⁸⁹Zr-immuno-PET: towards a non-invasive clinical tool to measure target engagement of therapeutic antibodies in-vivo

Abstract

Rationale: Zirconium-89-immuno-positron emission tomography (⁸⁹Zr-immuno-PET) is a promising non-invasive clinical tool to measure target engagement of monoclonal antibodies (mAbs); in normal tissues to predict toxicity and in tumors to predict efficacy. However, quantification of ⁸⁹Zr-immuno-PET will need to move beyond standardized uptake values (SUV), since total uptake may contain a significant non-target-specific contribution. Non-specific uptake is reversible (e.g. blood volume) or irreversible (due to ⁸⁹Zr-residualization after mAb degradation). The aim of this study was to assess non-specific uptake in normal tissues as a first critical step towards quantification of target engagement in normal tissues and tumors using ⁸⁹Zr-immuno-PET. Methods: Data from clinical studies with 4 ⁸⁹Zr -labeled intact IgG1 antibodies were collected, resulting in a total of 128 PET scans (1 to 7 days p.i. from 36 patients: ⁸⁹Zr-antiCD20 (n = 9), ⁸⁹Zr -antiEGFR (n = 7), ⁸⁹Zr -antiPSMA (n = 10) and ⁸⁹Zr -HER2 (n = 10). Non-specific uptake was defined as uptake measured in tissues without known target expression. Patlak graphical evaluation of transfer constants was used to estimate the reversible (V_t) and irreversible (K_i) contributions to the total measured uptake for the kidney, liver, lung and spleen. Baseline values were calculated per tissue combining all mAbs without target expression (kidney: ⁸⁹Zr-antiCD20, ⁸⁹Zr-antiEGFR, ⁸⁹Zr-antiHER; liver: ⁸⁹Zr-antiCD20; lung: ⁸⁹Zr-antiCD20, ⁸⁹Zr-antiEGFR, ⁸⁹Zr-antiPSMA; spleen: ⁸⁹Zr-antiEGFR, ⁸⁹Zr-antiHER2). Results: Baseline V_t for the kidney, liver, lung and spleen was 0.20, 0.24, 0.09 and 0.24 mL·cm^-3, respectively. Baseline K_i was 0.7, 1.1, 0.2 and 0.5 μL·g^-1·h^-1 for the kidney, liver, lung and spleen. For ⁸⁹Zr-antiPSMA, a four-fold higher (K_i) was observed for the kidney, indicating target engagement. In this case, non-specific uptake accounted for 66, 34 and 22% of the total signal in the kidney at 1, 3, 7 days p.i. respectively. Conclusion: This study shows that non-specific uptake of mAbs for tissues without target expression can be quantified using ⁸⁹Zr-immuno-PET at multiple time points. These results form a crucial base for measurement of target-engagement by therapeutic antibodies in-vivo with ⁸⁹Zr-immuno-PET. For future studies, a pilot phase including at least 3 scans ≥ 1 day p.i., is required to assess non-specific uptake as a function of time, to optimize study design for detection of target engagement.