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

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 Ò) directed against carcinoembryonic antigen (CEA) on tumor cells and cluster of differentiation 3 (CD3) on T-cells. Experimental Design: 89 Zr-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 89 Zr-AMG 211 þ 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 lym-phoid tissues including spleen and bone marrow (SUV mean 3.2 and 1.8, respectively), and the SUV mean decreased more slowly than in other healthy tissues. 89 Zr-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 SUV max 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-inhuman study shows high, specific 89 Zr-AMG 211 accumulation in CD3-rich lymphoid tissues, as well as a clear, inter-and intraindividual heterogeneous tumor uptake.

The Biodistribution of a CD3 and EpCAM Bispecific T-Cell Engager Is Driven by the CD3 Arm

“…This study in immunocompetent mice shows that the [ 89 Zr]Zr-DFO-N-suc-muS110 distribution is predominantly mediated by its higher affinity for CD3 compared to EpCAM. (12). For AMG 211, the affinity for CEA was higher (KD = 5.5 nM) than for CD3 (KD = 310 nM).…”

“…Recently, a first small clinical PET-imaging study was performed with zirconium-89 ( 89 Zr)-labeled AMG 211, a BiTE molecule targeting CD3 and carcinoembryonic antigen (CEA). Here, heterogeneous tumor uptake within and between patients as well as uptake in lymphoid tissue was shown (12).…”

Modeling Pharmacokinetics and Pharmacodynamics of Therapeutic Antibodies: Progress, Challenges, and Future Directions

“…Another well-known example of using modeling to optimize binding properties is BiTE, whose treatment effects are more dependent on the synapse formation. A very high affinity to CD3 can result in monovalent binding, leading to premature activation of T cells and accumulations of antibodies in the CD3-rich tissues [223]. PK/PD modeling can help evaluate optimal target affinity in different local tissue environments for decisionmaking in the early stage of antibody development [76,79,208,[224][225][226][227][228].…”

Preclinical PET imaging of bispecific antibody ERY974 targeting CD3 and glypican 3 reveals that tumor uptake correlates to T cell infiltrate

“…The distribution of an 89 Zr-labeled 54 kDa bispecific T cell engager AMG211 targeting CD3ε (affinity 310 nM) and carcinoembryonic antigen (affinity 5.5 nM) was studied in a feasibility study in nine patients with advanced gastrointestinal adenocarcinomas. 21 [ 89 Zr] Zr-N-suc-Df-AMG211 clearly accumulated in spleen and bone marrow, both CD3-rich tissues. Uptake of [ 89 Zr] Zr-N-suc-Df-AMG211 in tumor lesions was highly heterogeneous within and between patients.…”