Nonclinical Safety Assessment of AMG 553, an Investigational Chimeric Antigen Receptor T-Cell Therapy for the Treatment of Acute Myeloid Leukemia

Adult 0301 basic medicine 0303 health sciences Receptors, Chimeric Antigen Cell- and Tissue-Based Therapy 3. Good health Leukemia, Myeloid, Acute Macaca fascicularis 03 medical and health sciences Cell Line, Tumor Cats Clinical and Translational Toxicology Animals Humans
DOI: 10.1093/toxsci/kfaa098 Publication Date: 2020-06-17T11:23:49Z
ABSTRACT
Abstract Feline McDonough Sarcoma-like tyrosine kinase 3 (FLT3), a tyrosine-protein involved in hematopoiesis, is detectable on the cell surface of approximately 80% leukemia isolates from adult patients with acute myeloid (AML). AMG 553 an investigational chimeric antigen receptor (CAR) T-cell immunotherapy for treatment AML. FLT3 expression analysis and vitro vivo studies were leveraged to evaluate nonclinical safety 553. Cynomolgus monkeys administered autologous anti-FLT3 CAR T cells demonstrated no evidence T-cell-mediated toxicity, expansion, or persistence, likely due restricted protein healthy animals. This highlights limited value such assessment modality when directed against target expression. To complement these directly potential toxicities eliciting cytotoxicity vivo, data cynomolgus monkey toxicology 2 bispecific engager molecules targeting leveraged; findings consistent targeted killing bone marrow expressing FLT3. Potential 553-induced was assessed wide range normal human primary lines; observed FLT3-positive AML lines percentage CD34+ cells. In conclusion, suggest that can cells, whereas only affecting hematopoietic stem progenitor supporting clinical development.
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