Kirsten L Moek 1 , Stijn J H Waaijer 1 , Iris C Kok 1 , Frans V Suurs 1 , Adrienne H Brouwers 2 , C Willemien Menke-van der Houven van Oordt 3 , Thijs T Wind 1 , Jourik A Gietema 1 , Carolien P Schröder 1 , Shekar V K Mahesh 2 , Annelies Jorritsma-Smit 4 , Marjolijn N Lub-de Hooge 4 , Rudolf S N Fehrmann 1 , Derk Jan A de Groot 1 , Elisabeth G E de Vries 5 Show Affiliations »
Abstract
PURPOSE: Biodistribution of bispecific antibodies in patients is largely unknown. We therefore performed a feasibility study in 9 patients with advanced gastrointestinal adenocarcinomas to explore AMG 211 biodistribution (also known as MEDI-565), an approximately 55 kDa bispecific T-cell engager (BiTE®) directed against carcinoembryonic antigen (CEA) on tumor cells and cluster of differentiation 3 (CD3) on T-cells. EXPERIMENTAL DESIGN: 89Zr-labeled AMG 211 as tracer was administered alone or with cold AMG 211, for 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 hours. 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 (IQR) 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, whereas tumor lesions were not visualized, possibly reflecting target saturation. CONCLUSIONS: This first-in-human study shows high, specific 89Zr-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter- and intraindividual heterogeneous tumor uptake. ©2019 American Association for Cancer Research.
PURPOSE: Biodistribution of bispecific antibodies in patients is largely unknown. We therefore performed a feasibility study in 9 patients with advanced gastrointestinal adenocarcinomas to explore AMG 211 biodistribution (also known as MEDI-565), an approximately 55 kDa bispecific T-cell engager (BiTE®) directed against carcinoembryonic antigen (CEA ) on tumor cells and cluster of differentiation 3 (CD3) on T-cells. EXPERIMENTAL DESIGN: 89Zr-labeled AMG 211 as tracer was administered alone or with cold AMG 211, for 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 hours. 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 (IQR) 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, whereas tumor lesions were not visualized, possibly reflecting target saturation. CONCLUSIONS: This first-in-human study shows high, specific 89Zr-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter- and intraindividual heterogeneous tumor uptake. ©2019 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
Year: 2019
PMID： 30745297 DOI： 10.1158/1078-0432.CCR-18-2918
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531