G.A.M.S. van Dongen

Biodistribution of 89Zr-trastuzumab and PET Imaging of HER2-Positive Lesions in Patients With Metastatic Breast Cancer

We performed a feasibility study to determine the optimal dosage and time of administration of the monoclonal antibody zirconium‐89 (89Zr)‐trastuzumab to enable positron emission tomography (PET) imaging of human epidermal growth factor receptor 2 (HER2)‐positive lesions. Fourteen patients with HER2‐positive metastatic breast cancer received 37 MBq of 89Zr‐trastuzumab at one of three doses (10 or 50 mg for those who were trastuzumab‐naive and 10 mg for those who were already on trastuzumab treatment). The patients underwent at least two PET scans between days 2 and 5. The results of the study showed that the best time for assessment of 89Zr‐trastuzumab uptake by tumors was 4–5 days after the injection. For optimal PET‐scan results, trastuzumab‐naive patients required a 50 mg dose of 89Zr‐trastuzumab, and patients already on trastuzumab treatment required a 10 mg dose. The accumulation of 89Zr‐trastuzumab in lesions allowed PET imaging of most of the known lesions and some that had been undetected earlier. The relative uptake values (RUVs) (mean ± SEM) were 12.8 ± 5.8, 4.1 ± 1.6, and 3.5 ± 4.2 in liver, bone, and brain lesions, respectively, and 5.9 ± 2.4, 2.8 ± 0.7, 4.0 ± 0.7, and 0.20 ± 0.1 in normal liver, spleen, kidneys, and brain tissue, respectively. PET scanning after administration of 89Zr‐trastuzumab at appropriate doses allows visualization and quantification of uptake in HER2‐positive lesions in patients with metastatic breast cancer.

Pilot Study on the Feasibility of PET/CT Lymphoscintigraphy with 89Zr-Nanocolloidal Albumin for Sentinel Node Identification in Oral Cancer Patients

With conventional imaging techniques such as planar lymphoscintigraphy and SPECT/CT, preoperative sentinel node (SN) identification can be difficult when the SN is near the primary tumor, as is the case in floor-of-mouth carcinomas. PET/CT lymphoscintigraphy may improve the detection and localization of such SNs. Methods: In this study, the clinical feasibility of PET/CT lymphoscintigraphy using 89Zr-nanocolloidal albumin was evaluated in 5 oral cancer patients. PET/CT lymphoscintigraphy was performed after peritumoral injection of 89Zr-nanocolloidal albumin. The routine SN procedure, including SPECT/CT using 99mTc-nanocolloidal albumin, was performed on the same patients 7–9 d after the injection of 89Zr-nanocolloidal albumin. Results: Comparison of radiocolloid distribution on PET/CT and SPECT/CT showed identical drainage patterns. Moreover, PET/CT was able to identify additional foci near the primary tumor. Conclusion: This pilot PET/CT study on SN detection indicated that lymphoscintigraphy using 89Zr-nanocolloidal albumin is feasible.

Platinum(II) as bifunctional linker in antibody-drug conjugate formation: Coupling of a 4-nitrobenzo-2-oxa-1,3-diazole fluorophore to trastuzumab as a model.

The potential of platinum(II) as a bifunctional linker in the coordination of small molecules, such as imaging agents or (cytotoxic) drugs, to monoclonal antibodies (mAbs) was investigated with a 4‐nitrobenzo‐2‐oxa‐1,3‐diazole (NBD) fluorophore and trastuzumab (Herceptin™) as a model antibody. The effect of ligand and reaction conditions on conjugation efficiency was explored for [Pt(en)(L‐NBD)Cl](NO3) (en=ethylenediamine), with L=N‐heteroaromatic, N‐alkyl amine, or thioether. Conjugation proceeded most efficiently at pH 8.0 in the presence of NaClO4 or Na2SO4 in tricine or HEPES buffer. Reaction of N‐coordinated complexes (20 equiv) with trastuzumab at 37 °C for 2 h, followed by removal of weakly bound complexes with excess thiourea, afforded conjugates with an NBD/mAb ratio of 1.5–2.9 that were stable in phosphate‐buffered saline at room temperature for at least 48 h. In contrast, thioether‐coordinated complexes afforded unstable conjugates. Finally, surface plasmon resonance analysis showed no loss in binding affinity of trastuzumab after conjugation.

Personalizing NSCLC therapy by characterizing tumors using TKI-PET and immuno-PET

Non-small cell lung cancer (NSCLC) therapy has entered a rapidly advancing era of precision medicine with an ever increasing number of drugs directed against a variety of specific tumor targets. Amongst these new agents, tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) are most frequently used. However, as only a sensitive subgroup of patients benefits from targeting drugs, predictive biomarkers are needed. Positron emission tomography (PET) may offer such a biomarker for predicting therapy efficacy. Some of the TKIs and mAbs that are in clinical use can be radioactively labeled and used as tracers. PET can visualize and quantify tumor specific uptake of radiolabeled targeting drugs, allowing for characterization of their pharmacokinetic behavior. In this review, the clinical potential of PET using radiolabeled TKIs (TKI-PET) and mAbs (immuno-PET) in NSCLC is discussed, and an overview is provided of the most relevant preclinical and clinical studies.

OP0222 Non-Invasive Pet Imaging of B-Cells in RA Patients Initiating Rituximab Treatment

Background In last decade rituximab (RTX), a B-cell targeted monoclonal antibody, has been introduced to treat rheumatoid arthritis (RA) patients but with variable response rates (30-50%). To increase treatment efficacy and reduce costs, treatment should be individualized to match the spectrum of RA. B-cell targeted therapy has been hypothesized to be most effective in a more B-cell mediated RA disease, possibly correlated to serological status (1). Whole body Positron Emission Tomography (PET) is capable to show B-cells targeting with high specificity in lymphoma patients using 89Zr-RTX (2). In addition, our group previously demonstrated the potential of PET for non-invasive visualization of immunological targets in RA (3). Objectives To investigate the feasibility of non-invasive imaging of B-cells in RA patients who initiate RTX treatment by [89Zr]RTX PET-CT. Methods Anti-B cell therapy naïve RA patients (n=20; female18/20; age 53±11; 65% IgM RF/a-CCP +) with clinical arthritis in at least two hand joints, who were eligible for RTX treatment, were included. Directly after the first therapeutic RTX infusion (1000 mg, without methylprednisolone), 18MBq [89Zr]-10 mg RTX was administered. Whole body PET-CT and detailed images of wrists and hands (22 joints/patient) were acquired at 3, and in addition, in a subpopulation at 6 days post-injection (p.i.). Thereafter, RTX treatment was continued according to standard clinical protocol. Areas of enhanced uptake on PET were defined and quantified as maximum standardized uptake values (SUVmax). Wrist and hand joints were clinically assessed for swelling and tenderness. Results Visually, all patients showed at least one hand joint with increased focal tracer uptake (87/440 joints; mean/patient ± SD 4.4±4.9) (Figure 1) with distribution: metacarpophalangeal (n=44/200), proximal interphalangeal (n=22/200) and wrist joints (n=21/40). Interestingly, 66% of PET-positive joints (57/87) corresponded to clinical findings of arthritis, while PET additionally displayed possible subclinical disease activity in another 30 joints (34%). Quantitative analysis showed high mean SUVmax values of hotspots in hand joints (2.98±1.46) which were up to 4 times higher than maximum background uptake, but varying between patients (range SUVmax 1.2-8.0), regardless of serological status. Stability of joint uptake was found over time (3-6 days p.i.) while the tracer cleared from circulation, pointing at specific binding in joints. Whole body PET-CT also demonstrated tracer uptake in extra-articular tissues especially in liver, spleen and in 5/20 patients slightly enhanced uptake in at least one peripheral lymph node. Conclusions [89Zr]RTX PET-CT seems to be a sensitive tool for in vivo identification of B-cells in arthritic joints and extra-articular tissues in RA patients. Whether quantitative differences in uptake (articular and body distribution) correlate to clinical and RTX response data is currently investigated in a prospective study. References Isaacs JD et al; Ann Rheum Dis 2013. Muylle K et al; Ann Oncol 2008. van der Laken CJ et al; Arthritis Rheum 2008. Acknowledgements This study was financially supported by Hoffmann-La-Roche,The Netherlands Disclosure of Interest S. Bruijnen: None declared, M. Tsang-A-Sjoe: None declared, H. Raterman: None declared, T. Ramwadhdoebe: None declared, D. Vugts: None declared, G. Van Dongen: None declared, M. Huisman: None declared, O. Hoekstra: None declared, P. Tak Grant/research support from: P.P. Tak participated in this study from his position at the Academic Medical Center, Amsterdam, The Netherlands. GSK did neither sponsor this study nor supported this study otherwise. P.P.Tak also has affiliations at Cambridge and Ghent but his activities at these locations were not involved in the current study., A. Voskuyl: None declared, C. van der Laken: None declared