Zr-89-labeled Bispecific T-cell Engager AMG 211 PET Shows AMG 211 Accumulation in CD3-rich Tissues and Clear, Heterogeneous Tumor Uptake

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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 (R)) directed against carcinoembryonic antigen (CEA) on tumor cells and cluster of differentiation 3 (CD3) on T-cells.

Experimental Design: Zr-89-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-mg Zr-89-AMG 211 + 1,800-mg 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. Zr-89-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 Zr-89-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter-and intraindividual heterogeneous tumor uptake.

Original languageEnglish
Pages (from-to)3517-3527
Number of pages12
JournalClinical Cancer Research
Volume25
Issue number12
Early online date11-Feb-2019
DOIs
Publication statusPublished - 15-Jun-2019

Keywords

  • NORMAL ORGAN WEIGHTS
  • II-THE-BRAIN
  • CARCINOEMBRYONIC ANTIGEN
  • CLINICAL-PHARMACOLOGY
  • ANTIBODY CONSTRUCTS
  • BLINATUMOMAB
  • EXPRESSION
  • BITE(R)
  • CANCER
  • BIODISTRIBUTION

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