Moek KL, Waaijer SJH, Kok IC, Suurs FV, Brouwers AH, Menke-van der Houven van Oordt CW, Wind TT, Gietema JA, Schröder CP, Mahesh SVK, Jorritsma-Smit A, Lub-de Hooge MN, Fehrmann RSN, de Groot DJ, de Vries EG.
Purpose: Biodistribution of bispecific antibodies in patients is largely unknown. We therefore performed a feasibility study in nine patients with advanced gastrointestinal adenocarcinomas to explore AMG 211 biodistribution (also known as MEDI-565), a ~55 kDa bispecific T-cell engager directed against carcinoembryonic antigen on tumor cells and cluster of differentiation 3 (CD3) on T-cells. Methods:89Zr-labeled AMG 211 as tracer, was administered alone or with cold AMG 211, for positron emission tomography (PET) imaging before and/or during AMG 211 treatment. Results: Before AMG 211 treatment, the optimal imaging dose was 200 µg 89Zr-AMG 211 + 1,800 µg cold AMG 211. At 3 hours the highest blood pool standardized uptake value (SUV)mean was 4.0, and tracer serum half-life was 3.3 hour. CD3-mediated uptake was clearly observed in CD3-rich lymphoid tissues including spleen and bone marrow (SUVmean 3.2 and 1.8, respectively), and the SUVmean decreased more slowly than in other healthy tissues. 89Zr-AMG 211 remained intact in plasma and was excreted predominantly via the kidneys in degraded forms. Of 43 visible tumor lesions, 37 were PET quantifiable, with a SUVmax of 4.0 (interquartile range 2.7 – 4.4) at 3 hours using the optimal imaging dose. The tracer uptake differed between tumor lesions 5-fold within and 9-fold between patients. During AMG 211 treatment tracer was present in the blood pool, while tumor lesions were not visualized, possibly reflecting target saturation. Conclusion: This first-in-human study shows high, specific 89Zr-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter- and intra-individual heterogeneous tumor uptake.