Immuno-positron emission tomography (immunoPET) is a paradigmshifting molecular imaging modality combining the superior targeting specificity of monoclonal antibody (mAb) and the inherent sensitivity of PET technique. A variety of radionuclides and mAbs have been exploited to develop immunoPET probes, which has been driven by the development and optimization of radiochemistry and conjugation strategies. In addition, tumor-targeting vectors with a short circulation time (e.g., Nanobody) or with an enhanced binding affinity (e.g., bispecific antibody) are being used to design novel immunoPET probes. Accordingly, several immunoPET probes, such as 89 Zr-Df-pertuzumab and 89 Zr-atezolizumab, have been successfully translated for clinical use. By noninvasively and dynamically revealing the expression of heterogeneous tumor antigens, immunoPET imaging is gradually changing the theranostic landscape of several types of malignancies. ImmunoPET is the method of choice for imaging specific tumor markers, immune cells, immune checkpoints, and inflammatory processes. Furthermore, the integration of immunoPET imaging in antibody drug development is of substantial significance because it provides pivotal information regarding antibody targeting abilities and distribution profiles. Herein, we present the latest immunoPET imaging strategies and their preclinical and clinical applications. We also emphasize current conjugation strategies that can be leveraged to develop next-generation immunoPET probes. Lastly, we discuss practical considerations to tune the development and translation of immunoPET imaging strategies.

The rapidly evolving field of cancer immunotherapy recently saw the approval of several new therapeutic antibodies. Several cell therapies, for example, chimeric antigen receptor-expressing T cells (CAR-T), are currently in clinical trials for a variety of cancers and other diseases. However, approaches to monitor changes in the immune status of tumors or to predict therapeutic responses are limited. Monitoring lymphocytes from whole blood or biopsies does not provide dynamic and spatial information about T cells in heterogeneous tumors. Positron emission tomography (PET) imaging using probes specific for T cells can noninvasively monitor systemic and intratumoral immune alterations during experimental therapies and may have an important and expanding value in the clinic.

Overexpression and/or mutations of the receptor tyrosine kinase (RTK) subfamilies, such as epidermal growth factor receptors (EGFR) and vascular endothelial growth factor receptors (VEGFR), are closely associated with tumor cell growth, differentiation, proliferation, apoptosis, and cellular invasiveness. Monoclonal antibodies (mAb) and tyrosine kinase inhibitors (TKI) specifically inhibiting these RTKs have shown remarkable success in improving patient survival in many cancer types. However, poor response and even drug resistance inevitably occur. In this setting, the ability to detect and visualize RTKs with noninvasive diagnostic tools will greatly refine clinical treatment strategies for cancer patients, facilitate precise response prediction, and improve drug development. Positron emission tomography (PET) agents using targeted radioactively labeled antibodies have been developed to visualize tumor RTKs and are changing clinical decisions for certain cancer types. In the present review, we primarily focus on PET imaging of RTKs using radiolabeled antibodies with an emphasis on the clinical applications of these immunoPET probes. .