Advances and challenges in immunoPET methodology

Abstract

Immuno-positron emission tomography (immunoPET) enables imaging of specific targets that play a role in targeted therapy and immunotherapy, such as antigens on cell membranes, targets in the disease microenvironment, or immune cells. The most common immunoPET applications use a monoclonal antibody labeled with a relatively long-lived positron emitter such as ⁸⁹Zr (T _1/2 = 78.4 h), but smaller antibody-based constructs labeled with various other positron emitting radionuclides are also being investigated. This molecular imaging technique can thus guide the development of new drugs and may have a pivotal role in selecting patients for a particular therapy. In early phase immunoPET trials, multiple imaging time points are used to examine the time-dependent biodistribution and to determine the optimal imaging time point, which may be several days after tracer injection due to the slow kinetics of larger molecules. Once this has been established, usually only one static scan is performed and semi-quantitative values are reported. However, total PET uptake of a tracer is the sum of specific and nonspecific uptake. In addition, uptake may be affected by other factors such as perfusion, pre-/co-administration of the unlabeled molecule, and the treatment schedule. This article reviews imaging methodologies used in immunoPET studies and is divided into two parts. The first part summarizes the vast majority of clinical immunoPET studies applying semi-quantitative methodologies. The second part focuses on a handful of studies applying pharmacokinetic models and includes preclinical and simulation studies. Finally, the potential and challenges of immunoPET quantification methodologies are discussed within the context of the recent technological advancements provided by long axial field of view PET/CT scanners.

Keywords: PET/CT; imaging; immunoPET; kinetic modeling; monoclonal antibody; quantification; zirconium.

Figure 1

Schematic representation of PET uptake components for radiometal and radiohalogen labeled mAbs. Radiolabeled mAbs are injected into the blood and, after initial distribution, are reversibly present inside the blood volume fraction and the interstitial space of the tissue. Subsequently, specific (target engagement) and non-specific binding (Fc receptors) processes can occur, both reversibly and irreversibly. After irreversible binding of the radiolabeled mAb, the mAb-antigen construct gets internalized and degraded, after which free radiometal atoms stay inside the cell and radiohalogen atoms can leave the cell. Redrawn from Wijngarden et al. (39) (CC BY 4.0 License).

Figure 2

Schematic illustration of the two-tissue compartment model. $C_P$, $C_{\mathrm{ND}}$ and $C_S$ represent arterial plasma, non-displaceable tissue and specific tissue concentrations. $K_1$ to $k_4$ are rate constants for the transport between compartments. $V_B$ is the fractional blood volume within the PET region of interest. Its contribution to the total signal $C_{\mathrm{PET}}$ depends on the arterial whole blood concentration. For simplicity, however, only the arterial plasma compartment is shown.

Figure 3

Example plasma concentration $C_P$ and tissue concentration $C_{PET}$ for a ⁸⁹Zr-labeled mAb and a ⁸⁹Zr-labeled minibody. These (typical) curves were simulated based on the work of Huisman et al. (71) (mAb) and Omidvari et al. (17) (minibody). It should be noted that plasma and tissue kinetics are highly dependent on the tracer and the target tissue.

Figure 4

Immuno-PET signal components in a phase 1 dose escalation study. Tissue-to-blood ratio as a function of antibody dose. Figure taken from Jauw et al. (CC BY 4.0 License) (158).