flow cytometry and histology in tissues collected from post-imaging biodistribution validated targeting of CD11b⁺ MDSCs and TAMs.

Results: There was significant Zr-89-anti-CD11b Ab uptake in the tumor ipsilateral right brain (SUV_{mean =} 2.6 ± 0.24) compared to contralateral left brain (SUV_{mean =} 0.6 ± 0.11). Blocking with 10-fold lower specific activity ⁸⁹Zr-anti-CD11b Ab reduced the SUV in right brain with (SUV_mean = 0.11 ± 0.06). Spleen and lymph nodes showed high uptake, while bone and muscle uptake were low. These results correlated with biodistribution analysis. CD11b expression in the right and left brain were validated using flow cytometry, H&E and IHC, showing high CD11b expression in the right brain compared to left brain.

Conclusions: Imaging TAMs and MDSCs with ⁸⁹Zr-labeled anti-CD11b Ab targeting was validated in a mouse model of malignant gliomas, demonstrating the feasibility of monitoring immune response during immunotherapy.