In-depth cross-validation of human and mouse CD4-specific minibodies for noninvasive PET imaging of CD4+ cells and response prediction to cancer immunotherapy.
Stefania Pezzana, Simone Blaess, Jule Kortendieck, Nicole Hemmer, Bredi Tako, Claudia Pietura, Lara Ruoff, Simon Riel, Martin Schaller, Irene Gonzalez-Menendez, Leticia Quintanilla-Martinez, Alessandro Mascioni, Argin Aivazian, Ian Wilson, Andreas Maurer, Bernd J Pichler, Manfred Kneilling, Dominik Sonanini
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引用次数: 0
Abstract
Increasing evidence emphasizes the pivotal role of CD4+ T cells in orchestrating cancer immunity. Noninvasive in vivo imaging of the temporal dynamics of CD4+ T cells and their distribution patterns might provide novel insights into their effector and regulator cell functions during cancer immunotherapy (CIT). Methods: We conducted a comparative analysis of 89Zr-labeled anti-mouse (m) and anti-human (h) CD4-targeting minibodies (Mbs) for in vivo positron emission tomography (PET)/magnetic resonance imaging (MRI) of CD4+ T cells in human xenografts, syngeneic tumor-bearing wild-type (WT), and human CD4+ knock-in (hCD4-KI) mouse models. Results: Both 89Zr-CD4-Mbs yielded high radiolabeling efficiencies of >90%, immunoreactivities of >70%, and specific in vitro binding to their target antigens. The specificity of in vivo targeting of 89Zr-hCD4-Mb was confirmed by PET/MRI, revealing ~4-fold greater 89Zr-hCD4-Mb uptake in subcutaneous hCD4+ hematopoietic peripheral blood acute lymphoblastic leukemia tumors (HPB-ALL) than in solid hCD4- diffuse histiocytic lymphomas (DHL) and 89Zr-mCD4-Mb uptake in hCD4+ HPB-ALL tumors. In a comparative cross-validation study in anti-programmed death ligand (αPD-L1)/anti-4-1BB-treated orthotopic PyMT mammary carcinoma-bearing hCD4-KI and WT mice, we detected 2- to 3-fold enhanced species-specific 89Zr-hCD4-Mb or 89Zr-mCD4-Mb uptake within CD4+ cell-enriched secondary lymphatic organs (lymph nodes and spleens). The 89Zr-hCD4-Mb uptake in the PyMT tumors was more pronounced in hCD4-KI mice compared to the WT control littermates. Most importantly, MC38 adenocarcinoma-bearing mice treated with a combination of αPD-L1 and anti-lymphocyte-activation gene 3 (αLag-3) antibodies exhibited ~1.4-fold higher 89Zr-mCD4-Mb uptake than mice that were not responsive to therapy or sham-treated mice. Conclusion: CD4 PET/MRI enabled monitoring of the CD4+ cell distribution in secondary lymphatic organs and the tumor microenvironment, capable of predicting sensitivity to CIT. Our imaging approach will provide deeper insights into the underlying molecular mechanisms of CD4-directed cancer immunotherapies in preclinical mouse models and is applicable for clinical translation.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.