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CD123 expression patterns and selective targeting with a CD123-specific antibody-drug conjugate (IMGN632) in acute lymphoblastic leukemia.

Research paper by Evgeniya E Angelova, Charlene C Audette, Yelena Y Kovtun, Naval N Daver, Sa A SA Wang, Sherry S Pierce, Sergej N SN Konoplev, Haitham H Khogeer, Jeffrey L JL Jorgensen, Marina M Konopleva, Patrick A PA Zweidler-McKay, L Jeffrey LJ Medeiros, Hagop M HM Kantarjian, Elias J EJ Jabbour, Joseph D JD Khoury

Indexed on: 27 Oct '18Published on: 27 Oct '18Published in: Haematologica



Abstract

The potential of CD123-targeted therapies in acute lymphoblastic leukemia/lymphoma remains largely unexplored. We examined CD123 expression levels in a large cohort of acute lymphoblastic leukemia/lymphoma patients and assessed the in vitro impact of IMGN632, a conjugate of CD123-binding antibody with a novel DNA-alkylating payload. CD123 expression on leukemic blasts was surveyed in a large cohort of acute lymphoblastic leukemia/lymphoma patients using multicolor/multiparameter flow cytometry. The in vitro effect of IMGN632 was evaluated on B acute lymphoblastic leukemia/lymphoma cell lines and primary B acute lymphoblastic leukemia/lymphoma blasts. The study cohort (n=213) included 183 B acute lymphoblastic leukemia/lymphoma and 30 T acute lymphoblastic leukemia/lymphoma patients. CD123 expression was more prevalent in B acute lymphoblastic leukemia/lymphoma compared with T acute lymphoblastic leukemia/lymphoma (164/183, 89.6% vs. 13/30, 43.3%; p<0.0001), and within B acute lymphoblastic leukemia/lymphoma CD123 expression was more prevalent in Ph-positive versus Ph-negative patients (96.6% vs. 86.3%; p=0.033). In T acute lymphoblastic leukemia/lymphoma, 12/13 (92.3%) patients with CD123pos blasts had either early T precursor (ETP) or early non-ETP immunophenotype. IMGN632 was highly cytotoxic to B acute lymphoblastic leukemia/lymphoma cell lines, with IC50 values between 0.6 and 20 pM. In 5 of 8 patient samples, low pico-molar concentrations of IMGN632 eliminated more than 90% of the B acute lymphoblastic leukemia/lymphoma blast population, sparing normal lymphocytes. In conclusion, CD123 expression is prevalent across acute lymphoblastic leukemia/lymphoma subtypes, and the CD123-targeted antibody-drug conjugate IMGN632 demonstrates promising selective activity in pre-clinical models of B acute lymphoblastic leukemia/lymphoma. Copyright © 2018, Ferrata Storti Foundation.